中川 和彦 (ナカガワ カズヒコ)

  • 医学科 特任教授
Last Updated :2024/04/23

コミュニケーション情報 byコメンテータガイド

  • コメント

    肺がんを中心に抗がん剤の化学療法、早期臨床試験等を専門分野としており、がん患者の緩和医療、患者・家族とのコミュニケーションの促進を図ることによる全人的癌診療の実現に努めています。
  • 報道関連出演・掲載一覧

    <報道関連出演・掲載一覧> ●2024/1/27  NHK Eテレ「ETV特集:肺がんサバイバー第二弾」  肺がんについて ●2023/11/30  毎日新聞  分子標的薬について ●2023/12/5  静岡新聞  分子標的薬について ●2023/12/16  夕刊フジ  分子標的薬について ●2023/11/27  愛媛新聞  分子標的薬について ●2023/11/21  宮崎日日新聞   分子標的薬について ●2023/11/20  長崎新聞  分子標的薬について ●2023/11/16  信濃毎日新聞   分子標的薬について ●2021/10/4  読売テレビ「情報ライブミヤネ屋」  小倉智昭さんの肺にがんが転移したことについて ●2020/2/22・25 釧路新聞他  小細胞肺がんについて ●2019/10/10  日刊工業新聞  EGFR遺伝子異変を有する肺がん患者に新たな治療法を確立し、 従来の治療法から再増悪リスクを40%以上減少することを証明したことについて ●2018/10/27  TBS系JNNニュース  医療セミナー内の講演の様子について ●2018/10/5  関西テレビ報道ランナー  がん免疫療法について ●2018/10/2  読売テレビ「かんさい情報ネット ten.」  本庶佑氏がノーベル賞を受賞したことについて ●2018/9/7  読売新聞  がん治療について ●2018/4/20  関西医事新報  「化学療法wp横断的に実施する専門家を育成」 ●2017/2/2 読売テレビ「かんさい情報ネット ten.」 2月からのオプジーボ薬価改定について ●2017/1/17  オプシーボ+高脂血症薬の併用で  がん治療「効果アップ」について ●2016/10/30  毎日放送「映像'16」  がん治療における最新の化学療法や主治医として ●2016/10/3  読売テレビ「かんさい情報ネット ten.」  PD1抗体、オプジーボについて ●2016/8/2  毎日新聞  がん医療における緩和医療等について ●2015/05/12  毎日放送「VOICE」  進行がん患者に対する新薬の治験について。 ●2019/9/7  読売新聞  遺伝子」の異常に着目した肺がん治療について

研究者情報

学位

  • 博士(医学)(2001年03月 熊本大学)

ホームページURL

J-Global ID

研究キーワード

  • 臨床腫瘍学   Medical Oncology   

現在の研究分野(キーワード)

    肺がんを中心に抗がん剤の化学療法、早期臨床試験等を専門分野としており、がん患者の緩和医療、患者・家族とのコミュニケーションの促進を図ることによる全人的癌診療の実現に努めています。

研究分野

  • ライフサイエンス / 呼吸器内科学

学歴

  •         - 1983年   熊本大学   医学部
  •         - 1983年   熊本大学   Faculty of Medicine

所属学協会

  • 西日本胸部臨床腫瘍臨床研究機構(WJTOG)   がん分子標的治療研究会   欧州癌治療学会(ESMO)   日本呼吸器内視鏡学会   日本臨床腫瘍学会   日本呼吸器学会   日本癌治療学会   世界肺癌学会(IASLC/WCLC)   米国臨床腫瘍学会(ASCO)   日本内科学会   日本癌学会   日本肺癌学会   

研究活動情報

論文

  • Hidetoshi Hayashi; Kenji Chamoto; Ryusuke Hatae; Takashi Kurosaki; Yosuke Togashi; Kazuya Fukuoka; Megumi Goto; Yasutaka Chiba; Shuta Tomida; Takayo Ota; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Takeshi Yoshida; Tsutomu Iwasa; Kaoru Tanaka; Masayuki Takeda; Tomoko Hirano; Hironori Yoshida; Hiroaki Ozasa; Yuichi Sakamori; Kazuko Sakai; Keiko Higuchi; Hitoshi Uga; Chihiro Suminaka; Toyohiro Hirai; Kazuto Nishio; Kazuhiko Nakagawa; Tasuku Honjo
    Journal of Clinical Investigation 134 7 2024年04月
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Kenji Sawa; Yoshimasa Shiraishi; Ryota Saito; Junko Tanizaki; Yosuke Tamura; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Takaaki Tokito; Kenji Nagata; Takeshi Masuda; Yasushi Nakamura; Kazuko Sakai; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    British journal of cancer 2024年03月 
    BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.
  • Yoshimasa Shiraishi; Junji Kishimoto; Shunichi Sugawara; Hideaki Mizutani; Haruko Daga; Koichi Azuma; Hirotaka Matsumoto; Osamu Hataji; Kazumi Nishino; Masahide Mori; Takehito Shukuya; Haruhiro Saito; Motoko Tachihara; Hidetoshi Hayashi; Asuka Tsuya; Kazushige Wakuda; Noriko Yanagitani; Tomohiro Sakamoto; Satoru Miura; Akito Hata; Morihito Okada; Toshiyuki Kozuki; Yuki Sato; Taishi Harada; Koichi Takayama; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Isamu Okamoto
    JAMA oncology 2023年12月 
    IMPORTANCE: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. OBJECTIVE: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. DESIGN, SETTING, AND PARTICIPANTS: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. INTERVENTIONS: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. RESULTS: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. CONCLUSIONS AND RELEVANCE: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCT2080224500.
  • Kazushige Wakuda; Hiroyuki Yamaguchi; Hirotsugu Kenmotsu; Minoru Fukuda; Kentaro Ito; Yuko Tsuchiya-Kawano; Kentaro Tanaka; Taishi Harada; Yuki Nakatani; Satoru Miura; Toshihide Yokoyama; Tomomi Nakamura; Miiru Izumi; Atsushi Nakamura; Satoshi Ikeda; Koichi Takayama; Kenichi Yoshimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Kenji Sugio
    JTO clinical and research reports 4 12 100587 - 100587 2023年12月 
    INTRODUCTION: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. METHODS: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. RESULTS: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%-90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%-99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo-not reached). The overall response rate was 64.0% (95% CI: 45.2%-82.8%), median PFS was 11.5 months (95% CI: 6.9 mo-not reached), and median survival time was 23.7 months (95% CI: 16.5 mo-not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). CONCLUSIONS: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. TRIAL REGISTRATION: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.
  • Tomohiro Sakamoto; Taichi Matsubara; Takayuki Takahama; Toshihide Yokoyama; Atsushi Nakamura; Takaaki Tokito; Tatsuro Okamoto; Hiroaki Akamatsu; Masahide Oki; Yuki Sato; Kazunori Tobino; Satoshi Ikeda; Masahide Mori; Chihiro Mimura; Ken Maeno; Satoru Miura; Toshiyuki Harada; Kunihiro Nishimura; Manabu Hiraoka; Hirotsugu Kenmotsu; Junya Fujimoto; Mototsugu Shimokawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    JAMA network open 6 12 e2347700  2023年12月 
    IMPORTANCE: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. OBJECTIVE: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. DESIGN, SETTING, AND PARTICIPANTS: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. MAIN OUTCOMES AND MEASURES: The primary end point was the biomarker testing status. Treatment-related factors were examined. RESULTS: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. CONCLUSIONS AND RELEVANCE: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.
  • Tomohiro Maniwa; Jiro Okami; Tomohiro Miyoshi; Masashi Wakabayashi; Hiroshige Yoshioka; Takahiro Mimae; Makoto Endo; Aritoshi Hattori; Kazuo Nakagawa; Tetsuya Isaka; Mitsuhiro Isaka; Ryosuke Kita; Yuta Sekino; Noriko Mitome; Keiju Aokage; Hisashi Saji; Ryu Nakajima; Morihito Okada; Masahiro Tsuboi; Hisao Asamura; Haruhiko Fukuda; Shun-Ichi Watanabe
    The Journal of thoracic and cardiovascular surgery 2023年11月 
    OBJECTIVE: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region. METHODS: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor). RESULTS: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455). CONCLUSIONS: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors.
  • Takeshi Masuda; Satoru Miura; Yuki Sato; Motoko Tachihara; Akihiro Bessho; Atsushi Nakamura; Taichi Miyawaki; Kohei Yoshimine; Masahide Mori; Hideaki Shiraishi; Kosuke Hamai; Koji Haratani; Sumiko Maeda; Eriko Tabata; Chiyoe Kitagawa; Junko Tanizaki; Takumi Imai; Shohei Nogami; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Noboru Hattori
    Scientific Reports 13 1 2023年11月 
    Abstract Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.
  • Takehiro Uemura; Hirotsugu Kenmotsu; Daisuke Hazama; Shunsuke Teraoka; Hiroshi Kobe; Koichi Azuma; Teppei Yamaguchi; Takeshi Masuda; Toshihide Yokoyama; Kohei Otsubo; Koji Haratani; Daisuke Hayakawa; Masahide Oki; Shinnosuke Takemoto; Tomohiro Ozaki; Yusaku Akashi; Akito Hata; Hiroya Hashimoto; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer medicine 2023年11月 
    BACKGROUND: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. METHODS: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. RESULTS: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days). CONCLUSION: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.
  • Satoshi Ikeda; Masahiro Tsuboi; Kazuko Sakai; Toshihiro Misumi; Hiroaki Akamatsu; Hiroyasu Shoda; Noriaki Sakakura; Atsushi Nakamura; Yasuhisa Ohde; Hidetoshi Hayashi; Kyoichi Okishio; Morihito Okada; Ichiro Yoshino; Jiro Okami; Kazuhisa Takahashi; Norihiko Ikeda; Masayuki Tanahashi; Yuichi Tambo; Haruhiro Saito; Shinichi Toyooka; Hidetoshi Inokawa; Toyofumi Chen-Yoshikawa; Toshihide Yokoyama; Tatsuro Okamoto; Noriko Yanagitani; Masahide Oki; Makoto Takahama; Kenji Sawa; Hirohito Tada; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Kazuto Nishio
    Molecular oncology 2023年10月 
    The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
  • Junko Tanizaki; Hiroaki Kuroda; Toshihide Yokoyama; Makoto Takahama; Hiroyasu Shoda; Atsushi Nakamura; Yoshitaka Kitamura; Nobuaki Mamesaya; Yoshihisa Kadota; Kenji Sawa; Kyoichi Okishio; Morihito Okada; Chihiro Suminaka; Kenta Noda; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Kenji Chamoto; Tasuku Honjo; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    JTO Clinical and Research Reports 100590 - 100590 2023年10月
  • Kazushige Wakuda; Hirotsugu Kenmotsu; Yuki Sato; Atsushi Nakamura; Hiroaki Akamatsu; Motoko Tachihara; Satoru Miura; Toshihide Yokoyama; Keita Mori; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    BMC cancer 23 1 902 - 902 2023年09月 
    BACKGROUND: The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). METHODS: B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. DISCUSSION: The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. TRIAL REGISTRATION: jRCT identifier: jRCTs041210103.
  • Hirotsugu Kenmotsu; Nobuyuki Yamamoto; Toshihiro Misumi; Kiyotaka Yoh; Haruhiro Saito; Shunichi Sugawara; Koji Yamazaki; Kazuhiko Nakagawa; Kenji Sugio; Takashi Seto; Shinichi Toyooka; Hiroshi Date; Tetsuya Mitsudomi; Isamu Okamoto; Kohei Yokoi; Hideo Saka; Hiroaki Okamoto; Yuichi Takiguchi; Toshiaki Takahashi; Masahiro Tsuboi
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2300179  2023年09月 
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.
  • Tatsuya Yoshida; Toru Kumagai; Ryo Toyozawa; Ryohei Katayama; Makoto Nishio; Takashi Seto; Koichi Goto; Nobuyuki Yamamoto; Yuichiro Ohe; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Kazuhiko Nakagawa
    Cancer science 114 9 3698 - 3707 2023年09月 
    The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.
  • Kazuto Nishio; Kazuko Sakai; Makoto Nishio; Takashi Seto; Carla Visseren-Grul; Michelle Carlsen; Tomoko Matsui; Sotaro Enatsu; Kazuhiko Nakagawa
    Translational lung cancer research 12 8 1702 - 1716 2023年08月 
    BACKGROUND: An exploratory, proof-of-concept, liquid biopsy addendum to examine biomarkers within cell-free DNA (cfDNA) in the RELAY phase 3, randomized, double-blind, placebo-controlled study was conducted. RELAY showed improved progression-free survival (PFS) with ramucirumab (RAM), a human immunoglobulin G1 vascular endothelial growth factor receptor 2 antagonist, plus erlotinib (ERL), a tyrosine kinase inhibitor, compared with placebo (PL) plus ERL. METHODS: Treatment-naïve patients with endothelial growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer were randomized (1:1) to RAM + ERL or PL + ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations and EGFR-activating mutation allele counts were investigated by next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR), respectively. cfDNA concentration and fragment size were evaluated by real-time polymerase chain reaction and the BioAnalyzer. Patients with a valid baseline plasma sample were included (70 RAM + ERL, 61 PL + ERL). RESULTS: TP53 mutation was the most frequently co-occurring baseline gene alteration (43%). Post-study treatment discontinuation EGFR T790M mutation rates were 54.5% (6/11) and 41.2% (7/17) by ddPCR, and 22.2% (2/9) and 29.4% (5/17) by NGS, in the RAM + ERL and PL + ERL arms, respectively. EGFR-activating mutation allele count decreased at Cycle 4 in both treatment arms and was sustained at follow-up with RAM + ERL. PFS improved for patients with no detectable EGFR-activating mutation at Cycle 4 vs. those with detectable EGFR-activating mutation. Total cfDNA concentration increased from baseline at Cycle 4 and through to follow-up with RAM + ERL. cfDNA fragment size was similar between treatment arms at baseline [mean (standard deviation) base pairs: RAM + ERL, 173.4 (2.6); PL + ERL, 172.9 (3.2)] and was shorter at Cycle 4 with RAM + ERL vs. PL + ERL [169.5 (2.8) vs. 174.1 (3.3), respectively; P<0.0001]. Baseline vs. Cycle 4 paired analysis showed a decrease in cfDNA fragment size for 84% (48/57) and 23% (11/47) of patient samples in the RAM + ERL and PL + ERL arms, respectively. CONCLUSIONS: EGFR-activating mutation allele count was suppressed, total cfDNA concentration increased, and short fragment-sized cfDNA increased with RAM + ERL, suggesting the additional anti-tumor effect of RAM may contribute to the PFS benefit observed in RELAY with RAM + ERL vs. PL + ERL. TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT02411448.
  • Hye Ryun Kim; Shunichi Sugawara; Jong-Seok Lee; Jin-Hyoung Kang; Naoki Inui; Toyoaki Hida; Ki Hyeong Lee; Tatsuya Yoshida; Hiroshi Tanaka; Cheng-Ta Yang; Makoto Nishio; Yuichiro Ohe; Tomohide Tamura; Nobuyuki Yamamoto; Chong-Jen Yu; Hiroaki Akamatsu; Shigeru Takahashi; Kazuhiko Nakagawa
    Cancer medicine 12 16 17061 - 17067 2023年08月 
    BACKGROUND: ONO-4538-52/TASUKI-52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first-line) treatment of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow-up, 7.4 months), the independent radiology review committee-assessed progression-free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. METHODS: Here, we present the updated OS data. Patients with treatment-naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3-weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. RESULTS: Overall, 550 patients were randomized. At the time of the analysis (minimum follow-up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58-0.94). The 12-month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18-month OS rates were 69.0% vs. 61.9%. CONCLUSION: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first-line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1.
  • Yoshihiko Fujita; Hiromichi Matsuoka; Yasutaka Chiba; Junji Tsurutani; Takeshi Yoshida; Kiyohiro Sakai; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    Oncology letters 26 2 355 - 355 2023年08月 
    There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.
  • Chihiro Sato; Hisato Kawakami; Ryo Tanaka; Hironaga Satake; Kentaro Inoue; Yutaka Kimura; Junya Fujita; Ryohei Kawabata; Yasutaka Chiba; Taroh Satoh; Kazuhiko Nakagawa
    Scientific reports 13 1 10826 - 10826 2023年07月 
    Adjuvant S-1 monotherapy is the standard of care for stage II gastric cancer (GC) after curative resection in Japan, but its efficacy for microsatellite instability-high (MSI-H) tumors has remained unknown. Among a multi-institutional cohort of patients with stage II GC who underwent R0 resection followed by S-1 adjuvant chemotherapy between February 2008 and December 2018, we assessed MSI status with an MSI-IVD Kit (Falco). MSI status was assessable for 184 (88.5%) of the 208 enrolled patients, with MSI-H being identified in 24 (13.0%) individuals. Although neither relapse-free survival (RFS) (hazard ratio [HR] = 1.00, p = 0.997) nor overall survival (OS) (HR = 0.66, p = 0.488) differed between MSI-H versus microsatellite-stable (MSS) patients, MSI-H patients showed a nonsignificant but better RFS (HR = 0.34, p = 0.064) and OS (HR = 0.22, p = 0.057) than did MSS patients after adjustment for background characteristics by propensity score (PS) analysis. Gene expression analysis in the PS-matched cohort suggested that recurrence was associated with the immunosuppressive microenvironment in MSI-H tumors but with expression of cancer/testis antigen genes in MSS tumors. Our data reveal a better adjusted survival for MSI-H versus MSS stage II GC treated with S-1 adjuvant therapy, and they suggest that mechanisms of recurrence differ between MSI-H and MSS tumors.
  • Tsuneo Shimokawa; Hiroaki Okamoto; Ryunosuke Machida; Yuki Misumi; Yukio Hosomi; Yasuto Yoneshima; Hiroshi Tanaka; Kyoichi Okishio; Junichi Simizu; Koichi Goto; Hiroaki Akamatsu; Kaoru Kubota; Kazuhiko Nakagawa; Hidehito Horinouchi; Masahiko Ando; Tomoko Kataoka; Yuichiro Ohe
    Lung cancer (Amsterdam, Netherlands) 181 107195 - 107195 2023年07月 
    OBJECTIVES: Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC. MATERIALS AND METHODS: This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles. RESULTS: In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm). CONCLUSIONS: The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.
  • Makoto Nishio; Shinji Atagi; Koichi Goto; Yukio Hosomi; Takashi Seto; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshige Yoshioka; Naoyuki Nogami; Makoto Maemondo; Seisuke Nagase; Isamu Okamoto; Noboru Yamamoto; Yuriko Igawa; Kosei Tajima; Masahiro Fukuoka; Nobuyuki Yamamoto; Kazuto Nishio
    Translational lung cancer research 12 6 1167 - 1184 2023年06月 
    BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR-positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses. METHODS: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP). RESULTS: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes. CONCLUSIONS: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Shigeki Mitsuoka; Yasuto Yoneshima; Ryota Saito; Junko Tanizaki; Yasuhito Fujisaka; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Yuki Sato; Yusuke Nakano; Tomoyuki Otani; Kazuko Sakai; Shuta Tomida; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 10 1334 - 1350 2023年06月 
    INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 (PD-L1) inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III non-small cell lung cancer (NSCLC). However, about half of treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L/SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue as well as flow cytometric analysis of circulating immune cells. Progression-free survival (PFS) was compared based on these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors were revealed for treatment benefit regardless of genomic features. We also identified CD73-expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocytes (TILs) density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (HRs, 4.05 [95% CI, 1.17-14.04] for CD8+ TILs; 4.79 [95% CI, 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC, and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.
  • Kimio Yonesaka; Hidetoshi Hayashi; Atsushi Nakamura; Yuki Sato; Koichi Azuma; Shinya Sakata; Motoko Tachihara; Satoshi Ikeda; Toshihide Yokoyama; Kentaro Ito; Yukihiro Yano; Hirotaka Matsumoto; Haruko Daga; Akito Hata; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 2023年06月 
    BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial. METHODS: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment. RESULTS: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected. CONCLUSION: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment. CLINICAL TRIAL REGISTRATION: jRCTs051180009.
  • Toshiaki Takakura; Hiroaki Kanemura; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa; Hidetoshi Hayashi
    JTO clinical and research reports 4 6 100523 - 100523 2023年06月 
    Resistance to ROS1 tyrosine kinase inhibitors is inevitable, but it has been unclear whether crizotinib might be effective after the development of entrectinib resistance. We here present a case of ROS1-rearranged NSCLC that responded to crizotinib after tumor progression due to MET polysomy during entrectinib treatment. This case suggests that crizotinib is an effective option for patients with MET polysomy, even after disease progression on entrectinib.
  • Satoshi Ikeda; Masahiro Tsuboi; Kazuko Sakai; Toshihiro Misumi; Hiroaki Akamatsu; Yasuo Iwamoto; Noriaki Sakakura; Atsushi Nakamura; Yasuhisa Ohde; Hidetoshi Hayashi; Kyoichi Okishio; Morihito Okada; Ichiro Yoshino; Jiro Okami; Kazuhisa Takahashi; Norihiko Ikeda; Tetsuya Mitsudomi; Hirohito Tada; Kazuhiko Nakagawa; Kazuto Nishio
    Journal of Clinical Oncology 41 16{\_}suppl 8524 - 8524 2023年06月 
    8524 Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. Methods: This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738. Funding: AstraZeneca K.K.). Surgically resected lung cancer tissue specimens were analyzed for co-existing somatic mutations and tumor mutation burden (TMB) determined by Oncomine Tumor Mutation Load, and these data were matched with disease free survival (DFS) and overall survival (OS) data. Results: Of the 234 patients in the IMPACT study, 211 patients were enrolled, and 202 patients in the Per Protocol Set were analyzed. The most frequent co-existing somatic mutation was TP53 (58.4%), followed by CSMD3 (11.8%), NOTCH1 (9.9%) and SYNE1 (9.9%). The median TMB was 6.67 mutations/Mb, and only 15.2% had ≥10 mutations/Mb. EGFR mutation subtypes, TP53 co-mutation and TMB were not associated with DFS or OS in either the gefitinib or cis/vin groups. In the gefitinib group, patients with NOTCH1 mutation had significantly shorter OS (hazard ratio [HR] 4.18, 95%CI 1.65-10.61, p=0.003) and tended to have shorter DFS (HR 1.44, 95%CI 0.62-3.37, p=0.399) than those without NOTCH1 mutation. In the cis/vin group, patients with CREBBP mutation had significantly shorter DFS (HR 2.70, 95%CI 1.05-6.97, p=0.040) and tended to have shorter OS (HR 3.05, 95%CI 0.90-10.37, p=0.074) than those without CREBBP mutation. Conclusions: This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738 .
  • Hisato Kawakami; Yu Sunakawa; Eisuke Inoue; Ryo Matoba; Kenta Noda; Toshiyuki Sato; Chihiro Suminaka; Mami Yamaki; Yasuhiro Sakamoto; Ryohei Kawabata; Atsushi Ishiguro; Yusuke Akamaru; Yosuke Kito; Hiroshi Yabusaki; Jin Matsuyama; Masazumi Takahashi; Akitaka Makiyama; Hidetoshi Hayashi; Kenji Chamoto; Tasuku Honjo; Kazuhiko Nakagawa; Wataru Ichikawa; Masashi Fujii
    European Journal of Cancer 2023年05月
  • Keiju Aokage; Kenji Suzuki; Hisashi Saji; Masashi Wakabayashi; Tomoko Kataoka; Yuta Sekino; Haruhiko Fukuda; Makoto Endo; Aritoshi Hattori; Takahiro Mimae; Tomohiro Miyoshi; Mitsuhiro Isaka; Hiroshige Yoshioka; Ryu Nakajima; Kazuo Nakagawa; Jiro Okami; Hiroyuki Ito; Hiroaki Kuroda; Masahiro Tsuboi; Norihito Okumura; Makoto Takahama; Yasuhisa Ohde; Tadashi Aoki; Yasuhiro Tsutani; Morihito Okada; Shun-Ichi Watanabe
    The Lancet. Respiratory medicine 2023年03月 
    BACKGROUND: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO. METHODS: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing. FINDINGS: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred. INTERPRETATION: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm. FUNDING: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development.
  • 寺岡 俊輔; 赤松 弘朗; 高森 信吉; 三浦 理; 洪 泰浩; 三角 俊裕; 山本 信之; 中川 和彦
    和歌山医学 74 1 25 - 25 和歌山医学会 2023年03月
  • Takaki Akamine; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Yasushi Yatabe; Shun-Ichi Watanabe
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 63 3 2023年03月 
    OBJECTIVES: With recent improvements in surgical techniques for segmentectomy, we hypothesized that segmentectomy is feasible and more effective than wedge resection for non-small-cell lung cancer (NSCLC). We compared perioperative and oncological outcomes for segmentectomy and wedge resection. METHODS: We performed a retrospective analysis of 720 patients who underwent sublobar resection (segmentectomy, 479; wedge resection, 241) for clinical stage 0 or I NSCLC from January 2017 to June 2020. An adequate surgical margin was defined as a surgical margin distance of ≥2 cm or ≥ the total tumour size. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method for clinical stage IA. RESULTS: There was no significant difference in the rate of major (grade ≥III) complications between segmentectomy (1.7%) and wedge resection (1.2%) (P = 0.76). The probability of obtaining adequate surgical margins was significantly higher with segmentectomy (71.4%) versus wedge resection (59.5%) (P = 0.002), and the difference was especially prominent for clinical stage IA2 (75.3% vs 56.9%; P = 0.012). Among patients with clinical stage IA, segmentectomy significantly improved the RFS compared with wedge resection (hazard ratio 2.7; 95% confidence interval 1.60-4.61; log-rank P < 0.001). Subgroup analysis based on the tumour status revealed that segmentectomy had a better RFS in clinical stage IA2 (P < 0.001) and in pure-solid tumours (P = 0.022) than wedge resection. CONCLUSIONS: We demonstrate that segmentectomy is a feasible procedure with comparable safety outcomes and better surgical margins and cancer control than wedge resection, particularly for clinical stage IA2 NSCLC.
  • Masaya Yotsukura; Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Annals of surgical oncology 30 2 851 - 858 2023年02月 
    BACKGROUND: The 8th edition of the TNM stage classification of lung cancer was developed based on an evaluation of the 5-year prognosis using an international database. Since recurrence after 5 years postoperatively is known to develop, the applicability of the stage classification beyond 5 years after treatment needs to be evaluated. PATIENTS AND METHODS: Postoperative prognosis and prognostic indicators were analyzed using data for 648 patients of pathological stage IA adenocarcinoma, who underwent complete resection between 2007 and 2012. RESULTS: The median age was 66 years (interquartile range 60-73 years), and the median follow-up duration was 100 months (interquartile range 70-116 months). Overall survival probabilities for pathological stage IA1, IA2, and IA3 patients were 100%, 96.3%, and 91.5% at 5 postoperative years, and 94.2%, 89.8%, and 83.5% at 10 postoperative years, respectively (IA1 vs IA2: p = 0.05; IA2 vs IA3: p = 0.05). Multivariate analysis for overall survival of patients who survived without recurrence for 5 postoperative years revealed that age (hazard ratio 3.21, p = 0.02) was the only factor that was significantly associated with long-term survival. Stage classification (IA1, IA2, or IA3) was not an associated factor. The incidence of secondary primary lung cancer continued to increase, resulting in an estimated probability of 8.6% at 10 postoperative years. CONCLUSIONS: For patients who survived without recurrence for 5 postoperative years, age, not stage classification, was associated with survival thereafter. The long-term follow-up strategy does not need to be modified according to the stage classification, and screening for secondary primary lung cancer should be considered.
  • Masaya Yotsukura; Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Annals of surgical oncology 30 2 859 - 860 2023年02月
  • Masayuki Takeda; Mototsugu Shimokawa; Atsushi Nakamura; Kaname Nosaki; Yasutaka Watanabe; Terufumi Kato; Daisuke Hayakawa; Hiroshi Tanaka; Toshiaki Takahashi; Masahide Oki; Motoko Tachihara; Daichi Fujimoto; Hidetoshi Hayashi; Kakuhiro Yamaguchi; Shoichiro Yamamoto; Eiji Iwama; Koichi Azuma; Kazuo Hasegawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 177 44 - 50 2023年01月 
    BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. METHODS: We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer). RESULTS: From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6-42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10-4.30), and the rate of 12-month PFS was 17.3 %. CONCLUSIONS: Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease.
  • Seiichiro Mitani; Hisato Kawakami; Osamu Shiraishi; Hiroaki Kanemura; Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Kimio Yonesaka; Yasutaka Chiba; Takushi Yasuda; Kazuhiko Nakagawa
    Esophagus : official journal of the Japan Esophageal Society 20 2 290 - 290 2023年01月
  • Takashi Kurosaki; Kenji Chamoto; Shinichiro Suzuki; Hiroaki Kanemura; Seiichiro Mitani; Kaoru Tanaka; Hisato Kawakami; Yo Kishimoto; Yasuharu Haku; Katsuhiro Ito; Toshiyuki Sato; Chihiro Suminaka; Mami Yamaki; Yasutaka Chiba; Tomonori Yaguchi; Koichi Omori; Takashi Kobayashi; Kazuhiko Nakagawa; Tasuku Honjo; Hidetoshi Hayashi
    Frontiers in immunology 14 1325462 - 1325462 2023年 
    INTRODUCTION: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. METHODS: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). RESULTS: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. CONCLUSION: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.
  • Yuichi Ozawa; Nobuyuki Yamamoto; Kouji Yamamoto; Kentaro Ito; Hirotsugu Kenmotsu; Hidetoshi Hayashi; Takehito Shukuya; Daichi Fujimoto; Shunichi Sugawara; Seiji Niho; Yuichiro Ohe; Hiroaki Okamoto; Kazuhiko Nakagawa; Katsuyuki Kiura; Ichiro Yoshino; Akihiko Gemma
    Japanese Journal of Lung Cancer 63 3 161 - 181 2023年 
    Objective. Although data accumulated in clinical trials have higher accuracy compared to real-world data and are irreplaceably valuable, most previous clinical trial data have been left unutilized. Methods. The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced non-small cell lung cancer (NSCLC) to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results. Eight trials, JCOG9812, JCOG 0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; histological type (squamous cell carcinoma/adenocarcinoma/other NSCLC/unknown) 517/629/138/4; and stage IIIA/B, 536/752. The median overall survival was 24.6 months, with 2-, 5-, and 10-year survival rates of 51.1%, 22.5%, and 13.8%, respectively, in all enrollments. The median progression-free survival (PFS) was 9.5 months, with 2-, 5-, and 10-year PFS rates of 22.4%, 13.0%, and 9.1%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusion. The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.
  • Kana Fujimoto; Satomi Watanabe; Yuto Yasuda; Emi Date; Yasuhiro Kawabata; Hiroaki Kanemura; Takayuki Takahama; Kimio Yonesaka; Norishige Iizuka; Ken-Ichi Takahashi; Osamu Kawakami; Tomohiro Ozaki; Kazuhiko Nakagawa
    Thoracic cancer 14 2 214 - 217 2023年01月 
    High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.
  • Seiichiro Mitani; Hisato Kawakami; Osamu Shiraishi; Hiroaki Kanemura; Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Kimio Yonesaka; Yasutaka Chiba; Takushi Yasuda; Kazuhiko Nakagawa
    Esophagus : official journal of the Japan Esophageal Society 20 2 281 - 289 2022年12月 
    BACKGROUND: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC. METHODS: PD-L1 expression in paired diagnostic biopsy and surgically resected tissues from ESCC patients who underwent surgical resection after receiving two or three NAC-DCF cycles was evaluated. PD-L1 positivity was defined as a combined positive score (CPS) of 10% ≤ . Gene expression analysis was conducted using samples before NAC-DCF. RESULTS: Sixty-six paired samples from 33 patients were included in PD-L1 expression analysis, and 33 Pre-NAC samples acquired by diagnostic biopsy were included in gene expression analysis. Pretreatment, 3 (9%), 13 (39%), and 17 (52%) patients harbored tumors with CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. After NAC-DCF, 5 (15%), 15 (45%), and 13 (39%) tumors presented CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. The concordance rate between Pre-and Post-NAC-DCF samples was 45%. Patients with PD-L1-negative tumors both before and after NAC-DCF (n = 9) had shorter survival and different gene expression profile characterized by upregulation in WNT signaling or neutrophils. CONCLUSIONS: A substantial PD-L1 expression alteration was observed, resulting in low concordance rate before and after NAC-DCF. Tumors persistently lacking PD-L1 had distinct gene expression profile with worse clinical outcomes, raising the need for further investigation.
  • Atsushi Miyamoto; Hirofumi Michimae; Yasuharu Nakahara; Shinobu Akagawa; Kazuhiko Nakagawa; Yuji Minegishi; Takashi Ogura; Shigeto Hontsu; Hiroshi Date; Kazuhisa Takahashi; Sakae Homma; Kazuma Kishi
    Respiratory investigation 61 2 284 - 295 2022年12月 
    BACKGROUND: The clinical questions of whether chemotherapy as initial treatment, compared with best supportive care (BSC), improves overall survival (OS) and whether it increases the occurrence risk of acute exacerbation of idiopathic interstitial pneumonia (IIP) in patients with advanced-stage lung cancer and IIP remain inconclusive. This study addresses these issues, given that chemotherapy-related acute exacerbation of IIP may be a direct cause of mortality in these patients. METHODS: We enrolled 1003 patients from 110 Japanese institutions and collected clinical profiles from 707 and 296 patients in the chemotherapy (men: women, 645:62; mean age, 70.4 ± 6.9 years) and BSC (men: women, 261:35; mean age, 75.2 ± 7.8) groups, respectively. We used propensity score matching to create 222 matched pairs from both groups using patient demographic data (age, sex, smoking status, performance status, history of acute exacerbation of IIP, desaturation on exertion, clinical diagnosis of IIP, high-resolution computed tomography findings, serum fibrotic markers, pulmonary function status, and lung cancer histopathology). Logistic or Cox regression analyses were performed using matched data to assess the effects of chemotherapy on the risk of acute exacerbation of IIP or OS, respectively. RESULTS: In the well-matched cohort, chemotherapy improved OS (hazard ratio: 0.629, 95% confidence interval [CI]: 0.506-0.783, p < 0.0001); however, it involved significant acute exacerbation of IIP (odds ratio: 1.787, 95% CI: 1.026-3.113) compared to BSC. CONCLUSIONS: Compared with BSC, chemotherapy can improve OS in patients with advanced-stage lung cancer and IIP; however, it increases the risk of acute exacerbation of IIP.
  • Yukihiro Yoshida; Nozomu Saeki; Masaya Yotsukura; Kazuo Nakagawa; Hirokazu Watanabe; Yasushi Yatabe; Shun-Ichi Watanabe
    JTCVS open 12 410 - 425 2022年12月 
    OBJECTIVE: We aimed to visualize complicated patterns of lymph node metastases in surgically resected non-small cell lung cancer by applying a data mining technique. METHODS: In this retrospective study, 783 patients underwent lobectomy or pneumonectomy with systematic mediastinal lymph node dissection for non-small cell lung cancer between January 2010 and December 2018. Surgically resected lymph nodes were classified according to the International Association for the Study of Lung Cancer lymph node map. Network analysis generated patterns of lymph node metastases from stations 1 to 14, and the degree of connection between 2 lymph node stations was assessed. RESULTS: The median number of lymph nodes examined per patient was 20, and the pathological N category was pN0 in 428 cases, pN1 in 132, pN2 in 221, and pN3 in 2. N1 lymph node stations had strong associations with superior mediastinal lymph node stations for patients with primary tumors in the upper lobes and with station 7 for the lower lobes. There was also a connection from the N1 lymph node stations to superior mediastinal lymph node stations in the lower lobes. In the right middle lobe, an even distribution from station 12m toward stations 2R, 4R, and 7 was noted. We released an interactive web application to visualize these data: http://www.canexapp.com. CONCLUSIONS: Lymph node metastasis patterns differed according to the lobe bearing the tumor. Our results support the need for clinical trials to further investigate selective mediastinal lymph node dissection.
  • Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Kiyohiro Sakai; Takeshi Yoshida; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    The Oncologist 2022年11月 
    Abstract Background We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. Methods A randomized, multicenter, open-label trial was conducted at a Japanese hospital’s palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. Results Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). Conclusion Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.
  • Nobuyuki Katakami; Toshihide Yokoyama; Satoshi Morita; Tatsuro Okamoto; Yoshiko Urata; Yoshihiro Hattori; Yasuo Iwamoto; Yuki Sato; Norihiko Ikeda; Toshiaki Takahashi; Haruko Daga; Tetsuya Oguri; Yasuhito Fujisaka; Kazumi Nishino; Shunichi Sugawara; Toshiyuki Kozuki; Masahide Oki; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    International journal of clinical oncology 28 1 79 - 88 2022年11月 
    BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.
  • Toshio Shimizu; Kazuhiko Nakagawa; Hidetoshi Hayashi; Tsutomu Iwasa; Hisato Kawakami; Satomi Watanabe; Noboru Yamamoto; Kan Yonemori; Takafumi Koyama; Jun Sato; Kenji Tamura; Keiichi Kikuchi; Kenichiro Akaike; Shiho Takeda; Masayuki Takeda
    Investigational new drugs 41 1 1 - 12 2022年11月 
    To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).
  • Masaya Yotsukura; Kazuo Nakagawa; Chihiro Takemura; Yukihiro Yoshida; Kimiteru Ito; Hirokazu Watanabe; Masahiko Kusumoto; Yasushi Yatabe; Shun-Ichi Watanabe
    Japanese journal of clinical oncology 52 11 1321 - 1326 2022年11月 [査読有り]
     
    INTRODUCTION: This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma. METHODS: Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component. RESULTS: Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component. CONCLUSIONS: Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay.
  • 武田 真幸; 下川 元継; 中村 敦; 野崎 要; 渡辺 恭孝; 加藤 晃史; 早川 乃介; 田中 洋史; 高橋 利明; 立原 素子; 林 秀敏; 藤本 大智; 山口 覚博; 山本 将一朗; 岩間 映二; 東 公一; 沖 昌英; 長谷川 一男; 山本 信之; 中川 和彦
    肺癌 62 6 660 - 660 (NPO)日本肺癌学会 2022年11月
  • 中村 敦; 善家 義貴; 仁保 誠治; 岡本 龍郎; 原 聡志; 赤澤 結貴; 細見 幸生; 林 秀敏; 寺岡 俊輔; 横山 俊秀; 尾崎 智博; 上野 清伸; 行徳 宏; 三角 俊裕; 中川 和彦; 山本 信之; 坪井 正博
    肺癌 62 6 648 - 648 (NPO)日本肺癌学会 2022年11月
  • 阪本 智宏; 松原 太一; 高濱 隆幸; 横山 俊秀; 中村 敦; 時任 高章; 岡本 龍郎; 赤松 弘朗; 沖 昌英; 佐藤 悠城; 飛野 和則; 西村 邦裕; 平岡 学; 釼持 広知; 藤本 淳也; 下川 元継; 山本 信之; 中川 和彦
    肺癌 62 6 491 - 491 (NPO)日本肺癌学会 2022年11月
  • 未治療EGFR陽性NSCLCに対するOsimertinib+BevacizumabとOsimertinibのランダム化第2相試験 WJOG9717L
    桐田 圭輔; 釼持 広知; 坂井 和子; 盛 啓太; 加藤 晃史; 菅原 俊一; 米嶋 康臣; 東 公一; 中川 和彦; 山本 信之; 西尾 和人; 高橋 利明
    肺癌 62 6 566 - 566 (NPO)日本肺癌学会 2022年11月
  • 切除可能非小細胞肺癌II-IIIA期における可溶性免疫因子の検討(WJOG12319LTR)
    谷崎 潤子; 黒田 浩章; 横山 俊秀; 高濱 誠; 庄田 浩康; 中村 敦; 北村 嘉隆; 豆鞘 伸昭; 門田 嘉久; 光岡 茂樹; 沖塩 協一; 岡田 守人; 坂井 和子; 千葉 康敬; 西尾 和人; 茶本 健司; 本庶 佑; 山本 信之; 中川 和彦; 林 秀敏
    肺癌 62 6 594 - 594 (NPO)日本肺癌学会 2022年11月
  • Kohsuke Isomoto; Koji Haratani; Takahiro Tsujikawa; Yusuke Makutani; Hisato Kawakami; Masayuki Takeda; Kimio Yonesaka; Kaoru Tanaka; Tsutomu Iwasa; Hidetoshi Hayashi; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 174 71 - 82 2022年10月 
    OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). MATERIALS AND METHODS: Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. RESULTS: Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. CONCLUSION: The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary.
  • がん遺伝子パネル検査FoundationOneによる肺癌の遺伝子変異の測定
    米阪 仁雄; 高濱 隆幸; 黒崎 隆; 川中 雄介; 金村 宙昌; 磯本 晃佑; 鈴木 慎一郎; 三谷 誠一郎; 中川 和彦; 白石 直樹; 小田 いつき; 西郷 和真; 池川 敦子; 福岡 和也; 武田 真幸; 西尾 和人
    肺癌 62 5 439 - 439 (NPO)日本肺癌学会 2022年10月
  • がん遺伝子パネル検査FoundationOneによる肺癌の遺伝子変異の測定
    米阪 仁雄; 高濱 隆幸; 黒崎 隆; 川中 雄介; 金村 宙昌; 磯本 晃佑; 鈴木 慎一郎; 三谷 誠一郎; 中川 和彦; 白石 直樹; 小田 いつき; 西郷 和真; 池川 敦子; 福岡 和也; 武田 真幸; 西尾 和人
    肺癌 62 5 439 - 439 (NPO)日本肺癌学会 2022年10月
  • 進展型小細胞肺癌における免疫チェックポイント阻害薬の効果と腫瘍微小免疫環境の関連
    金村 宙昌; 林 秀敏; 原谷 浩司; 中川 和彦; 冨田 秀太; 谷崎 潤子; 鈴木 慎一郎; 川中 雄介; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 大谷 知之; 伊藤 彰彦; 坂井 和子; 西尾 和人
    肺癌 62 5 442 - 442 (NPO)日本肺癌学会 2022年10月
  • Hirotsugu Kenmotsu; Kazushige Wakuda; Keita Mori; Terufumi Kato; Shunichi Sugawara; Keisuke Kirita; Yasuto Yoneshima; Koichi Azuma; Kazumi Nishino; Shunsuke Teraoka; Takehito Shukuya; Ken Masuda; Hidetoshi Hayashi; Ryo Toyozawa; Satoru Miura; Daichi Fujimoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Toshiaki Takahashi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17 9 1098 - 1108 2022年09月 
    INTRODUCTION: To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations. METHODS: We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review. RESULTS: Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700-1.060, 95% confidence interval: 0.531-1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm. CONCLUSIONS: This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.
  • Naoki Haratake; Mototsugu Shimokawa; Takashi Seto; Hiroshige Yoshioka; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Tetsuya Mitsudomi
    International journal of clinical oncology 27 9 1404 - 1412 2022年09月 
    BACKGROUND: Pemetrexed is common cytotoxic chemotherapy among non-squamous non-small cell lung cancer (non-Sq-NSCLC) patients; however, among epidermal growth factor receptor (EGFR)-positive lung cancer, there is no clear evidence to support the efficacy of sequential treatment with pemetrexed. MATERIAL AND METHODS: We performed a post-hoc analysis of subsequent chemotherapies among 144 patients who received the post-protocol treatment in the phase III trial WJTOG 3405 comparing gefitinib to cisplatin plus docetaxel, and analyzed the effect of pemetrexed on overall survival (OS). RESULTS: Patients with treatment including pemetrexed exhibited significantly longer OS in comparison to those without pemetrexed; the median OS in the pemetrexed + and pemetrexed- patients were 40.7 months and 28.0 months, respectively (0.55 of HR [95% CI: 0.38-0.80, p = 0.0020]). On the other hand, other treatments, including docetaxel, TS-1 and paclitaxel showed no significant impact on OS. The multivariate analysis with a time-dependent Cox proportional hazards model showed that treatment including pemetrexed, as well as PS 0 and post-operative recurrence, were independent predictors of a good prognosis. Moreover, among patients who received at least four lines of prior treatment, pemetrexed + treatment also significantly prolonged OS in comparison to pemetrexed- treatment (median OS pemetrexed + vs. pemetrexed-: 44.4 months vs. 32.6 months; HR: 0.55 [95% CI: 0.31-0.94, p = 0.0290]). CONCLUSIONS: Sequential treatment including pemetrexed against EGFR-mutated NSCLC might be associated with a better outcome. It was considered that pemetrexed should be administered without fail as a sequential treatment to improve the prognosis of EGFR-mutated NSCLC as well as like EGFR-tyrosine kinase inhibitors.
  • Satoru Hagiwara; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Chishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology research : the official journal of the Japan Society of Hepatology 52 9 754 - 761 2022年09月 
    AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.
  • Hiroaki Kanemura; Hidetoshi Hayashi; Shuta Tomida; Junko Tanizaki; Shinichiro Suzuki; Yusuke Kawanaka; Asuka Tsuya; Yasushi Fukuda; Hiroyasu Kaneda; Keita Kudo; Takayuki Takahama; Ryosuke Imai; Koji Haratani; Yasutaka Chiba; Tomoyuki Otani; Akihiko Ito; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    JTO clinical and research reports 3 8 100373 - 100373 2022年08月 
    Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.
  • Satoru Hagiwara; Takeshi Yoshida; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Cishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology research : the official journal of the Japan Society of Hepatology 52 10 888 - 892 2022年07月 
    AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.
  • がん疼痛に対するオピオイド選択のための多型バイオマーカーの探索
    藤田 至彦; 松岡 弘道; 鶴谷 純司; 千葉 康敬; 酒井 清裕; 吉田 健史; 大武 陽一; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 17 Suppl. S.179 - S.179 (NPO)日本緩和医療学会 2022年07月
  • Hiroaki Akamatsu; Shunsuke Teraoka; Shinkichi Takamori; Satoru Miura; Hidetoshi Hayashi; Akito Hata; Yukihiro Toi; Yoshimasa Shiraishi; Nobuaki Mamesaya; Yuki Sato; Naoki Furuya; Jun Oyanagi; Yasuhiro Koh; Toshihiro Misumi; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research OF1-OF7  2022年06月 
    PURPOSE: To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS: Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS: Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8-18.7%] and median PFS of 2.6 months (95% CI, 1.6-2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSIONS: Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
  • 高濱 隆幸; 米阪 仁雄; 白石 直樹; 小田 いつき; 池川 敦子; 西郷 和真; 福岡 和也; 中川 和彦
    近畿大学医学雑誌 47 1-2 19 - 25 近畿大学医学会 2022年06月 
    近年、次世代シークエンサー(NGS)の臨床応用が進み、がんに生じた遺伝子変化を網羅的に解析することが可能となった。包括的がんゲノムプロファイリング(CGP)検査を実施することで、がん化に関わる原因遺伝子が明らかになると同時に、治療の選択肢が増え、恩恵を受ける症例が出てきている。近畿大学病院ゲノム医療センターでは、2019年に日本においてCGP検査が保険適応を受けて以降、がん関連遺伝子検査がスムーズに進むよう業務を行っている。エキスパートパネルの運営を通して、患者や主治医への適切な遺伝子解析結果を届けることを目標とし、また二次的所見への対応などを行ってきた。本稿では、CGP検査の現状について概説し、特に課題の多い出口戦略について、治療への到達率を高めるために必要なことは何か考察をしたい。(著者抄録)
  • Tomohiro Nakayama; Koji Haratani; Takashi Kurosaki; Kaoru Tanaka; Kazuhiko Nakagawa
    Translational Cancer Research 11 6 1824 - 1828 2022年06月
  • Hiroaki Akamatsu; Shunsuke Teraoka; Shinkichi Takamori; Satoru Miura; Hidetoshi Hayashi; Akito Hata; Yukihiro Toi; Yoshimasa Shiraishi; Nobuaki Mamesaya; Yuki Sato; Naoki Furuya; Jun Oyanagi; Yasuhiro Koh; Toshihiro Misumi; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 2022年05月 
    PURPOSE: To explore the efficacy of retreatment with immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS: Advanced NSCLC patients who had achieved complete response (CR), partial response (PR), or stable disease for {greater than or equal to}6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval {greater than or equal to} 60 days before registration. Patients were treated with nivolumab (240 mg/body) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS: Sixty-one patients were enrolled during October 2017-February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAEs) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% (95% confidence interval [CI]: 2.8-18.7%) and median PFS of 2.6 months (95% CI: 1.6-2.8 months) while five responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (hazard ratio: 2.02, p = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSION: Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
  • Hidetoshi Hayashi; Kimio Yonesaka; Atsushi Nakamura; Daichi Fujimoto; Koichi Azuma; Shinya Sakata; Motoko Tachihara; Satoshi Ikeda; Toshihide Yokoyama; Osamu Hataji; Yukihiro Yano; Katsuya Hirano; Haruko Daga; Hideaki Okada; Yasutaka Chiba; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 168 38 - 45 2022年04月 
    INTRODUCTION: Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). METHODS: Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered. The primary end point was 12-month progression-free survival (PFS) probability. RESULTS: Forty-six patients were enrolled and treated with study therapy. The 12-month PFS probability was 70.2% (60% confidence interval [CI], 63.9-75.6%; 95% CI, 54.2-81.5%), which did not meet the primary end point. After a median follow-up time of 25.7 months, the median PFS was 21.3 months (95% CI, 16.3 months-not reached). The overall response rate was 69.6% (95% CI, 54.2-82.3%). The most common treatment-related adverse events (any grade or grade ≥ 3, respectively) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%), and paronychia (52.2%, 0%). Five cases of pneumonitis, two of grade 2 and thres of grade 3, were apparent, all of which developed during osimertinib treatment. Exploratory evaluation of circulating tumor DNA suggested that coexisting TP53 mutations did not influence PFS for the alternating therapy. CONCLUSIONS: Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR- mutated advanced NSCLC did not meet its primary end point, despite the encouraging efficacy and safety profile of this treatment strategy.
  • Makoto Nishio; Kazuto Nishio; Martin Reck; Edward B Garon; Fumio Imamura; Tomoya Kawaguchi; Hiroyuki Yamaguchi; Satoshi Ikeda; Katsuya Hirano; Carla Visseren-Grul; Matteo Ceccarelli; Sameera R Wijayawardana; Annamaria Zimmermann; Tomoko Matsui; Sotaro Enatsu; Kazuhiko Nakagawa
    JTO clinical and research reports 3 4 100303 - 100303 2022年04月 
    Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3-73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit-risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.
  • Hidetoshi Hayashi; Shunichi Sugawara; Yasushi Fukuda; Daichi Fujimoto; Satoru Miura; Keiichi Ota; Yuichi Ozawa; Satoshi Hara; Junko Tanizaki; Koichi Azuma; Shota Omori; Motoko Tachihara; Kazumi Nishino; Akihiro Bessho; Yasutaka Chiba; Koji Haratani; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 5 893 - 902 2022年03月 
    PURPOSE: Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. PATIENTS AND METHODS: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. CONCLUSIONS: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
  • J Tanizaki; K Yonemori; K Akiyoshi; H Minami; H Ueda; Y Takiguchi; Y Miura; Y Segawa; S Takahashi; Y Iwamoto; Y Kidera; K Fukuoka; A Ito; Y Chiba; K Sakai; K Nishio; K Nakagawa; H Hayashi
    Annals of oncology : official journal of the European Society for Medical Oncology 33 2 216 - 226 2022年02月 
    BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
  • Kohsuke Isomoto; Koji Haratani; Satomi Watanabe; Masayuki Takeda; Tsutomu Iwasa; Kazuhiko Nakagawa
    Investigational new drugs 40 1 194 - 197 2022年02月 
    Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.
  • Takashi Seto; Kaname Nosaki; Mototsugu Shimokawa; Ryo Toyozawa; Shunichi Sugawara; Hidetoshi Hayashi; Haruyasu Murakami; Terufumi Kato; Seiji Niho; Hideo Saka; Masahide Oki; Hiroshige Yoshioka; Isamu Okamoto; Haruko Daga; Koichi Azuma; Hiroshi Tanaka; Kazumi Nishino; Rie Tohnai; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 10 2 2022年02月 
    BACKGROUND: PD-L1 expression on tumor cells is a marker of PD-1/PD-L1 antibody treatment efficacy for advanced non-small cell lung cancer (NSCLC). PD-L1 antibody (atezolizumab) prolongs overall survival (OS) compared with platinum doublet as first-line treatment for NSCLC with high PD-L1 expression. Bevacizumab enhanced cytotoxic agent and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor efficacy in non-squamous (NS)-NSCLC, and PD-1/PD-L1 antibodies in preclinical models. METHODS: This single-arm phase II study investigated clinical benefits of adding bevacizumab 15 mg/kg to atezolizumab 1200 mg fixed dose in a first-line setting for advanced NS-NSCLC patients with PD-L1 expression ≥50% without EGFR/ALK/ROS1 alterations. Primary endpoint was objective response rate (ORR) assessed by central review committee. Secondary endpoints were progression-free survival (PFS), duration of response (DOR), OS, and safety. RESULTS: Of 39 enrolled patients, 33 (84.6%) had stage IV NSCLC and 36 (92.3%) had smoking history. As of March 31, 2020, no patient had a complete response and 25 patients had a partial response (ORR=64.1%, 95% CI 47.18 to 78.80). Twelve-month PFS and OS rates were 54.9% (35.65 to 70.60) and 70.6% (50.53 to 83.74), respectively. The median DOR in 25 responders was 10.4 months (4.63-not reached). The median treatment cycle was 12 (1 to 27). Nineteen patients discontinued study treatment because of disease progression (N=17) or immune-related adverse events (AEs) (N=2) (sclerosing cholangitis or encephalopathy). There were 23 serious AEs in 12 patients, but no grade 4/5 toxicity. CONCLUSIONS: Atezolizumab with bevacizumab is a potential treatment for NS-NSCLC with high PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-184038.
  • Bob T Li; Egbert F Smit; Yasushi Goto; Kazuhiko Nakagawa; Hibiki Udagawa; Julien Mazières; Misako Nagasaka; Lyudmila Bazhenova; Andreas N Saltos; Enriqueta Felip; Jose M Pacheco; Maurice Pérol; Luis Paz-Ares; Kapil Saxena; Ryota Shiga; Yingkai Cheng; Suddhasatta Acharyya; Patrik Vitazka; Javad Shahidi; David Planchard; Pasi A Jänne
    The New England journal of medicine 386 3 241 - 251 2022年01月 
    BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
  • Hirohito Tada; Tetsuya Mitsudomi; Toshihiro Misumi; Kenji Sugio; Masahiro Tsuboi; Isamu Okamoto; Yasuo Iwamoto; Noriaki Sakakura; Shunichi Sugawara; Shinji Atagi; Toshiaki Takahashi; Hidetoshi Hayashi; Morihito Okada; Hidetoshi Inokawa; Hiroshige Yoshioka; Kazuhisa Takahashi; Masahiko Higashiyama; Ichiro Yoshino; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 40 3 231 - 241 2022年01月 
    PURPOSE: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation. PATIENTS AND METHODS: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS). RESULTS: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively. CONCLUSION: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.
  • Kimio Yonesaka; Junko Tanizaki; Osamu Maenishi; Koji Haratani; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Kazuko Sakai; Yasutaka Chiba; Asuka Tsuya; Hiroki Goto; Eri Otsuka; Hiroaki Okida; Maki Kobayashi; Ryoto Yoshimoto; Masanori Funabashi; Yuuri Hashimoto; Kenji Hirotani; Takashi Kagari; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 390 - 403 2022年01月 
    PURPOSE: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. EXPERIMENTAL DESIGN: Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. RESULTS: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. CONCLUSIONS: Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.
  • Shinichiro Suzuki; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 428 - 428 2022年01月
  • Tomoyuki Otani; Hiroaki Kanemura; Masatomo Kimura; Seiichiro Mitani; Masayuki Takeda; Mitsuru Matsuki; Noriomi Matsumura; Takao Satou; Kazuhiko Nakagawa; Akihiko Ito
    International journal of surgical pathology 30 6 10668969211069963 - 10668969211069963 2022年01月 
    Only four cases of colorectal adenocarcinoma with a yolk sac tumor (YST) component have been reported in the English literature. No genetic investigation has been performed in these cases. We report a case of colorectal adenocarcinoma in which the recurrent tumor had a YST component. A 49-year-old woman presented with a pelvic tumor three years after endoscopic mucosal resection of sigmoid colon adenocarcinoma. The pelvic tumor consisted of an undifferentiated carcinoma component and a YST component. The serum alpha-fetoprotein level was elevated to 42 ng/mL. Treatment as conventional colorectal carcinoma produced some anticancer effects, but the patient died 14 months after the recurrence and 49 months after the EMR. With the help of the next-generation sequencing results of the recurrent tumor, APC c.835 - 8A > G and TP53 c.524G > A (p.R175H) mutations were identified by direct sequencing in both the primary and the recurrent tumors, confirming the relationship between the two metachronous tumors.
  • Yusuke Makutani; Hisato Kawakami; Takahiro Tsujikawa; Kanako Yoshimura; Yasutaka Chiba; Akihiko Ito; Junichiro Kawamura; Koji Haratani; Kazuhiko Nakagawa
    Frontiers in oncology 12 956270 - 956270 2022年 
    Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.
  • Yu Okubo; Jumpei Kashima; Takashi Teishikata; Yuji Muraoka; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Hirokazu Watanabe; Masahiko Kusumoto; Shun-Ichi Watanabe; Yasushi Yatabe
    Journal of thoracic oncology 17 1 67 - 75 2022年01月 [査読有り]
     
    INTRODUCTION: Because several articles have reported a prognostic association with the radiologic features of ground-glass opacity, we explored whether the histologic presence of a lepidic component had similar significance. METHODS: We retrospectively evaluated 380 consecutive surgically resected lung adenocarcinomas (ADCs) of pathologic (p)stage IA. The tumors were classified into lepidic-positive and lepidic-negative ADCs. Clinicopathologic characteristics, radiographic ground-glass opacity status, and disease-free survival were compared between lepidic-positive and lepidic-negative ADCs and between part-solid and solid nodules on computed tomography images. RESULTS: Of the 380 cases, 176 (46.3%) were lepidic-positive ADCs. Of the overall patients with pT1, lepidic-positive ADCs were found to have significantly better recurrence-free survival (5 y, 95.4% versus 87.0%, p = 0.005), but this significance was not reproduced in pT1 subcategories (pT1a, pT1b, and pT1c). Furthermore, the presence of the lepidic component was not an independent prognostic factor in the multivariate analysis (hazard ratio = 0.46 [95% confidence interval: 0.19-1.14], p = 0.09). We also analyzed the extent of the lepidic component with 10% incremental valuables. Although we found that a 10% or greater extent of lepidic component made the recurrence-free survival difference the largest, a clear prognostic impact was not obtained with this cutoff point. CONCLUSIONS: Although lepidic-positive ADCs tended to have a favorable outcome, the lepidic component was not a clear independent prognostic factor in pstage I ADC.
  • Shinya Sakata; Kohei Otsubo; Hisako Yoshida; Kentaro Ito; Atsushi Nakamura; Shunsuke Teraoka; Naohisa Matsumoto; Yoshimasa Shiraishi; Koji Haratani; Motohiro Tamiya; Satoshi Ikeda; Satoru Miura; Junko Tanizaki; Shota Omori; Hiroshige Yoshioka; Akito Hata; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer science 113 1 221 - 228 2022年01月 
    Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.
  • Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Junko Tanizaki; Ryoji Kato; Seiichiro Mitani; Yusuke Kawanaka; Takashi Kurosaki; Yoshikazu Hasegawa; Takafumi Okabe; Kaoru Tanaka; Yusaku Akashi; Tomohiro Ozaki; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    European journal of cancer (Oxford, England : 1990) 161 44 - 54 2022年01月 
    BACKGROUND: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. METHODS: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. RESULTS: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. CONCLUSION: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted.
  • Ernest Nadal; Hidehito Horinouchi; Jin-Yuan Shih; Kazuhiko Nakagawa; Martin Reck; Edward B Garon; Yu-Feng Wei; Jens Kollmeier; Bente Frimodt-Moller; Emily Barrett; Olga Lipkovich; Carla Visseren-Grul; Silvia Novello
    Drug safety 45 1 45 - 64 2022年01月 
    INTRODUCTION: RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC). OBJECTIVE: This article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY. METHODS: Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments. RESULTS: The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care. CONCLUSION: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT02411448.
  • Naonori Kawakubo; Yu Okubo; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Kan Yonemori; Hirokazu Watanabe; Yasushi Yatabe; Shun-Ichi Watanabe
    The Journal of surgical research 272 61 - 68 2021年12月 
    BACKGROUND AND OBJECTIVES: Mediastinal germ cell tumor (MGCT) is a relatively rare tumor. Complete resection after chemotherapy is a standard treatment against this disease. However, the risk factors of incomplete resection are unclear. Therefore, we analyzed survival rates and risk factors for incomplete resection based on preoperative imaging. METHODS: We retrospectively reviewed the medical records of patients (n = 56) with MGCT operated at National Cancer Center Hospital, and analyzed preoperative computed tomography (CT) data in terms of relationship of the tumor and vessels, and investigated survival rate and risk factors for incomplete resection. RESULTS: A total of 56 patients underwent resection of MGCT. The 5-y progression-free survival (PFS) and overall survival (OS) were 79% and 83%. In multivariate analysis, complete resection was the only significant prognostic factor for better PFS (hazard ratio (HR) = 9.083, P= 0.00021) and OS (HR = 5.519, P= 0.0445). The preoperative CT finding of arteries (including the aorta, right brachiocephalic artery, left common carotid artery, and left subclavian artery) surrounded by the tumor was a predictor of incomplete resection (odds ratio = 10.089, P= 0.049). CONCLUSIONS: Complete resection is essential for improving the survival of MGCT, and the risk stratification using preoperative CT imaging brings important information to achieve the complete resection.
  • 谷崎 潤子; 鈴木 慎一郎; 金村 宙昌; 岩朝 勤; 川上 尚人; 田中 薫; 吉田 健史; 米阪 仁雄; 伊藤 彰彦; 坂井 和子; 木寺 康裕; 福岡 和也; 千葉 康敬; 西尾 和人; 中川 和彦; 林 秀敏
    近畿大学医学雑誌 46 3-4 20A - 20A 近畿大学医学会 2021年12月
  • Miyako Satouchi; Kaname Nosaki; Toshiaki Takahashi; Kazuhiko Nakagawa; Keisuke Aoe; Takayasu Kurata; Akimasa Sekine; Atsushi Horiike; Tatsuro Fukuhara; Shunichi Sugawara; Shigeki Umemura; Hideo Saka; Isamu Okamoto; Nobuyuki Yamamoto; Hiroshi Sakai; Kazuma Kishi; Nobuyuki Katakami; Hidehito Horinouchi; Toyoaki Hida; Hiroaki Okamoto; Shinji Atagi; Tatsuo Ohira; Shi Rong Han; Kazuo Noguchi; Victoria Ebiana; Katsuyuki Hotta
    Cancer science 112 12 5000 - 5010 2021年12月 
    This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.
  • Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo; Kosuke Minaga; Yoriaki Komeda; Ken Kamata; Masatomo Kimura; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuomi Ueshima; Yasunori Minami; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Cishina; Hiroshi Ida; Ah-Mee Park; Naoshi Nishida
    Scientific Reports 11 1 9242 - 9242 2021年12月 
    AbstractImmune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
  • Nobuyuki Yamamoto; Yoichi Nakanishi; Akihiko Gemma; Kazuhiko Nakagawa; Takahiko Sakamoto; Ayumi Akamatsu; Yuichiro Ohe
    Cancer science 112 11 4692 - 4701 2021年11月 
    Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).
  • Naoki Haratake; Hidetoshi Hayashi; Mototsugu Shimokawa; Yusuke Nakano; Koichi Azuma; Masahide Oki; Keiichi Ota; Hiroshige Yoshioka; Tomohiro Sakamoto; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Takashi Seto
    Clinical lung cancer 23 3 e257-e263  2021年10月 
    INTRODUCTION: Osimertinib is a standard first-line treatment for non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR-tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance-associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R. PATIENTS AND METHODS: A total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival. CONCLUSION: This is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals.
  • Taichi Miyawaki; Hirotsugu Kenmotsu; Hideyuki Harada; Yasuhisa Ohde; Yasutaka Chiba; Koji Haratani; Tamio Okimoto; Tomohiro Sakamoto; Kazushige Wakuda; Kentaro Ito; Takehiro Uemura; Shinya Sakata; Yoshihito Kogure; Yasumasa Nishimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    BMC cancer 21 1 1121 - 1121 2021年10月 
    BACKGROUND: Synchronous oligometastatic non-small cell lung cancer (NSCLC) is generally characterised by the limited number of metastases at the time of diagnosis. Several clinical trials have shown that local ablative therapy (LAT) at all sites of the disease might be beneficial for patients with oligometastatic NSCLC. In recent years, the combination of programmed cell death 1 (PD-1) inhibitors or programmed cell death ligand 1 with cytotoxic chemotherapy has become a new standard treatment for patients with metastatic NSCLC. Furthermore, multisite LAT would inherently reduce the overall tumour burden, and this could promote T cell reinvigoration to enhance the efficacy of PD-1 inhibitors. Few studies have evaluated the efficacy of the combination of PD-1 inhibitors with LAT at all sites of disease. The aim of the present multicentre single-arm phase II study is to evaluate the efficacy of LAT at all sites of disease following standard platinum doublet chemotherapy with pembrolizumab in patients with oligometastatic NSCLC. METHODS: Thirty patients with synchronous oligometastatic NSCLC will be enrolled in the trial. All patients will receive 2-4 cycles of a systemic treatment including pembrolizumab and chemotherapy as induction therapy. Patients who will receive LAT will be determined by a multidisciplinary tumour board, including medical oncologists, radiation oncologists, and thoracic surgeons. LAT will be administered at all sites of disease within 21-56 days of the last dose of induction therapy and will be followed by maintenance therapy within 42 days of the last day of LAT. The primary endpoint is the progression-free survival (PFS) rate of 24 months from the date of initiation of LAT. The secondary endpoints are toxicity, response to induction therapy, PFS, overall survival, and the frequency of LAT. DISCUSSION: This study will provide novel data on the efficacy and safety profile of the combination of LAT and chemotherapy plus immune-checkpoint inhibitors in patients with synchronous oligometastatic NSCLC. If the primary endpoint of this study is met, extensive phase III studies further assessing this strategy will be recommended. TRIAL REGISTRATION: jRCT identifier: jRCTs041200046 (date of initial registration: 28 October 2020).
  • 宿谷 威仁; 藤本 大智; 林 秀敏; 伊藤 健太郎; 小澤 雄一; 釼持 広知; 中川 和彦; 光冨 徹哉; 弦間 昭彦; 山本 信之
    肺癌 61 6 517 - 517 (NPO)日本肺癌学会 2021年10月
  • 白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • 岩本 康男; 多田 弘人; 光冨 徹哉; 杉尾 賢二; 坪井 正博; 岡本 勇; 坂倉 範昭; 菅原 俊一; 安宅 信二; 高橋 利明; 林 秀敏; 岡田 守人; 井野川 英利; 吉岡 弘鎮; 高橋 和久; 東山 聖彦; 吉野 一郎; 中川 和彦
    肺癌 61 6 594 - 594 (NPO)日本肺癌学会 2021年10月
  • 寺岡 俊輔; 赤松 弘朗; 林 秀敏; 藤本 大智; 早田 敦志; 原谷 浩司; 小澤 雄一; 吉田 健司; 岩朝 勤; 下川 敏雄; 富井 啓介; 中川 和彦; 山本 信之
    肺癌 61 6 498 - 498 (NPO)日本肺癌学会 2021年10月
  • 高森 信吉; 赤松 弘朗; 寺岡 俊輔; 林 秀敏; 三浦 理; 秦 明登; 戸井 之裕; 白石 祥理; 豆鞘 伸昭; 佐藤 悠城; 古屋 直樹; 洪 泰浩; 山本 信之; 中川 和彦
    肺癌 61 6 627 - 627 (NPO)日本肺癌学会 2021年10月
  • 米阪 仁雄; 谷崎 潤子; 前西 修; 川上 尚人; 田中 薫; 林 秀敏; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 舟橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    肺癌 61 6 623 - 623 2021年10月
  • 鈴木 慎一郎; 米阪 仁雄; 寺村 岳士; 竹原 俊幸; 加藤 了資; 酒井 瞳; 原谷 浩司; 谷崎 潤子; 川上 尚人; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 61 6 629 - 629 (NPO)日本肺癌学会 2021年10月
  • 福田 泰; 林 秀敏; 菅原 俊一; 佐藤 悠城; 三浦 理; 大田 恵一; 小澤 雄一; 原 聡志; 谷崎 潤子; 東 公一; 大森 翔太; 立原 素子; 西野 和美; 別所 昭宏; 原谷 浩司; 坂井 和子; 西尾 和人; 山本 信之; 中川 和彦
    肺癌 61 6 677 - 677 (NPO)日本肺癌学会 2021年10月
  • 上村 剛大; 釼持 広知; 福田 悟史; 宮脇 太一; 羽間 大祐; 神戸 寛史; 寺岡 俊輔; 松尾 規和; 山口 哲平; 益田 武; 横山 俊秀; 大坪 孝平; 橋本 大哉; 山本 信之; 中川 和彦
    肺癌 61 6 654 - 654 (NPO)日本肺癌学会 2021年10月
  • 金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • ベンダムスチン塩酸塩経口剤(SyB C-0501)の進行性固形がん患者に対する第1相臨床試験
    武田 真幸; 中川 和彦; 林 秀敏; 岩朝 勤; 川上 尚人; 渡邉 諭美; 山本 昇; 米盛 勧; 小山 隆文; 佐藤 潤; 田村 研治; 菊池 圭一; 赤池 健一郎; 竹田 志保; 清水 俊雄
    日本癌治療学会学術集会抄録集 59回 O13 - 5 2021年10月
  • 小細胞癌のICI(Treatment of SCLC) 再発小細胞肺がんに対するペムブロリズマブ+アムルビシンの多施設共同第II相試験
    寺岡 俊輔; 赤松 弘朗; 林 秀敏; 藤本 大智; 早田 敦志; 原谷 浩司; 小澤 雄一; 吉田 健司; 岩朝 勤; 下川 敏雄; 富井 啓介; 中川 和彦; 山本 信之
    肺癌 61 6 498 - 498 (NPO)日本肺癌学会 2021年10月
  • ICIが有効であった進行・再発非小細胞肺がんに対するニボルマブの第II相試験(WJOG9616L)
    高森 信吉; 赤松 弘朗; 寺岡 俊輔; 林 秀敏; 三浦 理; 秦 明登; 戸井 之裕; 白石 祥理; 豆鞘 伸昭; 佐藤 悠城; 古屋 直樹; 洪 泰浩; 山本 信之; 中川 和彦
    肺癌 61 6 627 - 627 (NPO)日本肺癌学会 2021年10月
  • 小細胞癌のICI(Treatment of SCLC) 進展型小細胞肺癌における腫瘍微小免疫環境の網羅的解析
    金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • オンコマイン検査成功率改善に向けた検査内製化と検査工程の見直し
    白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • 遺伝子異常未検出の非小細胞肺癌を対象とするGuardant360による遺伝子解析の前向き観察研究 WJOG13620L
    上村 剛大; 釼持 広知; 福田 悟史; 宮脇 太一; 羽間 大祐; 神戸 寛史; 寺岡 俊輔; 松尾 規和; 山口 哲平; 益田 武; 横山 俊秀; 大坪 孝平; 橋本 大哉; 山本 信之; 中川 和彦
    肺癌 61 6 654 - 654 (NPO)日本肺癌学会 2021年10月
  • EGFR変異陽性術後NSCLCに対するシスプラチン+ビノレルビンとゲフィチニブの第3相比較試験(WJOG6410L)
    岩本 康男; 多田 弘人; 光冨 徹哉; 杉尾 賢二; 坪井 正博; 岡本 勇; 坂倉 範昭; 菅原 俊一; 安宅 信二; 高橋 利明; 林 秀敏; 岡田 守人; 井野川 英利; 吉岡 弘鎮; 高橋 和久; 東山 聖彦; 吉野 一郎; 中川 和彦
    肺癌 61 6 594 - 594 (NPO)日本肺癌学会 2021年10月
  • 日本肺癌学会による既存肺がん臨床試験データの統合とデータベース化,及びその共有と再利用体制の構築
    小澤 雄一; 伊藤 健太郎; 釼持 広知; 宿谷 威仁; 林 秀敏; 藤本 大智; 大江 裕一郎; 岡本 浩明; 木浦 勝行; 菅原 俊一; 中川 和彦; 仁保 誠治; 吉野 一郎; 弦間 昭彦; 山本 信之
    肺癌 61 6 662 - 662 (NPO)日本肺癌学会 2021年10月
  • Hiroaki Akamatsu; Haruyasu Murakami; Hideyuki Harada; Junichi Shimizu; Hidetoshi Hayashi; Haruko Daga; Yoshikazu Hasegawa; Young Hak Kim; Terufumi Kato; Shoji Tokunaga; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 10 1745 - 1752 2021年10月 
    INTRODUCTION: About 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted. METHODS: Chemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366). RESULTS: Between August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45-74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%-). The overall response rate was 81.5% (95% CI: 63.3%-91.3%), median PFS was 18.6 months (95% CI: 12.0-24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo-not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each). CONCLUSIONS: This prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.
  • Kazuhiko Nakagawa; Ernest Nadal; Edward B Garon; Makoto Nishio; Takashi Seto; Nobuyuki Yamamoto; Keunchil Park; Jin-Yuan Shih; Luis Paz-Ares; Bente Frimodt-Moller; Annamaria H Zimmermann; Sameera Wijayawardana; Carla Visseren-Grul; Martin Reck
    Clinical cancer research : an official journal of the American Association for Cancer Research 27 19 5258 - 5271 2021年10月 
    PURPOSE: In EGFR-mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. PATIENTS AND METHODS: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. RESULTS: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. CONCLUSIONS: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.
  • EGFR阻害剤によるHER3の発現亢進及び抗HER3パトリツマブデルクステカンの抗腫瘍効果の増強
    米阪 仁雄; 谷崎 潤子; 前西 修; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 船橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    日本癌学会総会記事 80回 [E14 - 4] 2021年09月
  • Masafumi Yamaguchi; Hirohito Tada; Tetsuya Mitsudomi; Takashi Seto; Kohei Yokoi; Nobuyuki Katakami; Kazuhiko Nakagawa; Makoto Oda; Mitsunori Ohta; Toshiyuki Sawa; Motohiro Yamashita; Norihiko Iked; Hideo Saka; Masahiko Higashiyama; Hiroaki Nomori; Hiroshi Semba; Shunichi Negoro; Yasutaka Chiba; Mototsugu Shimokawa; Masahiro Fukuoka; Yoichi Nakanishi
    International journal of clinical oncology 26 12 2216 - 2223 2021年08月 
    BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.
  • Hiroyuki Yamaguchi; Kazushige Wakuda; Minoru Fukuda; Hirotsugu Kenmotsu; Hiroshi Mukae; Kentaro Ito; Kenji Chibana; Kohji Inoue; Satoru Miura; Kentaro Tanaka; Noriyuki Ebi; Takayuki Suetsugu; Taishi Harada; Keisuke Kirita; Toshihide Yokoyama; Yuki Nakatani; Kenichi Yoshimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Kenji Sugio
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 12 2121 - 2132 2021年08月 
    OBJECTIVES: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. METHODS: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. RESULTS: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. CONCLUSIONS: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
  • Shinichiro Suzuki; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 27 20 5697 - 5707 2021年08月 
    PURPOSE: Treatment with KRAS G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS G12C NSCLC cells. EXPERIMENTAL DESIGN: Clones of sotorasib-sensitive KRAS G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy number evaluation. The underlying mechanisms of resistance were investigated using immunological examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo Results: Unbiased screening detected subclonal evolution of MET amplification in KRAS G12C NSCLC cells that had developed resistance to sotorasib in vitro MET knockdown using siRNA restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/KRAS G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. CONCLUSIONS: MET amplification leads to the development of resistance to KRAS G12C inhibitors in NSCLC. Dual blockade of MET and KRAS G12C could be a treatment option for MET amplified, KRAS G12C-mutated NSCLC.
  • Oiso N; Yanagihara S; Nakagawa K; Kawada A
    The Journal of Dermatology 48 8 e390 - e392 2021年08月 [査読有り]
  • Toshiharu Sakurai; Marco A De Velasco; Kazuko Sakai; Tomoyuki Nagai; Hiroki Nishiyama; Kentaro Hashimoto; Hirotsugu Uemura; Hisato Kawakami; Kazuhiko Nakagawa; Hiroyuki Ogata; Kazuto Nishio; Masatoshi Kudo
    Molecular oncology 2021年07月 
    Immune checkpoint inhibitors (ICIs) are widely used to treat various malignancies. Although the gut microbiome is known to influence the efficacy of ICIs on epithelial tumors, the functional interactions between gut taxa and colonic mucosa remain poorly understood. Here we performed transcriptomic profiling and 16S rRNA sequencing to investigate the relationships between mucosal gene expression and microbial composition with ICI responses and gastrointestinal immune-related adverse events (GI irAEs). In responders, genes related to DNA repair and cell cycle signatures were enriched in responders whereas signatures related to innate immune response, NFAT and IFN-γ signaling pathways were enriched in nonresponders. Gut microbial composition revealed an association between moderate GI irAE and favorable response to ICI therapy. Favorable therapeutic responses to ICI and GI irAE treatments were associated with taxa classified as Enterobacteriaceae and were related to ribonucleoprotein complex biogenesis, cytokine-mediated signaling pathway, tRNA metabolic process, and ribonucleoprotein complex assembly in the colon. These findings open new perspectives for improving the efficacy and safety of cancer immunotherapy.
  • Masaya Yotsukura; Noriko Motoi; Akihiko Yoshida; Yukihiro Yoshida; Kazuo Nakagawa; Shun-Ichi Watanabe
    Pathology international 2021年07月 
    We describe a rare case of malignant pleural mesothelioma (MPM) that developed squamous differentiation. MPM can present various patterns of histology, but squamous differentiation has not been reported in any surgically resected cases to date. The patient was a 50-year-old female without smoking habit who had right MPM and underwent pleurectomy/decortication after chemotherapy. Pathological examination of the surgical specimen found that the MPM contained squamous cancer cells with apparent keratinization close to the tubulopapillary epithelioid tumor cells. Squamous differentiation was recognized close to the mesothelial proliferation, and the topographical origin of the tumor could not be recognized in the lung. The tubulopapillary tumor cells were positive for cytokeratin 5/6, Wilms tumor-1, and calretinin, and negative for thyroid transcription factor-1 (TTF-1), claudin-4, and p40. Squamous cells were positive for cytokeratin 5/6 and p40, and negative for Wilms tumor-1, calretinin, and TTF-1. Loss of BRCA1 associated protein-1 (BAP1) was observed in both the tubulopapillary and squamous tumor cells. Based on the loss of BAP1 and no history of smoking, we diagnosed this case as a rare differentiation of biphasic-type MPM into squamous cell carcinoma.
  • Esuteru Hirokawa; Satomi Watanabe; Kazuko Sakai; Masayuki Takeda; Chihiro Sato; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    Thoracic Cancer 12 16 2283 - 2287 2021年07月 
    Epidermal growth factor receptor (EGFR) kinase domain duplication (KDD) has been identified as an oncogenic driver in 0.05% to 0.14% of non-small cell lung cancer (NSCLC) patients. However, little is known of the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for such patients. Here, we report the case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18-25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib. As far as we are aware, this is the first report of EGFR-TKI efficacy for carcinomatous meningitis in a NSCLC patient harboring EGFR-KDD.
  • Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kimiteru Ito; Hirokazu Watanabe; Tetsuo Narita; Shun-Ichi Watanabe; Masaya Yotsukura; Noriko Motoi; Yasushi Yatabe
    The Journal of thoracic and cardiovascular surgery 2021年07月 
    OBJECTIVE: This retrospective study examined whether adding the maximum standardized uptake value of a primary tumor to the consolidation-to-tumor ratio from a high-resolution computed tomography scan can improve the predictive accuracy for pathological noninvasive lung cancer and lead to better patient selection for sublobar resection. METHODS: We included 926 patients with clinical stage IA non-small cell lung cancer. Pathological noninvasive cancer (n = 515) was defined as any case without lymphatic invasion, vascular invasion, or lymph node metastasis. The prediction accuracies of maximum standardized uptake value and consolidation-to-tumor ratio were evaluated using receiver operating characteristic curves and area under the curve. RESULTS: For consolidation-to-tumor ratio or maximum standardized uptake value alone, the area under the curves were 0.733 (95% confidence interval, 0.708-0.758) and 0.842 (95% confidence interval, 0.816-0.866), respectively. When the consolidation-to-tumor ratio and maximum standardized uptake value were combined, the area under the curve was 0.854 (95% confidence interval, 0.829-0.876). However, to obtain a predictive specificity of 97%, sensitivity needed to be 42.5% for the consolidation-to-tumor ratio, 38.3% for the maximum standardized uptake value, and 45.0% for these 2 in combination. CONCLUSIONS: Our results suggest that despite the high area under the curve for maximum standardized uptake value, caution is needed when using maximum standardized uptake value to select candidates for sublobar resection. We found that a low maximum standardized uptake value did not mean the tumor was a pathological noninvasive lung cancer. Therefore, using consolidation-to-tumor ratios from high-resolution computed tomography to decide whether sublobar resection is appropriate for patients with clinical stage IA non-small cell lung cancer is better than using maximum standardized uptake value when setting specificity to a conservative 97% for predicting pathological noninvasive lung cancer.
  • Hiroaki Akamatsu; Shunsuke Teraoka; Hidetoshi Hayashi; Daichi Fujimoto; Atsushi Hayata; Koji Haratani; Yuichi Ozawa; Takeshi Yoshida; Tsutomu Iwasa; Toshio Shimokawa; Keisuke Tomii; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    JTO clinical and research reports 2 7 100184 - 100184 2021年07月 
    Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1-3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%-72.2%). Median PFS was 4.0 months (95% CI: 2.8-7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3-21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.
  • Ryoji Kato; Hidetoshi Hayashi; Kazuko Sakai; Shinichiro Suzuki; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Yoshikane Nonagase; Kaoru Tanaka; Takeshi Yoshida; Masayuki Takeda; Kimio Yonesaka; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    International Journal of Clinical Oncology 26 9 1628 - 1639 2021年06月 
    BACKGROUND: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). METHODS: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance. RESULTS: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib. CONCLUSIONS: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
  • 胸腔原発巨大Ewing肉腫の1切除例
    岡内 義隆; 須田 健一; 宗 淳一; 西野 将矢; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉; 田中 薫; 中川 和彦
    肺癌 61 3 238 - 238 (NPO)日本肺癌学会 2021年06月
  • Timothy A Yap; Kazuhiko Nakagawa; Nobukazu Fujimoto; Kozo Kuribayashi; Tormod Kyrre Guren; Luana Calabrò; Ronnie Shapira-Frommer; Bo Gao; Steven Kao; Ignacio Matos; David Planchard; Arkendu Chatterjee; Fan Jin; Kevin Norwood; Hedy L Kindler
    The Lancet. Respiratory medicine 9 6 613 - 621 2021年06月 
    BACKGROUND: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. METHODS: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. INTERPRETATION: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
  • Kazuhiko Nakagawa; Takashi Kijima; Morihito Okada; Masahiro Morise; Motoyasu Kato; Katsuya Hirano; Nobukazu Fujimoto; Mitsuhiro Takenoyama; Hiroshi Yokouchi; Yuichiro Ohe; Toyoaki Hida; Keisuke Aoe; Takumi Kishimoto; Masato Hirokawa; Hironori Matsuki; Yutaro Kaneko; Taketo Yamada; Chikao Morimoto; Masayuki Takeda
    JTO clinical and research reports 2 6 100178 - 100178 2021年06月 
    Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.
  • Kazuto Nishio; Takashi Seto; Makoto Nishio; Martin Reck; Edward B Garon; Kazuko Sakai; Koichi Goto; Terufumi Kato; Yoichi Nakanishi; Toshiaki Takahashi; Nobuyuki Yamamoto; Katsuyuki Kiura; Yuichiro Ohe; Tomohide Tamura; Carla Visseren-Grul; Bente Frimodt-Moller; Rebecca R Hozak; Sameera R Wijayawardana; Annamaria Zimmermann; Gosuke Homma; Sotaro Enatsu; Kazuhiko Nakagawa
    JTO clinical and research reports 2 6 100171 - 100171 2021年06月 
    Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.
  • がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)
    松岡 弘道; 鶴谷 純司; 千葉 康敬; 藤田 至彦; 酒井 清裕; 吉田 健史; 大武 陽一; 名倉 美樹; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 16 Suppl. S217 - S217 (NPO)日本緩和医療学会 2021年06月
  • Hitomi Sakai; Hisato Kawakami; Takeshi Teramura; Yuta Onodera; Elizabeth Somers; Keiji Furuuchi; Toshimitsu Uenaka; Ryoji Kato; Kazuhiko Nakagawa
    Clinical and translational medicine 11 6 e454  2021年06月 
    BACKGROUND: The main function of folate receptor α (FOLRα) has been considered to mediate intracellular folate uptake and induce tumor cell proliferation. Given the broad spectrum of expression among malignant tumors, including gastric cancer (GC) but not in normal tissue, FOLRα represents an attractive target for tumor-selective drug delivery. However, the efficacy of anti-FOLRα monoclonal antibodies (mAbs) has not been proved so far, with the reason for this failure remaining unclear, raising the need for a better understanding of FOLRα function. METHODS: The distribution of FOLRα in GC cells was evaluated by immunohistochemistry. The impacts of FOLRα expression on the survival of GC patients and GC cell lines were examined with the Gene Expression Omnibus database and by siRNA of FOLRα. RNA-sequencing and Microarray analysis was conducted to identify the function of FOLRα. Proteins that interact with FOLRα were identified with shotgun LC-MS/MS. The antitumor efficacy of the anti-FOLRα mAb farletuzumab as well as the antibody-drug conjugate (ADC) consists of the farletuzumab and the tublin-depolymerizing agent eribulin (MORAb-202) was evaluated both in vitro and in vivo. RESULTS: FOLRα was detected both at the cell membrane and in the cytoplasm. Shorter overall survival was associated with FOLRα expression in GC patients, whereas reduction of FOLRα attenuated cell proliferation without inducing cell death in GC cell lines. Transcriptomic and proteomic examinations revealed that the FOLRα-expressing cancer cells possess a mechanism of chemotherapy resistance supported by MDM2, and FOLRα indirectly regulates it through a chaperone protein prohibitin2 (PHB2). Although reduction of FOLRα brought about vulnerability for oxaliplatin by diminishing MDM2 expression, farletuzumab did not suppress the MDM2-mediated chemoresistance and cell proliferation in GC cells. On the other hand, MORAb-202 showed significant antitumor efficacy. CONCLUSIONS: The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα-expressing tumor.
  • がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)
    松岡 弘道; 鶴谷 純司; 千葉 康敬; 藤田 至彦; 酒井 清裕; 吉田 健史; 大武 陽一; 名倉 美樹; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 16 Suppl. S217 - S217 (NPO)日本緩和医療学会 2021年06月
  • Osamu Nishiyama; Shigeki Shimizu; Koji Haratani; Kosuke Isomoto; Junko Tanizaki; Hidetoshi Hayashi; Ryo Yamazaki; Takashi Oomori; Yusaku Nishikawa; Akiko Sano; Kazuhiko Nakagawa; Yuji Tohda
    BMC pulmonary medicine 21 1 155 - 155 2021年05月 
    BACKGROUND: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition. PATIENTS AND METHODS: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed. RESULTS: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes. CONCLUSION: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.
  • Masaya Yotsukura; Hisao Asamura; Noriko Motoi; Jumpei Kashima; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 8 1312 - 1320 2021年04月 
    INTRODUCTION: The WHO classification of lung tumors defines adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) as cancers with no or limited histologic invasive components. The probability of patients with AIS or MIA being recurrence free for 5 years postoperatively has been found to be 100%. This study aimed to analyze the prognosis of patients with AIS or MIA after more than 5 postoperative years. METHODS: We reviewed the pathologic findings of 4768 patients who underwent resection for lung cancer between 1998 and 2010. Of these, 524 patients with curative resection for AIS (207 cases, 39.5%) and MIA (317 cases, 60.5%) were included. Postoperative recurrence, survival, and development of secondary primary lung cancer (SPLC) were analyzed. RESULTS: Of the included patients, 342 (65.3%) were of female sex, 333 (63.5%) were nonsmokers, and 229 (43.7%) underwent sublobar resection. Average pathologic total tumor diameter was 15.2 plus or minus 5.5 mm. Median postoperative follow-up period was 100 months (range: 1-237). No recurrence of lung cancer was observed for either AIS or MIA cases. Estimated 10-year postoperative disease-specific survival rates were 100% and 100% (p = 0.72), and overall survival rates were 95.3% and 97.8% (p = 0.94) for AIS and MIA cases, respectively. Estimated incidence rates of metachronous SPLC at 10 years after surgery were 5.6% and 7.7% for AIS and MIA, respectively (p = 0.45), and these were not correlated with the EGFR mutation status. CONCLUSIONS: Although the development of metachronous SPLC should be noted, the risk of recurrence is quite low at more than 5 years after resection of AIS and MIA. This finding strengthens the clinical value of distinguishing AIS and MIA from other adenocarcinomas of the lung.
  • Akira Hamada; Junichi Soh; Akito Hata; Kiyoshi Nakamatsu; Mototsugu Shimokawa; Yasushi Yatabe; Hiroyuki Oizumi; Masahiro Tsuboi; Hidehito Horinouchi; Ichiro Yoshino; Masayuki Tanahashi; Shinichi Toyooka; Morihito Okada; Hiroyasu Yokomise; Motohiro Yamashita; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Tetsuya Mitsudomi
    Clinical lung cancer S1525-7304 21 596 - 600 2021年04月 [査読有り]
     
    INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
  • 中村 敦; 坂田 晋也; 大坪 孝平; 伊藤 健太郎; 寺岡 俊輔; 松本 直久; 白石 祥理; 原谷 浩司; 田宮 基裕; 池田 慧; 益田 武; 時任 高章; 立原 素子; 高濱 隆幸; 吉田 寿子; 山本 信之; 中川 和彦
    日本呼吸器学会誌 10 増刊 144 - 144 (一社)日本呼吸器学会 2021年04月
  • 中村 敦; 坂田 晋也; 大坪 孝平; 伊藤 健太郎; 寺岡 俊輔; 松本 直久; 白石 祥理; 原谷 浩司; 田宮 基裕; 池田 慧; 益田 武; 時任 高章; 立原 素子; 高濱 隆幸; 吉田 寿子; 山本 信之; 中川 和彦
    日本呼吸器学会誌 10 増刊 144 - 144 (一社)日本呼吸器学会 2021年04月
  • Masayuki Takeda; Takayuki Takahama; Kazuko Sakai; Shigeki Shimizu; Satomi Watanabe; Hisato Kawakami; Kaoru Tanaka; Chihiro Sato; Hidetoshi Hayashi; Yoshikane Nonagase; Kimio Yonesaka; Naoki Takegawa; Tatsuya Okuno; Takeshi Yoshida; Soichi Fumita; Shinichiro Suzuki; Koji Haratani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Hisashi Handa; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    The oncologist 26 4 e588-e596  2021年04月 
    BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
  • Yoshitaka Zenke; Masahiro Tsuboi; Yasutaka Chiba; Kayoko Tsujino; Miyako Satouchi; Kenji Sawa; Junichi Shimizu; Haruko Daga; Daichi Fujimoto; Masahide Mori; Takuya Aoki; Toshiyuki Sawa; Shota Omori; Hideo Saka; Yasuo Iwamoto; Motoyasu Okuno; Tomonori Hirashima; Kosuke Kashiwabara; Motoko Tachihara; Nobuyuki Ymamoto; Kazuhiko Nakagawa
    JAMA oncology 7 6 904 - 909 2021年03月 
    Importance: Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non-small-cell lung cancer. Objective: To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT. Design, Setting, and Participants: This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non-small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019. Interventions: A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation. Main Outcomes and Measures: The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT. Results: From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report. Conclusion and Relevance: In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT. Trial Registration: UMIN Clinical Trial Registry: UMIN000030811.
  • 赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    和歌山医学 72 1 41 - 41 和歌山医学会 2021年03月
  • 【病気とくすり2021 基礎と実践Expert's Guide】病原微生物・悪性新生物とくすり 悪性腫瘍 肺癌
    磯本 晃佑; 武田 真幸; 中川 和彦
    薬局 72 4 2124 - 2128 (株)南山堂 2021年03月
  • Nobukazu Fujimoto; Morihito Okada; Takashi Kijima; Keisuke Aoe; Terufumi Kato; Kazuhiko Nakagawa; Yuichiro Takeda; Toyoaki Hida; Kuninobu Kanai; Jun Hirano; Yuichiro Ohe
    JTO clinical and research reports 2 3 100135 - 100135 2021年03月 
    Introduction: We examined the long-term efficacy and safety of nivolumab, a human monoclonal antibody that inhibits interactions between the programmed cell death protein-1 receptor and its ligands (programmed death-ligand 1 and programmed death-ligand 2), in Japanese patients with malignant pleural mesothelioma (MPM). Methods: Japanese patients with previously treated MPM (one or two regimens) were enrolled in a single-arm, phase 2 study and received nivolumab intravenously 240 mg every 2 weeks until progressive disease or unacceptable toxicity. The primary end point was the centrally assessed objective response rate. Other end points included overall survival (OS), progression-free survival (PFS), treatment-related adverse events, and patient-reported outcomes (Lung Cancer Symptom Scale for mesothelioma and EuroQOL visual analog scale). Patient enrollment started on June 16, 2016. Here, we report 3-year follow-up data (cutoff date: November 12, 2019). Results: Thirty-four patients were enrolled. The centrally assessed objective response rate was previously reported (29.4%). The 2- and 3-year OS rates were 35.3% and 23.5%, respectively, and the corresponding PFS rates were 17.0% and 12.7%. Median OS and PFS were 17.3 and 5.9 months, respectively. Eight patients were alive at 3 years of follow-up. Nivolumab was well tolerated and no new safety signals were found. The patient-reported outcomes were maintained without marked deteriorations during the study. Conclusions: Our results reveal clinically relevant long-term efficacy and safety of nivolumab for the treatment of MPM.
  • James Chih-Hsin Yang; Tony S K Mok; Shun Lu; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yuan-Kai Shi; Li Zhang; Ross A Soo; Satoshi Morita; Tomohide Tamura
    JTO clinical and research reports 2 3 100142 - 100142 2021年03月 
    Introduction: Despite recent advances in NSCLC treatment, specific data on the elderly population remain limited. In this post hoc subgroup analysis of the East Asia S-1 Trial in Lung Cancer (EAST-LC) trial, we compared S-1 and docetaxel (DTX) in patients aged 70 years old and above with pretreated advanced NSCLC. Methods: Patients were randomly assigned (1:1) to receive S-1 (orally, twice daily on d 1-28 of a 6-wk cycle) or DTX (intravenously, on d 1 of a 3-wk cycle). The initial S-1 dose was 80, 100, or 120 mg/day on the basis of body surface area, and the DTX doses were 60 mg/m2 (Japan) or 75 mg/m2 (outside Japan). The primary end point was overall survival, and secondary end points included progression-free survival, response rate, quality of life (QOL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30, and safety. Results: Among 189 patients aged 70 years and above assessed as the full analysis set, baseline characteristics were generally similar between treatment arms. The median overall survival was 14.7 (S-1) versus 12.1 months (DTX); the hazard ratio was equal to 0.76, with a 95% confidence interval (CI) of 0.54-1.07. The median progression-free survival was similar in both arms (both 4.1 mo, hazard ratio = 0.84, 95% CI: 0.60-1.18); and the response rate was 12.9% (S-1) and 14.0% (DTX). The adjusted mean QOL score difference (S-1-DTX until wk 48) was 7.41 (95% CI: 0.37-14.46). Safety profiles were generally consistent with those of the overall EAST-LC population. Conclusions: S-1 revealed comparable efficacy, safety, and QOL versus DTX in pretreated elderly patients with advanced NSCLC. Results were consistent with the overall EAST-LC data.
  • Jean Paty; Rickard Sandin; Arlene Reisman; Yi-Long Wu; Maria Rita Migliorino; Xiangdong Zhou; Ying Cheng; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Jesús Corral; Adam Płużański; Rolf Linke; Oren Meyers; Tony S Mok
    Future oncology (London, England) 17 7 783 - 794 2021年03月 
    Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.
  • Makoto Nishio; Tatsuya Yoshida; Toru Kumagai; Toyoaki Hida; Ryo Toyozawa; Tadasuke Shimokawaji; Koichi Goto; Kazuhiko Nakagawa; Yuichiro Ohe; Takashi Seto; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Nobuyuki Yamamoto
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 3 452 - 463 2021年03月 
    INTRODUCTION: This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs). METHODS: This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)-assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%-49%) with median duration of response of 11.8 months (95% CI: 5.5-16.4). Disease control rate was 79% (95% CI: 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7-9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations. CONCLUSIONS: Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).
  • Ryoji Kato; Koji Haratani; Hidetoshi Hayashi; Kazuko Sakai; Hitomi Sakai; Hisato Kawakami; Kaoru Tanaka; Masayuki Takeda; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    British journal of cancer 124 5 914 - 924 2021年03月 
    BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8+ T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8+ T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8+ T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
  • Akira Ono; Haruyasu Murakami; Takashi Seto; Toshio Shimizu; Sawori Watanabe; Shigeru Takeshita; Kentaro Takeda; Junko Toyoshima; Itsuro Nagase; Erkut Bahceci; Maiko Morishita; Satoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa
    Drugs in R&D 21 1 65 - 78 2021年03月 
    BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.
  • Hiroaki Akamatsu; Yukihiro Toi; Hidetoshi Hayashi; Daichi Fujimoto; Motoko Tachihara; Naoki Furuya; Sakiko Otani; Junichi Shimizu; Nobuyuki Katakami; Koichi Azuma; Naoko Miura; Kazumi Nishino; Satoshi Hara; Shunsuke Teraoka; Satoshi Morita; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    JAMA oncology 7 3 386 - 394 2021年03月 
    Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. Design, Setting, and Participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). Conclusions and Relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.
  • Kentaro Ito; Takeharu Yamanaka; Hidetoshi Hayashi; Yoshihiro Hattori; Kazumi Nishino; Haruki Kobayashi; Yuko Oya; Toshihide Yokoyama; Takashi Seto; Koichi Azuma; Tomoya Fukui; Toshiyuki Kozuki; Atsushi Nakamura; Kentaro Tanaka; Katsuya Hirano; Takashi Yokoi; Haruko Daga; Shinya Sakata; Daichi Fujimoto; Masahide Mori; Ken Maeno; Takuya Aoki; Atsuhisa Tamura; Satoru Miura; Satoshi Watanabe; Hiroaki Akamatsu; Osamu Hataji; Kensuke Suzuki; Shigeto Hontsu; Koji Azuma; Akihiro Bessho; Akihito Kubo; Motoyasu Okuno; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    European journal of cancer (Oxford, England : 1990) 145 183 - 193 2021年03月 
    BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
  • Nobuyuki Yamamoto; Hideyuki Harada; Isamu Okamoto; Noriyuki Masuda; Kazushige Hayakawa; Miyako Satouchi; Toshinori Soejima; Makoto Nishio; Takuyo Kozuka; Koji Takeda; Masahiro Tanaka; Takashi Seto; Tomonari Sasaki; Hiroshi Tsubouchi; Yasuyuki Kakurai; Yasumasa Nishimura; Kazuhiko Nakagawa
    Clinical lung cancer 22 2 134 - 141 2021年03月 
    BACKGROUND: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m2; days 1 and 8, vinorelbine 20 mg/m2). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period. RESULTS: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%. CONCLUSION: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma.
  • Ying Cheng; Tony S Mok; Xiangdong Zhou; Shun Lu; Qing Zhou; Jianying Zhou; Yingying Du; Ping Yu; Xiaoqing Liu; Chengping Hu; You Lu; Yiping Zhang; Ki Hyeong Lee; Kazuhiko Nakagawa; Rolf Linke; Chew Hooi Wong; Yiyun Tang; Fanfan Zhu; Keith D Wilner; Yi-Long Wu
    Lung cancer (Amsterdam, Netherlands) 154 176 - 185 2021年02月 
    OBJECTIVES: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. MATERIALS AND METHODS: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. RESULTS: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively. CONCLUSION: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.
  • Xiuning Le; Monique Nilsson; Jonathan Goldman; Martin Reck; Kazuhiko Nakagawa; Terafumi Kato; Luis Paz Ares; Bente Frimodt-Moller; Katharina Wolff; Carla Visseren-Grul; John V Heymach; Edward B Garon
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 2 205 - 215 2021年02月 
    The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
  • Tony S Mok; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Alka Chawla; Rafael Rosell; Jesus Corral; Maria Rita Migliorino; Adam Pluzanski; Kay Noonan; Yiyun Tang; Malaika Pastel; Keith D Wilner; Yi-Long Wu
    Drugs 81 2 257 - 266 2021年02月 
    BACKGROUND: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. OBJECTIVE: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. PATIENTS AND METHODS: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). RESULTS: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. CONCLUSIONS: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).
  • Hiroaki Kanemura; Masayuki Takeda; Shigeki Shimizu; Kazuhiko Nakagawa
    Thoracic cancer 12 4 549 - 552 2021年02月 
    Capmatinib is a MET tyrosine kinase inhibitor (TKI) that has recently been approved for the treatment of advanced non-small cell lung cancer (NSCLC) positive for skipping mutations of MET exon 14 (METex14). Drug-induced interstitial lung disease (ILD) is a relatively rare, but potentially serious, side effect of TKIs administered for lung cancer treatment. Here we report a case of capmatinib-induced ILD in a patient with NSCLC harboring a METex14 skipping mutation. Capmatinib should be immediately discontinued if ILD is suspected, and treatment with corticosteroid should be considered.
  • Masayuki Takeda; Mototsugu Shimokawa; Atsushi Nakamura; Kaname Nosaki; Yasutaka Watanabe; Terufumi Kato; Daisuke Hayakawa; Hiroshi Tanaka; Toshiaki Takahashi; Yoshihito Kogure; Motoko Tachihara; Daichi Fujimoto; Kakuhiro Yamaguchi; Naohiko Hamaguchi; Isamu Okamoto; Koichi Azuma; Kazuo Hasegawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 22 4 376 - 380 2021年01月 
    Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.
  • Hiroshi Katayama; Junki Mizusawa; Haruhiko Fukuda; Shinichiro Nakamura; Kenich Nakamura; Nagahiro Saijo; Akira Yokoyama; Yuichro Ohe; Tetsu Shinkai; Kazuhiko Nakagawa; Tetsuya Abe; Shigeki Mitsuoka; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Masahiko Ando; Tomohide Tamura; Koji Takeda
    Japanese journal of clinical oncology 51 5 685 - 692 2021年01月 
    OBJECTIVE: Patients' actual age and performance status do not always accurately identify the 'fit elderly' for chemotherapy. This study aimed to determine whether four geriatric assessment tools could predict prognosis. METHODS: This study were analyzed using the data of two randomized phase III trials (JCOG0207 and JCOG0803/WJOG4307L) for elderly patients with advanced non-small cell lung cancer and included all eligible patients who were assessed before treatment with four geriatric assessment tools: the Barthel activities of daily living index, Lawton instrumental activities of daily living scale, Mini-Mental State Examination, and Geriatric Depression Scale-15. Univariable and multivariable analyses for overall survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as strata. RESULTS: This analysis included 330 patients aged 70-74, 75-79 or 80 or more (n = 95/181/54), with a performance status of 0 or 1 (n = 119/211). Patients were divided into three groups based on Mini-Mental State Examination and two groups based on Geriatric Depression Scale, but over 80% of patients had perfect scores for both activities of daily living and instrumental activities of daily living. In overall survival subgroup analyses by GA tool, only Mini-Mental State Examination scores were associated with substantial outcome differences (median survival times: 21.2, 13.5 and 12.2 months for scores 30, 29-24 and ≤23). After adjusting for baseline factors, the Mini-Mental State Examination, sex and performance status were tended to be worse overall survival. CONCLUSION: MMSE scores, performance status and sex, but not chronological age, effectively predicted the prognosis of elderly patients. Further studies should confirm that the Mini-Mental State Examination is useful for determining the indication of chemotherapy in elderly patients with advanced non-small cell lung cancer.
  • Sai-Hong Ignatius Ou; Yutaka Fujiwara; Alice T Shaw; Noboru Yamamoto; Kazuhiko Nakagawa; Frank Fan; Yuki Hao; Yanfei Gao; Pasi A Jänne; Takashi Seto
    JTO clinical and research reports 2 1 100108 - 100108 2021年01月 
    Introduction: Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation. Methods: Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety. Results: A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1-33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4-87.9) with a disease control rate of 100% (70.1-100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7-70.0) with a disease control rate of 88.3% (95% CI: 443.6-97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6-not reached) and 14.2 months (95% CI: 1.5-not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%). Conclusions: Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.
  • Takayasu Kurata; Kazuhiko Nakagawa; Miyako Satouchi; Takashi Seto; Takeshi Sawada; Shirong Han; Masae Homma; Kazuo Noguchi; Naoyuki Nogami
    Cancer treatment and research communications 29 100458 - 100458 2021年 
    INTRODUCTION: Pembrolizumab plus chemotherapy significantly improved outcomes over chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC) in phase 3 international trials. In the phase 1 KEYNOTE-011 study (parts B and C), we evaluated the safety/activity of pembrolizumab plus chemotherapy as first-line treatment in Japanese patients with advanced NSCLC. METHODS: Eligible patients received 4 cycles (every 3 weeks) of pembrolizumab 200 mg plus chemotherapy (cisplatin 75 mg/m2/carboplatin area under the curve [AUC] 5 mg/mL/min and pemetrexed 500 mg/m2 in part B [nonsquamous]; carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2/nab-paclitaxel 100 mg/m2 (weekly) in part C [squamous]), followed by maintenance pembrolizumab (and pemetrexed, part B). The primary endpoint was incidence of dose-limiting toxicities (DLTs) during the first 3 weeks of treatment. Overall response rate (ORR; RECIST v1.1 by central review) was exploratory. RESULTS: In part B (median follow-up, 16.0 months; n = 12) 1 DLT occurred (grade 4 hyponatremia). Grade ≥3 treatment-related adverse events (AEs) occurred in 9 patients (75%). Two patients had grade 5 treatment-related AEs (pneumonitis and interstitial lung disease). In part C (median follow-up, 9.9 months; n = 14), 2 DLTs occurred (both grade 3 febrile neutropenia). Grade ≥3 treatment-related AEs occurred in 11 patients (79%); none were fatal. ORR was 73% in part B and 50% in part C, irrespective of PD-L1 status. CONCLUSION: Safety results show first-line pembrolizumab plus chemotherapy is feasible in Japanese patients with advanced NSCLC. Antitumor activity was observed irrespective of PD-L1 status and was comparable to that in international studies. TRIAL REGISTER: ClinicalTrials.gov, NCT01840579.
  • Kazuko Sakai; Toshiharu Sakurai; Marco A De Velasco; Tomoyuki Nagai; Takaaki Chikugo; Kazuomi Ueshima; Yurie Kura; Takayuki Takahama; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo; Kazuto Nishio
    Frontiers in oncology 11 763468 - 763468 2021年 
    Immune checkpoint inhibitors (ICIs) have become the standard of care for several cancers. However, ICI therapy has also been associated with various immune-related adverse events (irAEs). Clinical manifestations of immune-related colitis resemble those of inflammatory bowel diseases such as ulcerative colitis (UC). The composition of the bowel microflora is thought to influence the development of inflammatory bowel disease and irAE colitis. We profiled the gene expressions and microbe compositions of colonic mucosa from patients with solid cancers receiving anti-PD-L1 antibody treatment; we then compared the expression profiles associated with irAE colitis with those associated with UC. The pathway enrichment analysis revealed functional similarities between inflamed regions of irAE colitis and UC. The common enriched pathways included leukocyte extravasation and immune responses, whereas non-inflamed mucosa from patients with irAE colitis was distinct from patients with UC and was characterized by the recruitment of immune cells. A similarity between the microbiota profiles was also identified. A decreased abundance of Bacteroides species was observed in inflamed regions from both irAE colitis and UC based on a microbiota composition analysis of 16S rDNA sequencing. Pathways associated with molecule transport systems, including fatty acids, were enriched in inflamed and non-inflamed irAE colitis and inflamed UC, similar to Piphillin-inferred KEGG pathways. While UC is characterized by local regions of inflammation, ICI treatment extends to non-inflammatory regions of the colonial mucosa where immune cells are reconstituted. This analysis of the similarity and heterogeneity of irAE colitis and UC provides important information for the management of irAE colitis.
  • Motoko Tachihara; Kayoko Tsujino; Takeaki Ishihara; Hidetoshi Hayashi; Yuki Sato; Takayasu Kurata; Shunichi Sugawara; Isamu Okamoto; Shunsuke Teraoka; Koichi Azuma; Haruko Daga; Masafumi Yamaguchi; Takeshi Kodaira; Miyako Satouchi; Mototsugu Shimokawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer management and research 13 9167 - 9173 2021年 
    Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.
  • A Phase II Study to Assess the Efficacy of Osimertinib in Patients With EGFR Mutation-positive NSCLC Who Developed Isolated CNS Progression (T790M-negative or Unknown) During First- or Second-generation EGFR-TKI or Systemic Disease Progression (T790M-negative) After Treatment With First- or Second-generation EGFR-TKI and Platinum-based Chemotherapy (WJOG12819L)
    Takeda M; Shimokawa M; Nakamura A; Nosaki K; Watanabe Y; Kato T; Hayakawa D; Tanaka H; Takahashi T; Kogure Y; Tachihara M; Fujimoto D; Yamaguchi K; Hamaguchi N; Okamoto I; Azuma K; Hasegawa K; Yamamoto N; Nakagawa; K
    Clin Lung Cancer. 22 4 376 - 380 2021年
  • Tomoya Fukui; Kazuko Sakai; Jiichiro Sasaki; Mikiko Ishihara Kakegawa; Satoshi Igawa; Hisashi Mitsufuji; Masayuki Takeda; Takayuki Takahama; Kazuhiko Nakagawa; Kazuto Nishio; Katsuhiko Naoki
    Cancer biomarkers : section A of Disease markers 31 2 119 - 126 2021年 
    BACKGROUND: The advancement of cancer genomics has allowed for multiplex gene assays using next-generation sequencing (NGS) to be practically implemented, however, a clinical practice system remains to be established. OBJECTIVE: We evaluated the feasibility of clinical sequencing using NGS-based multiplex gene assays between cooperating medical institutions in patients with advanced cancers. METHODS: In this observational study, DNA and RNA samples prepared from existing tumor tissues were subjected to comprehensive genomic profiling using targeted sequencing. RESULTS: From January 2017 to March 2019, 36 samples from 33 patients were assessed. Of all patients, 27 (82%) had lung cancer, with the median age of 50 years (range 38-83). Multiplex gene panel tests were successfully carried out on 35/36 (97%) samples. Potentially actionable gene alterations were identified in 10/30 (33%) samples (3 HER2, 2 KRAS, 2 ALK, 1 PIK3CA, 1 RET, and 1 CDKN2A). In the 6 samples examined for resistant mechanisms, ALK I1171N mutation and MET copy number gain were detected in 2 patients with ALK rearrangement-positive lung cancer. CONCLUSIONS: Clinical sequencing using NGS-based multiplex gene assays between collaborating domestic medical institutions was feasible, with a success rate of > 97%. Overall, clinical sequencing benefits therapeutic decision-making in patients with advanced cancer.
  • Satomi Watanabe; Masayuki Takeda; Tomoyuki Otani; Takeshi Yoshida; Kazuko Sakai; Elizabeth Olek; S Michael Rothenberg; Jennifer Kherani; Pearl P French; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    JCO precision oncology 5 2021年
  • Kenjiro Aogi; Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Keiko Iino; Chiyo K Imamura; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Hirotoshi Iihara; Shoichiro Ohtani; Ayako Okuyama; Keiko Ozawa; Yong-Il Kim; Hidenori Sasaki; Yasuo Shima; Masayuki Takeda; Eijiro Nagasaki; Toshihiko Nishidate; Takahiro Higashi; Kouichi Hirata
    International journal of clinical oncology 26 1 1 - 17 2021年01月 
    Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Toshihide Yokoyama; Junko Tanizaki; Tomohiro Ozaki; Hiroshige Yoshioka; Takayasu Kurata; Yosuke Tamura; Yasuhito Fujisaka; Kaoru Tanaka; Yoshikazu Hasegawa; Keita Kudo; Yasutaka Chiba; Kazuhiko Nakagawa
    The oncologist 26 1 19-e52  2021年01月 
    LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
  • Kazuhiko Nakagawa; Koichi Matsumura; Tayler Scory; Megan S Farris; Kelly A Larkin-Kaiser; Hironori Kikkawa; Jasmina I Ivanova; Keith D Wilner
    Future oncology (London, England) 17 1 103 - 115 2021年01月 
    Background: Five EGFR-tyrosine kinase inhibitors (EGFR TKIs) are currently available in the first-line setting for non-small-cell lung cancer (NSCLC) in Japan. The aim here was to compare the relative efficacy of EGFR TKIs in the Japanese population. Materials & methods: A systematic review identified randomized controlled trials examining the efficacy of first-line EGFR TKIs. A Bayesian network meta-analysis was used to assess these EGFR TKI comparisons for progression-free survival (PFS). Results: A total of seven randomized controlled trials were identified and considered for network meta-analysis. Dacomitinib showed a trend toward improved PFS versus all comparators. Conclusion: Dacomitinib demonstrated a trend toward improved PFS and therefore, should be considered one of the standard first-line therapies for Japanese patients diagnosed with EGFR+ non-small-cell lung cancer.
  • Takashi Kurosaki; Seiichiro Mitani; Kaoru Tanaka; Shinichiro Suzuki; Hiroaki Kanemura; Koji Haratani; Soichi Fumita; Tsutomu Iwasa; Hidetoshi Hayashi; Takeshi Yoshida; Kazuki Ishikawa; Mutsukazu Kitano; Naoki Otsuki; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anti-cancer drugs 32 1 95 - 101 2021年01月 
    Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.
  • Hideo Saka; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Toshiaki Takahashi; Hidehito Horinouchi; Mitsuhiro Takenoyama; Nobuyuki Katakami; Hiroshi Tanaka; Koji Takeda; Miyako Satouchi; Hiroshi Isobe; Makoto Maemondo; Koichi Goto; Tomonori Hirashima; Koichi Minato; Nobumichi Yada; Tomohide Tamura
    Japanese journal of clinical oncology 51 1 106 - 113 2021年01月 
    BACKGROUND: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. METHODS: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. RESULTS: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%). CONCLUSIONS: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.
  • Kazuko Sakai; Takayuki Takahama; Mototsugu Shimokawa; Koichi Azuma; Masayuki Takeda; Terufumi Kato; Haruko Daga; Isamu Okamoto; Hiroaki Akamatsu; Shunsuke Teraoka; Akira Ono; Tatsuo Ohira; Toshihide Yokoyama; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Kazuto Nishio
    Molecular oncology 15 1 126 - 137 2021年01月 
    The WJOG8815L phase II clinical study involves patients with non-small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third-generation EGFR-TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR-TKI-sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing-and T790M-EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation-positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression-free survival were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
  • Kazuko Sakai; Masahiro Tsuboi; Hirotsugu Kenmotsu; Takeharu Yamanaka; Toshiaki Takahashi; Koichi Goto; Haruko Daga; Tatsuo Ohira; Tsuyoshi Ueno; Tadashi Aoki; Kazuhiko Nakagawa; Koji Yamazaki; Yukio Hosomi; Koji Kawaguchi; Norihito Okumura; Yuichi Takiguchi; Akimasa Sekine; Tomohiro Haruki; Hiromasa Yamamoto; Yuki Sato; Hiroaki Akamatsu; Takashi Seto; Sho Saeki; Kenji Sugio; Makoto Nishio; Kazunori Okabe; Nobuyuki Yamamoto; Kazuto Nishio
    Cancer science 112 1 388 - 396 2021年01月 
    The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
  • Ryota Shibaki; Hiroaki Akamatsu; Terufumi Kato; Kazumi Nishino; Morihito Okada; Tetsuya Mitsudomi; Kazushige Wakuda; Kenichi Yoshimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Therapeutic advances in medical oncology 13 1758835920987647 - 1758835920987647 2021年 
    Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II-IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study. Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with EGFR mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
  • Hirotsugu Kenmotsu; Seiji Niho; Masahiro Tsuboi; Masashi Wakabayashi; Genichiro Ishii; Kazuo Nakagawa; Haruko Daga; Hiroshi Tanaka; Haruhiro Saito; Keiju Aokage; Toshiaki Takahashi; Toshi Menju; Takashi Kasai; Ichiro Yoshino; Koichi Minato; Morihito Okada; Junko Eba; Hisao Asamura; Yuichiro Ohe; Shun-Ichi Watanabe
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 36 4292 - 4301 2020年12月 
    PURPOSE: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.
  • Kenta Tsunekuni; Hisato Kawakami; Kazuaki Matsuoka; Hideki Nagase; Seiichiro Mitani; Kazuhiko Nakagawa
    Journal of clinical medicine 9 12 2020年12月 
    Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.
  • Miyako Satouchi; Kaname Nosaki; Toshiaki Takahashi; Kazuhiko Nakagawa; Keisuke Aoe; Takayasu Kurata; Akimasa Sekine; Atsushi Horiike; Tatsuro Fukuhara; Shunichi Sugawara; Shigeki Umemura; Hideo Saka; Isamu Okamoto; Nobuyuki Yamamoto; Hiroshi Sakai; Kazuma Kishi; Nobuyuki Katakami; Hidehito Horinouchi; Toyoaki Hida; Hiroaki Okamoto; Shinji Atagi; Tatsuo Ohira; Shi Rong Han; Kazuo Noguchi; Victoria Ebiana; Katsuyuki Hotta
    Cancer science 111 12 4480 - 4489 2020年12月 
    This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
  • Makoto Nishio; Takashi Seto; Martin Reck; Edward B Garon; Chao-Hua Chiu; Kiyotaka Yoh; Fumio Imamura; Keunchil Park; Jin-Yuan Shih; Carla Visseren-Grul; Bente Frimodt-Moller; Annamaria Zimmermann; Gosuke Homma; Sotaro Enatsu; Kazuhiko Nakagawa
    Cancer science 111 12 4510 - 4525 2020年12月 
    In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.
  • Sarina A Piha-Paul; Do-Youn Oh; Makoto Ueno; David Malka; Hyun Cheol Chung; Adnan Nagrial; Robin K Kelley; Willeke Ros; Antoine Italiano; Kazuhiko Nakagawa; Hope S Rugo; Filippo de Braud; Andrea Iolanda Varga; Aaron Hansen; Hui Wang; Suba Krishnan; Kevin G Norwood; Toshihiko Doi
    International journal of cancer 147 8 2190 - 2198 2020年10月 
    We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.
  • Hidetoshi Hayashi; Yuichi Takiguchi; Hironobu Minami; Kohei Akiyoshi; Yoshihiko Segawa; Hiroki Ueda; Yasuo Iwamoto; Chihiro Kondoh; Koji Matsumoto; Shin Takahashi; Hisateru Yasui; Toshiyuki Sawa; Yusuke Onozawa; Yasutaka Chiba; Yosuke Togashi; Yoshihiko Fujita; Kazuko Sakai; Shuta Tomida; Kazuto Nishio; Kazuhiko Nakagawa
    JAMA oncology 6 12 1931 - 1938 2020年10月 
    Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.
  • 当院におけるアベマシクリブの使用経験
    黒崎 隆; 岩朝 勤; 渡邉 諭美; 酒井 瞳; 橋本 幸彦; 菰池 佳史; 中川 和彦
    日本乳癌学会総会プログラム抄録集 28回 422 - 422 (一社)日本乳癌学会 2020年10月
  • EGFR陽性の切除不能・局所進行NSCLCに対するゲフィチニブ+胸部放射線同時併用の第II相試験(WJOG6911L)
    赤松 弘朗; 村上 晴泰; 原田 英幸; 林 秀敏; 駄賀 晴子; 長谷川 喜一; 金 永学; 加藤 晃史; 徳永 章二; 西村 恭昌; 山本 信之; 中川 和彦
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • EGFR-TKI増悪後のEGFR T790M陽性進行肺腺癌に対するオシメルチニブ+/-ベバシズマブの第2相試験(WJOG8715L)
    赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 立原 素子; 古屋 直樹; 大谷 咲子; 清水 淳市; 片上 信之; 東 公一; 三浦 奈保子; 西野 和美; 原 聡志; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • 分子標的治療・臨床試験 脳転移(放射線未治療)のあるNSCLCに対するOsimertinibの第II相試験 OCEAN study
    土屋 裕子; 山口 博之; 和久田 一茂; 福田 実; 釼持 広知; 知花 賢治; 三浦 理; 中川 和彦; 山本 信之; 杉尾 賢二
    日本癌治療学会学術集会抄録集 58回 WS22 - 4 (一社)日本癌治療学会 2020年10月
  • 伊藤 健太郎; 和久田 一茂; 山口 博之; 釼持 広知; 福田 実; 三浦 理; 知花 賢治; 中川 和彦; 山本 信之; 杉尾 賢二
    肺癌 60 6 563 - 563 (NPO)日本肺癌学会 2020年10月
  • 小澤 雄一; 山中 竹春; 伊藤 健太郎; 釼持 広知; 大江 裕一郎; 木浦 勝行; 菅原 俊一; 中川 和彦; 吉野 一郎; 弦間 昭彦; 山本 信之
    肺癌 60 6 641 - 641 (NPO)日本肺癌学会 2020年10月
  • 武田 真幸; 下川 元継; 中村 敦; 野崎 要; 渡辺 恭孝; 加藤 晃史; 早川 乃介; 田中 洋史; 高橋 利明; 沖 昌英; 立原 素子; 藤本 大智; 山口 覚博; 野上 尚之; 岡本 勇; 東 公一; 長谷川 一男; 山本 信之; 中川 和彦
    肺癌 60 6 579 - 579 (NPO)日本肺癌学会 2020年10月
  • 非扁平非小細胞肺癌に対するPem+CisとVnr+Cisの比較第III相試験における腫瘍変異負荷の意義(JIPANG-TR)
    坂井 和子; 坪井 正博; 釼持 広知; 後藤 功一; 大平 達夫; 中川 和彦; 細見 幸生; 滝口 裕一; 山本 寛斉; 赤松 弘朗; 佐伯 祥; 杉尾 賢二; 山本 信之; 西尾 和人
    日本癌学会総会記事 79回 OJ18 - 5 2020年10月
  • 鈴木 慎一郎; 原谷 浩司; 林 秀敏; 加藤 了資; 川中 雄介; 谷崎 潤子; 尾崎 智博; 黒崎 隆; 長谷川 喜一; 岡部 崇記; 明石 雄策; 千葉 康敬; 伊藤 彰彦; 中川 和彦
    肺癌 60 6 635 - 635 (NPO)日本肺癌学会 2020年10月
  • 豊澤 亮; 西尾 誠人; 吉田 達哉; 熊谷 融; 樋田 豊明; 下川路 伊亮; 後藤 功一; 大江 裕一郎; 瀬戸 貴司; 山本 信之; 工藤 健太郎; 朝戸 臣敬; Zhang Pingkuan; 中川 和彦
    肺癌 60 6 563 - 563 2020年10月
  • 金村 宙昌; 林 秀敏; 磯本 晃佑; 鈴木 慎一郎; 田中 薫; 吉田 健史; 武田 真幸; 中川 和彦
    肺癌 60 6 476 - 476 (NPO)日本肺癌学会 2020年10月
  • EGFR陽性の切除不能・局所進行NSCLCに対するゲフィチニブ+胸部放射線同時併用の第II相試験(WJOG6911L)
    赤松 弘朗; 村上 晴泰; 原田 英幸; 林 秀敏; 駄賀 晴子; 長谷川 喜一; 金 永学; 加藤 晃史; 徳永 章二; 西村 恭昌; 山本 信之; 中川 和彦
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • EGFR-TKI増悪後のEGFR T790M陽性進行肺腺癌に対するオシメルチニブ+/-ベバシズマブの第2相試験(WJOG8715L)
    赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 立原 素子; 古屋 直樹; 大谷 咲子; 清水 淳市; 片上 信之; 東 公一; 三浦 奈保子; 西野 和美; 原 聡志; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • 鈴木 慎一郎; 原谷 浩司; 林 秀敏; 加藤 了資; 川中 雄介; 谷崎 潤子; 尾崎 智博; 黒崎 隆; 長谷川 喜一; 岡部 崇記; 明石 雄策; 千葉 康敬; 伊藤 彰彦; 中川 和彦
    肺癌 60 6 635 - 635 (NPO)日本肺癌学会 2020年10月
  • 岩間 映二; 坂井 和子; 高濱 隆幸; 下川 元継; 東 公一; 武田 真幸; 加藤 晃史; 駄賀 晴子; 寺岡 俊輔; 高橋 利明; 大平 達夫; 横山 俊秀; 山本 信之; 中川 和彦; 西尾 和人
    肺癌 60 6 630 - 630 (NPO)日本肺癌学会 2020年10月
  • 非扁平非小細胞肺癌に対するPem+CisとVnr+Cisの比較第III相試験における腫瘍変異負荷の意義(JIPANG-TR)
    坂井 和子; 坪井 正博; 釼持 広知; 後藤 功一; 大平 達夫; 中川 和彦; 細見 幸生; 滝口 裕一; 山本 寛斉; 赤松 弘朗; 佐伯 祥; 杉尾 賢二; 山本 信之; 西尾 和人
    日本癌学会総会記事 79回 OJ18 - 5 2020年10月
  • Hitomi Sakai; Atsuko Koyama; Kaoru Tanaka; Satomi Watanabe; Miki Nakura; Toshiko Yasuda; Makiko Hayashi; Miyuki Endo; Kazuhiko Nakagawa
    Asia-Pacific journal of clinical oncology 16 5 e185-e191  2020年10月 
    PURPOSE: Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS: We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS: Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P < .05 for both), and younger participants were found to have higher full-scale scores in multivariate analysis (P < .05). CONCLUSIONS: DAS59 scores had a wide distribution, suggesting that psychological distress due to appearance changes showed large individual differences. Young and female patients tended to have high DAS59 full-scale scores, but some older and male patients also had high scores. Basic information regarding appearance changes should be provided to all patients before initiating cancer treatment. Both information provision prior to treatment and care at the time of actual appearance changes are important, and should be handled through a multidisciplinary approach.
  • Kiyotaka Yoh; Shinji Atagi; Martin Reck; Edward B Garon; Santiago Ponce Aix; Denis Moro-Sibilot; Katherine B Winfree; Bente Frimodt-Moller; Annamaria Zimmermann; Carla Visseren-Grul; Kazuhiko Nakagawa
    Current medical research and opinion 36 10 1667 - 1675 2020年10月 
    OBJECTIVE: In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4 months; HR = 0.59, 95% CI = 0.46-0.76; p < .0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes. METHODS: Patients received oral erlotinib (150 mg daily) plus intravenous ramucirumab (10 mg/kg) or placebo Q2W until progressive disease or unacceptable toxicity. Patients completed the Lung Cancer Symptom Scale (LCSS) and EQ-5D questionnaires at baseline and every other cycle. Analyses included time to deterioration (TtD) for LCSS via Kaplan-Meier method and Cox models and changes from baseline using mixed-model repeated-measures regression analysis. RESULTS: Overall patient compliance for LCSS and EQ-5D was >95%. TtD did not differ between treatment arms for LCSS Total Score (HR = 0.962, 95% CI = 0.690-1.343) and Average Symptom Burden Index (HR = 1.012, 95% CI = 0.732-1.400). TtD of individual LCSS items (appetite loss, fatigue, cough, shortness of breath, pain, symptom distress, difficulties with daily activities, quality of life) indicated no difference between arms; however, patient-reported blood in sputum was worse for ramucirumab/erlotinib (HR = 1.987, 95% CI = 1.206-3.275). Results of LCSS mean changes from baseline were consistent with TtD, indicating no significant differences between treatment arms except for blood in sputum. Mean changes from baseline in EQ-5D index score (p = .94) and visual analogue scale (p = .95) revealed no overall differences in health status between treatment arms. CONCLUSIONS: Patients' overall quality of life and symptom burden did not differ with the addition of ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC.
  • Aurélien Marabelle; Marwan Fakih; Juanita Lopez; Manisha Shah; Ronnie Shapira-Frommer; Kazuhiko Nakagawa; Hyun Cheol Chung; Hedy L Kindler; Jose A Lopez-Martin; Wilson H Miller Jr; Antoine Italiano; Steven Kao; Sarina A Piha-Paul; Jean-Pierre Delord; Robert R McWilliams; David A Fabrizio; Deepti Aurora-Garg; Lei Xu; Fan Jin; Kevin Norwood; Yung-Jue Bang
    The Lancet. Oncology 21 10 1353 - 1365 2020年10月 
    BACKGROUND: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. METHODS: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. FINDINGS: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. INTERPRETATION: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
  • Yoshimasa Shiraishi; Junji Kishimoto; Kentaro Tanaka; Shunichi Sugawara; Haruko Daga; Katsuya Hirano; Koichi Azuma; Osamu Hataji; Hidetoshi Hayashi; Motoko Tachihara; Tetsuya Mitsudomi; Takashi Seto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Isamu Okamoto
    Clinical lung cancer 21 5 472 - 476 2020年09月 [査読有り]
     
    BACKGROUND: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC. PATIENTS AND METHODS: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival. CONCLUSION: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.
  • Kaoru Tanaka; Satoshi Morita; Masahiko Ando; Takuma Yokoyama; Atsushi Nakamura; Hiroshige Yoshioka; Takashi Ishiguro; Satoru Miura; Ryo Toyozawa; Tetsuya Oguri; Haruko Daga; Ryo Ko; Akihiro Bessho; Motoko Tachihara; Yasuo Iwamoto; Katsuya Hirano; Yoichi Nakanishi; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Isamu Okamoto
    Cancer 126 16 3648 - 3656 2020年08月 
    BACKGROUND: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival. RESULTS: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe. CONCLUSIONS: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.
  • Masaya Yotsukura; Hisao Asamura; Shigeki Suzuki; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Noriko Motoi
    Data in brief 31 105785 - 105785 2020年08月 [査読有り]
     
    This article presents supplementary data for the research article by Yotsukura et al. entitled "Prognostic impact of cancer-associated active fibroblasts and invasive architectural patterns on early-stage lung adenocarcinoma" [1], which presented the postoperative prognosis for early-stage lung adenocarcinoma categorized according to histological findings. We included data of 1,032 resected cases of lung adenocarcinoma, which consisted of pathological stage IA invasive cancer and adenocarcinoma in situ resected at National Cancer Center Hospital, Tokyo, Japan, between 2007 and 2012. A pathological review was performed to assess total tumor size, size of invasion, histological subtype, lymphovascular invasion, and presence of cancer-associated active fibroblast (CAF). Tumor recurrence and overall survival were retrospectively recorded. Of the included cases, 166 (16.1%), and 866 (83.9%) were adenocarcinoma in situ and pathological stage IA, respectively. Pathological stage IA adenocarcinoma was further classified based on the histologial subtype and the presence of CAF. This data set may be useful for analyzing the postoperative prognosis of early-stage lung adenocarcinoma, in combination with detailed pathological findings including size of invasion, histological subtype, and presence of CAF.
  • 持続する上部消化管出血と高度直腸狭窄を伴うも経口摂取を継続した若年の原発不明癌症例
    酒井 瞳; 川中 雄介; 田中 薫; 武田 真幸; 前田 宗之; 中川 和彦
    Palliative Care Research 15 Suppl. S421 - S421 (NPO)日本緩和医療学会 2020年08月
  • Toshio Shimizu; Kazuto Nishio; Kazuko Sakai; Isamu Okamoto; Kunio Okamoto; Masayuki Takeda; Maiko Morishita; Kazuhiko Nakagawa
    Cancer chemotherapy and pharmacology 86 2 211 - 219 2020年08月 
    PURPOSE: This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC). METHODS: The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed. RESULTS: Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8  mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients. CONCLUSION: Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC. TRIAL REGISTRATION: UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).
  • Hitomi Sakai; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Molecular and clinical oncology 13 2 175 - 178 2020年08月 
    Anorectal melanoma is a rare disease with a poor prognosis and its response to immunotherapy remains poorly studied. The current study reports a case of recurrent anorectal melanoma in a 60-year-old woman that has exhibited a durable response to ipilimumab for >2 years. Given that the combination of nivolumab and ipilimumab was not approved for use in unresectable or metastatic melanoma at the time of presentation, the patient was initially treated with nivolumab monotherapy and switched to ipilimumab after nivolumab failure. The tumor was microsatellite stable, had an intermediate tumor mutation burden and was negative for programmed cell death-ligand-1 expression. However, the neutrophil-to-lymphocyte ratio in peripheral blood remained at <5 throughout the disease course. Although mucosal melanoma is not caused by ultraviolet radiation and has a lower mutation burden than cutaneous melanoma, the present case responded well to immunotherapy. Further evaluation of potential biomarkers for such patients is required.
  • Hiroaki Kanemura; Masayuki Takeda; Kazuhiko Nakagawa
    Translational lung cancer research 9 4 1617 - 1622 2020年08月
  • Kazuo Nakagawa; Yukihiro Yoshida; Masaya Yotsukura; Shun-Ichi Watanabe
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2020年07月 [査読有り]
     
    OBJECTIVES: The prognosis of patients with mediastinal lymph node (LN) metastasis (pN2 stage III disease) is still unsatisfactory. Both systemic and local recurrence should be prevented after curative surgery. The aim of this study was to explore the pattern of recurrence in patients with completely resected pN2 non-small-cell lung cancer (NSCLC) in the era of adjuvant chemotherapy. METHODS: We investigated 337 patients with completely resected cN0-1 and pN2 NSCLC from 2005 to 2016 at National Cancer Center Hospital, Japan. The patterns of recurrence were compared between patients who were managed by observation alone and those with adjuvant chemotherapy. In patients with regional LN recurrence, the pattern and site of recurrence were also explored. RESULTS: There were 195 (58.5%) men and 142 (41.5%) women with a mean age of 63.2 years. Fifty-five (16.3%) patients developed only regional LN recurrence, 116 (32.6%) patients developed only distant recurrence and 65 (19.3%) patients developed both regional LN recurrence and distant recurrence. The difference in the pattern of recurrence between patients with observation alone and those with adjuvant chemotherapy was not statistically significant (P = 0.145). As for the pattern of regional LN recurrence, 68 (20.2%) patients had LN recurrence inside the systematic nodal dissection area. CONCLUSIONS: Regional LN recurrence was observed in >30% of patients with completely resected pN2 NSCLC. About 20% of patients had recurrence inside the systematic nodal dissection area. Postoperative radiotherapy might be considered as an additional treatment strategy for these patients.
  • Yukihiro Yoshida; Masaya Yotsukura; Kazuo Nakagawa; Hirokazu Watanabe; Noriko Motoi; Shun-Ichi Watanabe
    The Thoracic and cardiovascular surgeon 2020年07月 [査読有り]
     
    BACKGROUND:  This retrospective study investigated the prognosis of patients with pathological N1 (pN1) nonsmall cell lung cancer (NSCLC). METHODS:  We included patients with pN1 NSCLC who underwent lobectomy or pneumonectomy with mediastinal lymph node dissection and achieved complete resection (R0) between January 2000 and December 2012. Patients who received neoadjuvant therapy were excluded. RESULTS:  A total of 249 patients were included. The mean age was 63.2 years, and 172 patients were males. Of the 249 patients, 200, 20, and 29 underwent lobectomy, bilobectomy, and pneumonectomy, respectively. The median observation period was 5.5 years. The 5-year overall survival (OS) rate was 64.6% (95% confidence interval: 58.3-70.4). Five-year OS rates were 79.8% for positive lymph nodes at station 13 or 14 (n = 57), 59.6% at station 12 (n = 72), 62.7% at station 11 (n = 69), and 56.9% at station 10 (n = 51) (log-rank test; p = 0.016); furthermore, the 5-year OS rate was 75.2% for patients with positive lymph nodes at a single station (n = 160) and 45.4% for patients with positive lymph nodes at multiple stations (n = 89) (log-rank test; p < 0.001). Five-year cumulative incidences of recurrence were equivalent between patients who received adjuvant chemotherapy and patients who did not (45.9 vs. 55.1%; Gray's test; p = 0.366). Distant recurrence was the most frequent mode of recurrence in both groups (70.8 and 67.3%). CONCLUSION:  The locations and the number of stations of the positive lymph nodes were identified as prognostic factors in patients with pN1 NSCLC. The primary mode of recurrence was distant recurrence irrespective of postoperative adjuvant chemotherapy.
  • Masaya Yotsukura; Hisao Asamura; Shigeki Suzuki; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Noriko Motoi
    Lung cancer (Amsterdam, Netherlands) 145 158 - 166 2020年07月 [査読有り]
     
    BACKGROUND: Invasion is a crucial indicator of the prognosis in lung adenocarcinoma. The 2015 WHO classification of lung tumors defined invasion of adenocarcinoma mainly by the presence of non-lepidic histological subtypes including papillary, acinar, micropapillary and solid patterns, and the presence of cancer-associated active fibroblasts (CAF). In this study, we focused specifically on early-stage lepidic adenocarcinoma with CAF to evaluate its prognostic significance. METHODS: We included 1032 resected cases of lung adenocarcinoma, which consisted of pathological stage IA invasive cancer and adenocarcinoma in situ (AIS). Invasive adenocarcinoma was classified into two subgroups according to the type of invasion, INV-1 and INV-2. We defined INV-1 as adenocarcinoma of a non-lepidic histological subtype with or without CAF, and INV-2 as lepidic adenocarcinoma with CAF. The clinicopathological characteristics and prognosis were retrospectively analyzed. RESULTS: Included cases were classified into 696 (67.4 %) INV-1, 170 (16.5 %) INV-2, and 166 (16.1 %) AIS. The estimated 5-year recurrence-free probabilities of INV-1, INV-2, and AIS were 92.9 %, 100 %, and 100 %, respectively (p <  0.001). Although there were significant differences between INV-1 and INV-2 in terms of gender (more males in INV-1, p =  0.039), smoking habit (more smokers in INV-1, p =  0.046), and lymphovascular invasion (more invasion in INV-1, p <  0.001), there was no difference between AIS and INV-2. CONCLUSION: The presence of CAF is not always associated with a worse prognosis, and therefore it does not seem appropriate to include the presence of CAF alone in diagnostic criteria for invasion in early-stage lung adenocarcinoma.
  • Aki K Kobayashi; Hidehito Horinouchi; Yuko Nakayama; Yuichiro Ohe; Masaya Yotsukura; Shinsuke Uchida; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Shun-Ichi Watanabe
    Lung cancer (Amsterdam, Netherlands) 145 105 - 110 2020年07月 [査読有り]
     
    BACKGROUND: Local recurrence after definitive chemoradiation therapy, chemotherapy or radiotherapy with curative intent is often seen in patients with advanced non-small cell lung cancer. We evaluated the feasibility of salvage pulmonary resection after definitive non-surgical treatments and the postoperative morbidity and mortality rates. METHODS: We retrospectively analyzed the characteristics and medical courses of patients who had undergone salvage pulmonary resections after local relapse or progression between January 2000 and March 2018 at the National Cancer Centre Hospital, Tokyo, Japan. All the candidates were evaluated, and curability by surgical resection was assessed by a multidisciplinary tumor board. RESULTS: A total of 38 patient received salvage surgery: 26 of the patients were men, and the median age was 64.5 years (range, 20-78 years). Among these 38 patients, salvage lung resection was performed after chemoradiotherapy in 23 patients, after chemotherapy in 9 patients, and after radiotherapy with curative intent in 6 patients. The surgical resection methods were as follows: 26 lobectomies (2 bilobectomy, 15 right upper, 5 right lower, 1 right middle, 2 left lower and 1 left upper), 8 pneumonectomies (5 left and 3 right), and 4 segmentectomies. A complete resection (R0 resection) was achieved in 35 cases (92.1 %). Postoperative complications were observed in 3 patients (prolonged air leakage, bronchopleural fistula and surgical site infection in 1 patient each). No postoperative deaths occurred within 30 days after surgery. CONCLUSION: Along with better outcomes after definitive chemoradiotherapy, chemotherapy, and radiotherapy, the frequency of salvage surgery has been increasing in recent years. Salvage pulmonary resections after definitive non-surgical treatments with curative intent are feasible with an acceptable morbidity rate and oncological outcomes in thoroughly assessed patients.
  • 黒崎 隆; 川上 尚人; 中川 和彦
    日本消化器病学会雑誌 117 臨増総会 A26 - A26 (一財)日本消化器病学会 2020年07月
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 151 - 151 (一社)日本頭頸部癌学会 2020年07月
  • 当院における分化型甲状腺癌および未分化癌に対するレンバチニブの使用経験
    吉田 健史; 田中 薫; 中川 和彦
    頭頸部癌 46 2 214 - 214 (一社)日本頭頸部癌学会 2020年07月
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 218 - 218 (一社)日本頭頸部癌学会 2020年07月
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 151 - 151 (一社)日本頭頸部癌学会 2020年07月
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 218 - 218 (一社)日本頭頸部癌学会 2020年07月
  • Naohiro Makise; Taisuke Mori; Hiroshi Kobayashi; Kazuo Nakagawa; Eijitsu Ryo; Jun Nakajima; Shinji Kohsaka; Hiroyuki Mano; Hiroyuki Aburatani; Akihiko Yoshida; Tetsuo Ushiku
    Histopathology 76 7 1023 - 1031 2020年06月 [査読有り]
     
    AIMS: Ectomesenchymal chondromyxoid tumour (ECT) is a rare benign intraoral tumour which almost exclusively presents as a small mass of the anterior dorsal tongue. Recently, the RREB1-MRTFB (previously known as MKL2) fusion gene has been identified in 90% of ECTs, all located in the tongue, emphasising its genetic distinctiveness. Here, we report two mesenchymal tumours involving the superior mediastinum of adult women with RREB1-MRTFB fusions. METHODS AND RESULTS: Both tumours presented as well-circumscribed paravertebral masses that were clinically suspected to be schwannoma. After fragmented resection, recurrence was not observed at 27 and 18 months. Although tumours were originally unclassifiable, next-generation sequencing detected identical RREB1 (exon 8)-MRTFB (exon 11) fusion transcripts, which were validated by reverse transcriptase-polymerase chain reaction, Sanger sequencing, and fluorescence in-situ hybridisation. Both tumours shared hyalinised areas with round cells embedded in a cord or reticular manner. The tumour cells showed mild nuclear atypia of possible degenerative type with very low mitotic activity, and were at least focally positive for S100, glial fibrillary acidic protein, smooth muscle actin and epithelial membrane antigen. Overall, these findings suggest that they may represent previously undescribed extra-glossal ECT involving the mediastinum. However, the histology was not classic for ECT, because that in case 2 was predominated by storiform growth of spindle cells, whereas the tumour in case 1 lacked myxoid change. CONCLUSIONS: We have provided the first evidence that RREB1-MRTFB fusion is not limited to tumours in the head region, and whether such tumours represent extra-glossal ECTs requires further research.
  • 鈴木 慎一郎; 田中 薫; 金村 宙昌; 磯本 晃佑; 原谷 浩二; 林 秀敏; 武田 真幸; 中川 和彦
    気管支学 42 Suppl. S390 - S390 (NPO)日本呼吸器内視鏡学会 2020年06月
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    気管支学 42 Suppl. S391 - S391 (NPO)日本呼吸器内視鏡学会 2020年06月
  • Naiyer A Rizvi; Byoung Chul Cho; Niels Reinmuth; Ki Hyeong Lee; Alexander Luft; Myung-Ju Ahn; Michel M van den Heuvel; Manuel Cobo; David Vicente; Alexey Smolin; Vladimir Moiseyenko; Scott J Antonia; Sylvestre Le Moulec; Gilles Robinet; Ronald Natale; Jeffrey Schneider; Frances A Shepherd; Sarayut Lucien Geater; Edward B Garon; Edward S Kim; Sarah B Goldberg; Kazuhiko Nakagawa; Rajiv Raja; Brandon W Higgs; Anne-Marie Boothman; Luping Zhao; Urban Scheuring; Paul K Stockman; Vikram K Chand; Solange Peters
    JAMA oncology 6 5 661 - 674 2020年05月 
    Importance: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. Objective: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Interventions: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. Conclusions and Relevance: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab. Trial Registration: ClinicalT rials.gov Identifier: NCT02453282.
  • Hidetoshi Hayashi; Kazuhiko Nakagawa
    International journal of clinical oncology 25 5 818 - 830 2020年05月 [査読有り]
     
    Immune checkpoint inhibitors (ICIs)-such as antibodies to programmed cell death-1 (PD-1), to its ligand PD-L1, or to cytotoxic T lymphocyte-associated protein-4 (CTLA-4)-are an evolving treatment option for several types of cancer, but only a limited number of patients benefit from such therapy. Preclinical studies have suggested that the combination of PD-1 or PD-L1 inhibitors with either cytotoxic chemotherapy or antibodies to CTLA-4 is a promising treatment strategy for advanced cancer. Indeed, combinations of cytotoxic chemotherapy and PD-1/PD-L1 inhibitors have been approved and are now used in clinical practice for the treatment of advanced non-small cell lung cancer and small cell lung cancer on the basis of positive results of large-scale clinical trials. In addition, the combination of antibodies to CTLA-4 (ipilimumab) and to PD-1 (nivolumab) has been found to confer a survival benefit in patients with melanoma or renal cell carcinoma. Several ongoing clinical trials are also investigating ICI combination therapy in comparison with standard therapy for other tumor types. The identification of patients likely to achieve a sufficient benefit from PD-1/PD-L1 inhibitor monotherapy remains a challenge; however, with the establishment of novel complementary biomarkers being needed. Preclinical and clinical investigations of immune-related adverse events of ICI combination therapy are also warranted to establish management strategies. In this review, we summarize the current landscape of combination therapy with PD-1/PD-L1 inhibitors plus either cytotoxic chemotherapy or CTLA-4 inhibitors to clarify the benefits of and outstanding clinical issues related to such treatment.
  • Makoto Nishio; Terufumi Kato; Seiji Niho; Noboru Yamamoto; Toshiaki Takahashi; Naoyuki Nogami; Hiroyasu Kaneda; Yuka Fujita; Keith Wilner; Mizuki Yoshida; Mitsuhiro Isozaki; Shinsuke Wada; Fumito Tsuji; Kazuhiko Nakagawa
    Cancer science 111 5 1724 - 1738 2020年05月 [査読有り]
     
    In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first-line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28-d cycles, in patients with EGFR-activating mutation-positive (EGFR-positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non-small cell lung cancer (NSCLC). The primary endpoint was progression-free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307-0.961]; 2-sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0-31.3] mo, 9.3 [95% CI, 7.4-14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first-line dacomitinib in Japanese patients with EGFR-positive advanced NSCLC.
  • Isamu Okamoto; Hiroshi Nokihara; Shogo Nomura; Seiji Niho; Shunichi Sugawara; Hidehito Horinouchi; Koichi Azuma; Yasuto Yoneshima; Haruyasu Murakami; Yukio Hosomi; Shinji Atagi; Tomohiro Ozaki; Atsushi Horiike; Yuka Fujita; Hiroaki Okamoto; Masahiko Ando; Nobuyuki Yamamoto; Yuichiro Ohe; Kazuhiko Nakagawa
    JAMA oncology 6 5 e196828  2020年05月 [査読有り]
     
    Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit. Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019. Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks. Main Outcomes and Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model. Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed. Conclusion and Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.
  • Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa
    BMC medicine 18 1 111 - 111 2020年04月
  • Kohsuke Isomoto; Koji Haratani; Hidetoshi Hayashi; Shigeki Shimizu; Shuta Tomida; Takashi Niwa; Toshihide Yokoyama; Yasushi Fukuda; Yasutaka Chiba; Ryoji Kato; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Takashi Ogura; Tadashi Ishida; Akihiko Ito; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 26 8 2037 - 2046 2020年04月 [査読有り]
     
    PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
  • 金村 宙昌; 林 秀敏; 原谷 浩司; 米阪 仁雄; 中川 和彦; 萩原 智; 工藤 正俊; 大谷 知之; 伊藤 彰彦
    肺癌 60 2 149 - 150 (NPO)日本肺癌学会 2020年04月
  • 佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 60 2 155 - 155 (NPO)日本肺癌学会 2020年04月
  • 鈴木 慎一郎; 原谷 浩司; 加藤 了資; 林 秀敏; 中川 和彦; 谷崎 潤子; 尾崎 智博; 岡部 崇記; 明石 雄策; 長谷川 喜一; 西尾 和人; 伊藤 彰彦
    肺癌 60 2 155 - 156 (NPO)日本肺癌学会 2020年04月
  • 米阪 仁雄; 林 秀敏; 鈴木 慎一郎; 加藤 了資; 武田 真幸; 中川 和彦; 岩間 映二; 岡本 勇; 安宅 信二; 西尾 和人
    肺癌 60 2 160 - 160 (NPO)日本肺癌学会 2020年04月
  • 加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 60 2 148 - 148 (NPO)日本肺癌学会 2020年04月
  • 西尾 和人; 坂井 和子; 櫻井 俊治; 上嶋 一臣; 永井 知行; 林 秀敏; 川上 尚人; 高濱 隆幸; 武田 真幸; 中川 和彦
    肺癌 60 2 165 - 165 (NPO)日本肺癌学会 2020年04月
  • 原谷 浩司; 米阪 仁雄; 中川 和彦; 前西 修
    肺癌 60 2 160 - 160 (NPO)日本肺癌学会 2020年04月
  • 三谷 誠一郎; 川上 尚人; 中川 和彦
    臨床消化器内科 35 5 495 - 500 (株)日本メディカルセンター 2020年04月 
    <文献概要>免疫チェックポイント阻害薬単剤の有効性は限定的であり,併用療法により,その有効性を高める試みが進んでいる.多くの併用療法が臨床試験において検討されている段階である.その代表的なものは,殺細胞性抗がん剤との併用,免疫チェックポイント阻害薬同士の併用であり,加えて,分子標的治療薬との併用も検討されている.治療開発が先行する他がん種の現況も紹介しつつ,消化器がんに対する免疫チェックポイント阻害薬と他剤との併用について解説する.
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 60 2 149 - 149 (NPO)日本肺癌学会 2020年04月
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 60 2 153 - 153 (NPO)日本肺癌学会 2020年04月
  • 岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 60 2 164 - 164 (NPO)日本肺癌学会 2020年04月
  • CAPP-Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討
    加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 60 2 148 - 148 (NPO)日本肺癌学会 2020年04月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響
    磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 60 2 149 - 149 (NPO)日本肺癌学会 2020年04月
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験
    田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 60 2 153 - 153 (NPO)日本肺癌学会 2020年04月
  • 免疫チェックポイント阻害薬奏効後に転移巣増大を来した肺癌症例の遺伝子的検討
    佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 60 2 155 - 155 (NPO)日本肺癌学会 2020年04月
  • 肺線維症をもつ悪性胸膜中皮腫患者へのニボルマブ使用報告
    岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 60 2 164 - 164 (NPO)日本肺癌学会 2020年04月
  • Takashi Seto; Koichi Azuma; Takeharu Yamanaka; Shunichi Sugawara; Hiroshige Yoshioka; Kazushige Wakuda; Shinji Atagi; Yasuo Iwamoto; Hidetoshi Hayashi; Isamu Okamoto; Hideo Saka; Shigeki Mitsuoka; Daichi Fujimoto; Kazumi Nishino; Atsushi Horiike; Haruko Daga; Takashi Sone; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yoichi Nakanishi
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 8 793 - 803 2020年03月 [査読有り]
     
    PURPOSE: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS: Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.
  • 【病気とくすり2020 基礎と実践Expert's Guide】病原微生物・悪性新生物とくすり 悪性腫瘍 頭頸部癌
    田中 薫; 中川 和彦
    薬局 71 4 2125 - 2128 (株)南山堂 2020年03月
  • Hiroaki Kanemura; Hidetoshi Hayashi; Satoru Hagiwara; Tomoyuki Otani; Koji Haratani; Kimio Yonesaka; Akihiko Ito; Masatoshi Kudo; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 3 e39-e42  2020年03月 [査読有り]
  • Nahomi Tokudome; Yasuhiro Koh; Hiroaki Akamatsu; Daichi Fujimoto; Isamu Okamoto; Kazuhiko Nakagawa; Toyoaki Hida; Fumio Imamura; Satoshi Morita; Nobuyuki Yamamoto
    BMC cancer 20 1 103 - 103 2020年02月 [査読有り]
     
    BACKGROUND: Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive. METHODS: West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay. RESULTS: Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746_A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244). CONCLUSIONS: The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies. TRIAL REGISTRATION: This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).
  • 消化器がん薬物療法up to date 切除不能進行再発胃癌に対するニボルマブ単独療法の臨床的予後予測因子の検討
    黒崎 隆; 川上 尚人; 三谷 誠一郎; 中川 和彦
    日本消化器病学会近畿支部例会プログラム・抄録集 112回 71 - 71 日本消化器病学会-近畿支部 2020年02月
  • Pulmonary tumor thrombotic microangiopathy(PTTM)により急激な転機をたどった下咽頭癌患者の一例
    川中 雄介; 川上 尚人; 中川 和彦; 吉田 健史; 清水 重喜
    日本内科学会雑誌 109 Suppl. 231 - 231 (一社)日本内科学会 2020年02月
  • irAE大腸炎を契機にICIの関与が疑われたStevens-Johnson症候群の1例
    黒崎 隆; 川上 尚人; 文田 壮一; 三谷 誠一郎; 中川 和彦
    日本内科学会雑誌 109 Suppl. 260 - 260 (一社)日本内科学会 2020年02月
  • Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Eriko Miyawaki; Junichi Shimizu; Tomohiro Ozaki; Daichi Fujimoto; Ryo Toyozawa; Atsushi Nakamura; Toshiyuki Kozuki; Kentaro Tanaka; Shunsuke Teraoka; Kazuhiro Usui; Kazumi Nishino; Osamu Hataji; Keiichi Ota; Noriyuki Ebi; Sho Saeki; Yuki Akazawa; Motoyasu Okuno; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 8 1 2020年02月 [査読有り]
     
    BACKGROUND: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. METHODS: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. RESULTS: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. CONCLUSIONS: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
  • Koji Haratani; Kimio Yonesaka; Shiki Takamura; Osamu Maenishi; Ryoji Kato; Naoki Takegawa; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Junji Tsurutani; Kazuto Nishio; Katsumi Doi; Masaaki Miyazawa; Kazuhiko Nakagawa
    The Journal of clinical investigation 130 1 374 - 388 2020年01月 [査読有り]
     
    Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
  • Hiroyuki Ito; Kenji Suzuki; Tomonori Mizutani; Keiju Aokage; Masashi Wakabayashi; Haruhiko Fukuda; Shun ichi Watanabe; Teruaki Koike; Yasuhiro Tsutani; Hisashi Saji; Kazuo Nakagawa; Yoshitaka Zenke; Kazuya Takamochi; Tadashi Aoki; Jiro Okami; Hiroshige Yoshioka; Satoshi Shiono; Morihito Okada
    Journal of Thoracic and Cardiovascular Surgery 2020年 [査読有り]
     
    © 2020 Objective: The aim of this study was to assess long-term outcomes after lobectomy in patients with clinical T1 N0 lung cancer based on thin-section computed tomography. Methods: We collected the data of patients with pathological adenocarcinoma who had undergone lobectomy. The patients were categorized into 4 groups according to a consolidation tumor ratio and tumor size. Groups A and B included tumors with consolidation tumor ratio ≤0.5 and size ≤3 cm. Group A consisted of tumors ≤2 cm. Group B consisted of the remaining tumors. Groups C and D consisted of tumors with consolidation tumor ratio >0.5. Group C consisted of those with tumors ≤2 cm and Group D consisted of tumors of size 2 to 3 cm. The 10-year overall survival and recurrence-free survival rates were examined. Results: Among the 543 patients, the 10-year overall survival was 80.4% and the 10-year recurrence-free survival rate was 77.1%. The 10-year overall survival for group A was 94.0%, 92.7% for group B, 84.1% for group C, and 68.8% for group D, and the 10-year recurrence-free survival rate for each group was 94.0%, 89.0%, 79.7%, and 66.1%, respectively. Group A + B showed better overall survival than group C + D (hazard ratio, 2.78; 95% confidence interval, 1.45-5.06) and better 10-year recurrence-free survival (hazard ratio, 2.74; 95% confidence interval, 1.55-4.88). No patient in group A had recurrence. Conclusions: Those patients with total tumor size ≤3 cm and consolidation tumor ratio ≤0.5 showed excellent prognosis and might be suitable candidates for sublobar resection. If noninferior survival of segmentectomy compared with lobectomy is confirmed in an ongoing Japan Clinical Oncology Group trial, segmentectomy will be included in the standard of care.
  • Yusuke Kawanaka; Hisato Kawakami; Shigeki Shimizu; Takeshi Yoshida; Hidetoshi Hayashi; Kazuto Nishio; Takao Satou; Kazuhiko Nakagawa
    Case Reports in Oncology 13 2 843 - 848 2020年 
    Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by tumor cell microemboli with occlusive fibrointimal remodeling in small pulmonary vessels. Platelet-derived growth factor (PDGF) has been implicated in the development of PTTM, and fibroblast growth factor (FGF) promotes PDGF signaling via PDGF receptor ß. We here describe a cancer patient who presented with dyspnea of uncertain etiology and whose condition worsened rapidly. A 68-year-old man with hypopharyngeal squamous cell carcinoma (cT4aN2bM0, stage IVA) was treated with surgery followed by radiation. Two years later, a lung metastatic lesion was surgically removed on the basis of suspected primary lung cancer. The patient was thereafter monitored without chemotherapy. Two months later, he had third-degree burns and received conservative therapy including debridement and application of trafermin (FGF2) spray. Two weeks later, he was hospitalized with complaints of fever and dyspnea. Pneumonia and pulmonary embolism were ruled out by chest computed tomography with pulmonary arterio-graphy, whereas intravascular lymphoma was excluded by laboratory testing. Malignant cells were detected in his peripheral blood on hospital day 8, and their number increased gradually thereafter. His respiratory symptoms worsened, and the patient died on hospital day 10. We concluded that the cause of death was PTTM, with the clinical course suggesting a possible relation to trafermin. This suggestion was supported by the detection of FGF receptor 2 overexpression in the primary tumor by immunostaining.
  • TAKASHI KUROSAKI; HISATO KAWAKAMI; SEIICHIRO MITANI; RYOHEI KAWABATA; TAKAYUKI TAKAHAMA; YOSHIKANE NONAGASE; SOICHI FUMITA; TOMOHIRO OZAKI; YASUTAKA CHIBA; TAKAO TAMURA; KAZUHIKO NAKAGAWA
    In Vivo 34 4 1921 - 1929 2020年
  • Helen Brown; Johan Vansteenkiste; Kazuhiko Nakagawa; Manuel Cobo; Thomas John; Craig Barker; Alexander Kohlmann; Alexander Todd; Matilde Saggese; Juliann Chmielecki; Aleksandra Markovets; Marietta Scott; Suresh S Ramalingam
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 1 138 - 143 2020年01月 [査読有り]
     
    INTRODUCTION: EGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125). METHODS: Of 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients. RESULTS: PD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and -negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15-0.60). For PD-L1-negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17-0.74). CONCLUSIONS: Clinical benefit with osimertinib was unaffected by PD-L1 expression status.
  • James Chih-Hsin Yang; Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Rebecca R Hozak; Tuan Stevon Nguyen; Wan Li Zhang; Sotaro Enatsu; Tarun Puri; Mauro Orlando
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 1 91 - 100 2020年01月 [査読有り]
     
    INTRODUCTION: Clinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib. METHODS: This was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m2 intravenously 3-weekly + 250 mg/day orally) or gefitinib. RESULTS: In total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event. CONCLUSIONS: Addition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.
  • Kazuhiko Nakagawa; Toyoaki Hida; Hiroshi Nokihara; Masahiro Morise; Koichi Azuma; Young Hak Kim; Takashi Seto; Yuichi Takiguchi; Makoto Nishio; Hiroshige Yoshioka; Toru Kumagai; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Ryo Koyama; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takashi Asakawa; Morihiko Hayashi; Wakako Hasegawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 139 195 - 199 2020年01月 [査読有り]
     
    OBJECTIVES: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). METHODS: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. RESULTS: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). CONCLUSIONS: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.
  • Natasha B Leighl; Nina Karaseva; Kazuhiko Nakagawa; Byoung-Chul Cho; Jhanelle E Gray; Tina Hovey; Andrew Walding; Anna Rydén; Silvia Novello
    European journal of cancer (Oxford, England : 1990) 125 49 - 57 2020年01月 [査読有り]
     
    BACKGROUND: In the FLAURA trial, osimertinib demonstrated superior progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial therapy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported outcomes from FLAURA are discussed here. METHODS: Patients (N = 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized treatment discontinuation were assessed using a mixed-effects model. A ≥10-point change was considered clinically relevant. Odds of improvement and time to deterioration were investigated. QLQ-C30 functioning scores were assessed post hoc. RESULTS: Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference favoring osimertinib for chest pain was not clinically relevant (-6.84 vs -3.88; p = 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p = 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs -3.91; p = 0.005). CONCLUSIONS: Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. CLINICAL TRIAL REGISTRATION: NCT02296125.
  • Takayuki Takahama; Koichi Azuma; Mototsugu Shimokawa; Masayuki Takeda; Hidenobu Ishii; Terufumi Kato; Haruhiro Saito; Haruko Daga; Yuko Tsuboguchi; Isamu Okamoto; Kohei Otsubo; Hiroaki Akamatsu; Shunsuke Teraoka; Toshiaki Takahashi; Akira Ono; Tatsuo Ohira; Toshihide Yokoyama; Kazuko Sakai; Nobuyuki Yamamoto; Kazuto Nishio; Kazuhiko Nakagawa
    Cancer 126 9 1940 - 1948 2020年01月 [査読有り]
     
    BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Koji Haratani; Takayuki Takahama; Ryoji Kato; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 139 28 - 34 2020年01月 [査読有り]
     
    OBJECTIVES: The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. MATERIALS AND METHODS: A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. RESULTS: Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049). CONCLUSIONS: Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
  • Kimio Yonesaka; Eiji Iwama; Hidetoshi Hayashi; Shinichiro Suzuki; Ryoji Kato; Satomi Watanabe; Takayuki Takahama; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Koichi Azuma; Yasutaka Chiba; Shinji Atagi; Kazuto Nishio; Isamu Okamoto; Kazuhiko Nakagawa
    Scientific reports 9 1 19501 - 19501 2019年12月 [査読有り]
     
    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1st-generation and 29 with 2nd-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1st-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1st-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2nd-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2nd-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
  • Naoki Takegawa; Junji Tsurutani; Hisato Kawakami; Kimio Yonesaka; Ryoji Kato; Koji Haratani; Hidetoshi Hayashi; Masayuki Takeda; Yoshikane Nonagase; Osamu Maenishi; Kazuhiko Nakagawa
    International journal of cancer 145 12 3414 - 3424 2019年12月 [査読有り]
     
    Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel antibody-drug conjugate composed of the anti-HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of [fam-] trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to [fam-] trastuzumab deruxtecan but not to conventional HER2-targeted therapies. Furthermore, [fam-] trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2-expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that [fam-] trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.
  • Keisuke Asakura; Yukihiro Yoshida; Hiroyuki Sakurai; Kazuo Nakagawa; Noriko Motoi; Shun-Ichi Watanabe
    World journal of surgery 43 12 3259 - 3266 2019年12月 [査読有り]
     
    BACKGROUND: Good prognosis following surgery for metachronous lung cancer has been reported. However, prognostic factors have not been fully investigated. The purpose of this study was to identify the preoperative predictor of survival in metachronous lung cancer. METHODS: Patients who underwent a second pulmonary resection for metachronous lung cancer at our institution between 2000 and 2014 were analyzed. RESULTS: A retrospective chart review identified 86 eligible patients (of 6213; 1.4%). The 5-year overall survival was 77%. All 86 cancers met Martini and Melamed's criteria for second primary cancer. However, on pathological examination based on morphological concordance between the initial and metachronous cancer, 73 (85%) cases were diagnosed as second primary cancer and 13 (15%) as a possible recurrent tumor. The 5-year overall survivals were 82% for second primary cancers and 52% for possible recurrent tumors. Tumor doubling time > 180 days (p < 0.001), pathological diagnosis of second primary cancer (p = 0.013), pathological stage IA (p = 0.016), interval between resections > 2 years (p = 0.040), and consolidation/tumor diameter ratio ≤ 0.5 (p = 0.045) were associated with superior overall survival. Multivariate Cox regression analysis identified tumor doubling time > 180 days as the only independent predictor of overall survival (hazard ratio 3.600, 95% confidence interval 1.226-10.338; p = 0.0196). CONCLUSIONS: Surgical resection for metachronous lung cancer is effective and feasible. Particularly, a tumor doubling time > 180 days is associated with superior survival in patients with metachronous lung cancer.
  • 木村 豊; 白石 治; 岩間 密; 加藤 寛章; 川上 尚人; 奥野 達哉; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 中川 和彦; 安田 卓司
    癌と化学療法 46 13 2173 - 2175 (株)癌と化学療法社 2019年12月 
    腎機能低下を伴う進行食道癌に対して術前化学療法(NAC)として5-FU+DTX+nedaplatin(NED)(UDON)療法を施行し、その有用性をretrospectiveに検討した。クレアチニン・クリアランス(Ccr)が50mL/min未満の進行食道癌5例を対象として、NACとしてUDON療法[5-FU640mg/m2(day1〜5)、NED72mg/m2(day1)、DTX28mg/m2(day1、15)、休薬2週間を1コース]を2コース施行した後に根治手術を施行した。化学療法の有害事象(AE)を評価し、臨床的な効果について検討した。患者背景は、男性4例、女性1例、年齢の中央値(範囲)79(58〜80)歳、performance status(PS)1:3、PS2:2例であった。腫瘍の主占居部位は、Ce 1、Ut 1、Mt 3例、進行度はcStage IIA1、IIIA2、IIIC2例であった。grade(Gr)3以上のAEは、好中球減少、低Na血症がそれぞれ2例、発熱性好中球減少、下痢がそれぞれ1例であった。抗腫瘍効果は部分奏効4例、安定1例、組織学的効果は、Gr 1a:Gr 1b=2:3であった。腎機能低下のため高用量CDDP投与が困難な進行食道癌患者に対するNACとして、UDON療法は有用である。(著者抄録)
  • H Yoshioka; M Shimokawa; T Seto; S Morita; Y Yatabe; I Okamoto; J Tsurutani; M Satouchi; T Hirashima; S Atagi; K Shibata; H Saito; S Toyooka; N Yamamoto; K Nakagawa; T Mitsudomi
    Annals of oncology : official journal of the European Society for Medical Oncology 30 12 1978 - 1984 2019年12月 
    BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
  • Koji Haratani; Masayuki Takeda; Kazuhiko Nakagawa
    Journal of thoracic disease 11 12 5635 - 5642 2019年12月 [査読有り]
  • Yutaka Kimura; Osamu Shiraishi; Mitsuru Iwama; Hiroaki Kato; Hisato Kawakami; Tatsuya Okuno; Yoko Hiraki; Atsushi Yasuda; Masayuki Shinkai; Motohiro Imano; Kazuhiko Nakagawa; Takushi Yasuda
    Gan to kagaku ryoho. Cancer & chemotherapy 46 13 2173 - 2175 2019年12月 [査読有り]
     
    BACKGROUND: In Japan, pre-operative 5-FU and cisplatin(CDDP)(FP)combination therapy has been the standard neoadjuvant chemotherapy(NAC)for advanced resectable esophageal cancer(EC); furthermore, the efficacy of the docetaxel (DTX)-containing triplet regimen, FP plus DTX, has been reported. However, patients with impaired renal function should not receive high-dose CDDP. We have been developing a non-CDDP-containing triplet regimen, comprising 5-FU, DTX, and nedaplatin(NED)(UDON), on a phase Ⅰ/Ⅱtrial basis. This retrospective study aimed to investigate the safety and efficacy of NAC with UDON in advanced EC patients with impaired renal function. METHODS: Five patients with advanced resectable EC with impaired renal function were enrolled in this study. Patients received NAC(5-FU, 640mg/m / 2, days 1-5; DTX, 28 mg/m2, days 1 and 15; and NED, 72mg/m2, day 1, q28, 2 courses); following this, they underwent esophagectomy. The primary endpoint was response rate, and the secondary endpoint was adverse event(AE). RESULTS: The median age was 79 years (range: 58-80 years). The ECOG performance status was 1/2 : 3/2. The main tumor locations were Ce/Ut/Mt : 1/1/3 and the cStages were ⅡA/ⅢA/ⅢC : 1/2/2. The RR(CR/PR/SD/PD : 0/4/1/0)was 80%. The pathological response was grade 1a/1b : 2/3. Major grade 3 or 4 AEs included neutropenia(40%), febrile neutropenia(20%), diarrhea(20%), and hyponatremia( 40%). There was no treatment-related death or reoperation. CONCLUSIONS: NAC with UDON might be feasible and effective in patients with advanced resectable EC with impaired renal function, who are ineligible for high-dose CDDP administration. We are planning a phaseⅡclinical study based on the present results.
  • Kazuhiko Nakagawa; Edward B Garon; Takashi Seto; Makoto Nishio; Santiago Ponce Aix; Luis Paz-Ares; Chao-Hua Chiu; Keunchil Park; Silvia Novello; Ernest Nadal; Fumio Imamura; Kiyotaka Yoh; Jin-Yuan Shih; Kwok Hung Au; Denis Moro-Sibilot; Sotaro Enatsu; Annamaria Zimmermann; Bente Frimodt-Moller; Carla Visseren-Grul; Martin Reck
    The Lancet. Oncology 20 12 1655 - 1669 2019年12月 [査読有り]
     
    BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.
  • 川中 雄介; 鈴木 慎一郎; 加藤 了資; 原谷 浩司; 林 秀敏; 中川 和彦; 楠 進; 山岸 裕子; 寺山 敦之
    肺癌 59 6 785 - 785 (NPO)日本肺癌学会 2019年11月
  • Yoshioka Hiroshige; Shimokawa Mototsugu; Seto Takashi; Morita Satoshi; Yatabe Yasushi; Okamoto Isamu; Tsurutani Junji; Satouchi Miyako; Hirashima Tomonori; Atagi Shinji; Shibata Kazuhiko; Saito Hiroshi; Toyooka Shinichi; Yamamoto Nobuyuki; Nakagawa Kazuhiko; Mitsudomi Tetsuya
    肺癌 59 6 629 - 629 2019年11月
  • 西山 理; 佐野 安希子; 林 秀敏; 西川 裕作; 谷崎 潤子; 原谷 浩司; 中川 和彦; 東田 有智
    肺癌 59 6 547 - 547 (NPO)日本肺癌学会 2019年11月
  • 横山 俊秀; 丹羽 崇; 林 秀敏; 小倉 昌和; 谷崎 潤子; 尾崎 智博; 吉岡 弘鎮; 倉田 宝保; 田村 洋輔; 藤阪 保仁; 田中 薫; 長谷川 喜一; 千葉 康敬; 中川 和彦
    肺癌 59 6 672 - 672 (NPO)日本肺癌学会 2019年11月
  • 田中 薫; 谷崎 潤子; 野長瀬 祥兼; 原谷 浩司; 酒井 瞳; 加藤 了資; 渡邉 諭美; 吉田 健史; 佐藤 千尋; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 694 - 694 (NPO)日本肺癌学会 2019年11月
  • 鈴木 慎一郎; 加藤 了資; 原谷 浩司; 林 秀敏; 谷崎 潤子; 尾崎 智博; 長谷川 喜一; 大田 隆代; 千葉 康敬; 伊藤 彰彦; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 800 - 800 (NPO)日本肺癌学会 2019年11月
  • 加藤 了資; 林 秀敏; 米阪 仁雄; 原谷 浩司; 酒井 瞳; 高濱 隆幸; 岩朝 勤; 田中 薫; 吉田 健史; 武田 真幸; 金田 裕靖; 清水 重喜; 坂井 和子; 伊藤 彰彦; 西尾 和人; 中川 和彦
    肺癌 59 6 575 - 575 (NPO)日本肺癌学会 2019年11月
  • 米阪 仁雄; 岩間 映二; 林 秀敏; 高濱 隆幸; 谷崎 潤子; 武田 真幸; 東 公一; 安宅 信二; 岡本 勇; 中川 和彦
    肺癌 59 6 723 - 723 (NPO)日本肺癌学会 2019年11月
  • 武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 原谷 浩司; 高濱 隆幸; 加藤 了資; 米阪 仁雄; 西尾 和人; 中川 和彦
    肺癌 59 6 723 - 723 2019年11月
  • 杉本 藍; 福井 朋也; 佐々木 治一郎; 石原 未希子; 日吉 康弘; 井川 聡; 坂井 和子; 武田 真幸; 高濱 隆幸; 中川 和彦; 西尾 和人; 猶木 克彦
    肺癌 59 6 765 - 765 (NPO)日本肺癌学会 2019年11月
  • 原谷 浩司; 米阪 仁雄; 高村 史記; 前西 修; 宮澤 正顯; 中川 和彦
    肺癌 59 6 568 - 568 (NPO)日本肺癌学会 2019年11月
  • 木村 豊; 白石 治; 岩間 密; 加藤 寛章; 川上 尚人; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 中川 和彦; 安田 卓司
    日本消化器病学会雑誌 116 臨増大会 A832 - A832 (一財)日本消化器病学会 2019年11月
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 清水 重喜; 富田 秀太; 丹羽 崇; 横山 俊秀; 福田 泰; 千葉 康敬; 加藤 了資; 谷崎 潤子; 田中 薫; 武田 真幸; 小倉 高志; 石田 直; 伊藤 彰彦; 中川 和彦
    肺癌 59 6 567 - 567 (NPO)日本肺癌学会 2019年11月
  • 野長瀬 祥兼; 武田 真幸; 東 公一; 林 秀敏; 原谷 浩司; 田中 薫; 米阪 仁雄; 石井 秀宜; 星野 友昭; 中川 和彦
    肺癌 59 6 765 - 765 (NPO)日本肺癌学会 2019年11月
  • 服部 剛弘; 山中 竹春; 伊藤 健太郎; 宮本 信吾; 竹本 真之輔; 池田 慧; 牛尾 良太; 臼井 一裕; 三登 峰代; 阪本 智宏; 杉山 智英; 木村 智樹; 海老 規之; 石井 知也; 猪又 峰彦; 柏原 光介; 岡田 秀明; 木村 望; 中川 和彦; 山本 信之
    肺癌 59 6 667 - 667 (NPO)日本肺癌学会 2019年11月
  • Masayuki Takeda; Yuichiro Ohe; Hidehito Horinouchi; Toyoaki Hida; Junichi Shimizu; Takashi Seto; Kaname Nosaki; Takumi Kishimoto; Itaru Miyashita; Masayuki Yamada; Yutaro Kaneko; Chikao Morimoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 137 64 - 70 2019年11月 [査読有り]
     
    OBJECTIVES: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies. MATERIAL AND METHODS: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs). RESULTS: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response. CONCLUSIONS: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.
  • Tsutomu Iwasa; Junji Tsurutani; Satomi Watanabe; Ryoji Kato; Yutaka Mizuno; Yasuyuki Kojima; Tsutomu Takashima; Nobuki Matsunami; Takashi Morimoto; Jun Yamamura; Shoichiro Ohtani; Yuko Tanabe; Tetsuhiro Yoshinami; Toshimi Takano; Yoshifumi Komoike; Kazuhiko Nakagawa
    BMC cancer 19 1 962 - 962 2019年10月 [査読有り]
     
    BACKGROUND: We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. METHODS: Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). RESULTS: This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). CONCLUSIONS: The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. TRIAL REGISTRATION: Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
  • Tatsuo Kimura; Tomoya Kawaguchi; Yasutaka Chiba; Hiroshige Yoshioka; Katsuya Watanabe; Takashi Kijima; Yoshihito Kogure; Tetsuya Oguri; Naruo Yoshimura; Takashi Niwa; Takashi Kasai; Hidetoshi Hayashi; Akira Ono; Kazuhisa Asai; Hiroshi Tanaka; Seiji Yano; Nobuyuki Yamamoto; Yoichi Nakanishi; Kazuhiko Nakagawa
    Japanese journal of clinical oncology 49 10 947 - 955 2019年10月 [査読有り]
     
    BACKGROUND: Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy. METHODS: This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2-16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients. RESULTS: In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2-32.1%) and 53.7% (95%CI: 37.4-69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1-4.5) and 11.3 (95%CI: 8.6-16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3-4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection. CONCLUSIONS: Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.
  • Satomi Watanabe; Tomoyuki Otani; Tsutomu Iwasa; Takayuki Takahama; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Clinical breast cancer 19 5 e589-e592  2019年10月 [査読有り]
  • Yoshikane Nonagase; Masayuki Takeda; Koichi Azuma; Hidetoshi Hayashi; Koji Haratani; Kaoru Tanaka; Kimio Yonesaka; Hidenobu Ishii; Tomoaki Hoshino; Kazuhiko Nakagawa
    Thoracic cancer 10 10 1928 - 1935 2019年10月 [査読有り]
     
    BACKGROUND: Non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one-fifth of NSCLC patients with acquired resistance to EGFR-TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. METHODS: Tumor tissue and plasma specimens were collected from 25 EGFR-mutated NSCLC patients before EGFR-TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme-linked immunosorbent assays. RESULTS: AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR-TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. CONCLUSION: Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR-mutated NSCLC.
  • Kimio Yonesaka; Kaoru Tanaka; Mutsukazu Kitano; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Katsumi Doi; Kazuhiko Nakagawa
    Oncogenesis 8 10 54 - 54 2019年09月 [査読有り]
     
    The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC. An unbiased comprehensive transcriptome analysis was performed on cetuximab-resistant HNSCC FaDuCR cells. The causative resistance genome was knocked down with siRNA, cell signaling was immunologically analyzed, and drug efficacy was evaluated in vitro and in vivo. The mRNA in situ hybridization (ISH) of the causative genome was performed using 28 excised HNSCC tumors and its relationship with cetuximab efficacy was analyzed. FaDuCR cells were resistant to cetuximab, whereas parental FaDu cells were susceptible to it. FaDuCR cells expressed consistently higher levels of phosphorylated Akt than FaDu cells despite cetuximab exposure. A comprehensive transcriptome analysis revealed that the HER3-ligand heregulin was upregulated in FaDuCR cells compared to FaDu cells. Heregulin knockdown in FaDuCR cells repressed HER3 and Akt phosphorylation and recovered cetuximab anticancer efficacy. In contrast, pan-HER family tyrosine kinase inhibitors such as afatinib decreased HER3 and Akt phosphorylation in FaDuCR cells and inhibited FaDuCR tumor growth. Two of the 28 HNSCC tumor samples presented aberrant heregulin expression comparable to that of FaDuCR cells and were resistant to cetuximab therapy. In HNSCC, heregulin-mediated HER3-Akt activation causes resistance to cetuximab but not to second-generation EGFR-tyrosine kinase inhibitors. Subpopulations with aberrant heregulin-expressing HNSCC might be resistant to cetuximab.
  • Morihito Okada; Takashi Kijima; Keisuke Aoe; Terufumi Kato; Nobukazu Fujimoto; Kazuhiko Nakagawa; Yuichiro Takeda; Toyoaki Hida; Kuninobu Kanai; Fumio Imamura; Satoshi Oizumi; Toshiaki Takahashi; Mitsuhiro Takenoyama; Hiroshi Tanaka; Jun Hirano; Yoshinobu Namba; Yuichiro Ohe
    Clinical cancer research : an official journal of the American Association for Cancer Research 25 18 5485 - 5492 2019年09月 [査読有り]
     
    PURPOSE: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. PATIENTS AND METHODS: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. RESULTS: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. CONCLUSIONS: Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.See related commentary by Mansfield and Zauderer, p. 5438.
  • Koji Haratani; Hidetoshi Hayashi; Takayuki Takahama; Yasushi Nakamura; Shuta Tomida; Takeshi Yoshida; Yasutaka Chiba; Takahiro Sawada; Kazuko Sakai; Yoshihiko Fujita; Yosuke Togashi; Junko Tanizaki; Hisato Kawakami; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 7 1 251 - 251 2019年09月 [査読有り]
     
    BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
  • Akifumi Nakamura; Minoru Esaki; Kazuo Nakagawa; Keisuke Asakura; Yoji Kishi; Satoshi Nara; Kazuaki Shimada; Shun-Ichi Watanabe
    General thoracic and cardiovascular surgery 67 9 782 - 787 2019年09月 [査読有り]
     
    OBJECTIVE: The outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors. METHODS: This retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital. RESULTS: The 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226-10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594-10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0-1 risk factors and those with 2-3 risk factors, respectively (P < 0.001). CONCLUSIONS: For patients who underwent pulmonary metastasectomy for hepatocellular carcinoma, median survival time was 25.0 months and decreased with three risk factors which included viral hepatitis, multiple number of pulmonary metastases, and the presence of other site recurrence before metastasectomy.
  • Hidehito Horinouchi; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Toshiaki Takahashi; Hideo Saka; Mitsuhiro Takenoyama; Nobuyuki Katakami; Hiroshi Tanaka; Koji Takeda; Miyako Satouchi; Hiroshi Isobe; Makoto Maemondo; Koichi Goto; Tomonori Hirashima; Koichi Minato; Naoki Sumiyoshi; Tomohide Tamura
    Cancer medicine 8 11 5183 - 5193 2019年09月 [査読有り]
     
    BACKGROUND: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials. METHODS: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed. RESULTS: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. CONCLUSION: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC. TRIAL REGISTRATION: JapicCTI-132072; JapicCTI-132073.
  • Hibiki Udagawa; Hiroaki Akamatsu; Kentaro Tanaka; Masayuki Takeda; Shintaro Kanda; Keisuke Kirita; Shunsuke Teraoka; Kazuhiko Nakagawa; Yutaka Fujiwara; Ikuko Yasuda; Sumiko Okubo; Masayuki Shintani; Matthew P Kosloski; Charity Scripture; Tomohide Tamura; Isamu Okamoto
    Lung cancer (Amsterdam, Netherlands) 135 145 - 150 2019年09月 [査読有り]
     
    OBJECTIVES: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. MATERIALS AND METHODS: Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. RESULTS: Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. CONCLUSIONS: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.
  • Hidetoshi Hayashi; Kazuto Nishio; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 23 2090 - 2090 2019年08月 [査読有り]
  • Kazuko Sakai; Masayuki Takeda; Shigeki Shimizu; Takayuki Takahama; Takeshi Yoshida; Satomi Watanabe; Tsutomu Iwasa; Kimio Yonesaka; Shinichiro Suzuki; Hidetoshi Hayashi; Hisato Kawakami; Yoshikane Nonagase; Kaoru Tanaka; Junji Tsurutani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Kazuto Nishio
    Scientific reports 9 1 11340 - 11340 2019年08月 [査読有り]
     
    Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.
  • PD-L1発現陰性/TMB Highの肺腺癌に対して化学療法とペムブロリズマブの併用療法を施行した1例
    金村 宙昌; 林 秀敏; 武田 真幸; 高濱 隆幸; 田中 薫; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 59 4 413 - 414 (NPO)日本肺癌学会 2019年08月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌のPD-L1発現率への影響
    磯本 晃佑; 原谷 浩司; 林 秀敏; 清水 重喜; 冨田 秀太; 丹羽 崇; 横山 俊秀; 福田 泰; 千葉 康敬; 加藤 了資; 谷崎 潤子; 田中 薫; 武田 真幸; 小倉 高志; 石田 直; 伊藤 彰彦; 中川 和彦
    肺癌 59 4 419 - 419 (NPO)日本肺癌学会 2019年08月
  • Jesús Corral; Tony S Mok; Kazuhiko Nakagawa; Rafael Rosell; Ki Hyeong Lee; Maria Rita Migliorino; Adam Pluzanski; Rolf Linke; Geeta Devgan; Weiwei Tan; Susan Quinn; Tao Wang; Yi-Long Wu
    Future oncology (London, England) 15 24 2795 - 2805 2019年08月 [査読有り]
     
    Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.
  • Keita Nakanishi; Kazuo Nakagawa; Keisuke Asakura; Yukihiro Yoshida; Hirokazu Watanabe; Shun-Ichi Watanabe
    World journal of surgery 43 7 1850 - 1856 2019年07月 [査読有り]
     
    BACKGROUND: Calcified lymph nodes (LNs) on computed tomography (CT) in patients with lung cancer are generally considered to be a benign feature. However, few studies have evaluated the pathological status of such calcified LNs. We investigated the clinicopathological findings of patients with calcified LNs on preoperative CT who underwent operation for lung cancer and assessed the frequency of metastasis to calcified LNs as well as the risk factors associated with such metastases. METHODS: This was a retrospective study of 72 consecutive patients with calcified LNs detected on preoperative CT who underwent pulmonary resection for primary lung cancer between 2011 and 2013. A total of 354 LN stations including 101 LN stations with calcified LNs were evaluated. RESULTS: The frequency of metastasis to calcified LNs was 19.4% (14 of 72 patients) on a per-person basis and 18.8% (19 of 101 stations) on a per-nodal station basis. When the size of calcification was major (>5 mm), the frequency of metastasis to such calcified LNs was significantly lower than when it was minor (≦5 mm) on a per-nodal station basis (11.1% vs 27.7%, P = 0.043). Furthermore, when the size of calcification was major and the status of LN stations with calcified LNs was single, there was no metastasis to such LN stations (0 of 26 stations). CONCLUSIONS: The frequency of metastasis to calcified LNs was about 20% on both a per-person and a per-nodal station basis. Although calcified LNs as well as non-calcified LNs should be dissected during operation, dissection of a single LN station with calcification, particularly major calcification, can be omitted.
  • Uchida S; Yoshida Y; Ohe Y; Nakayama Y; Motoi N; Kobayashi A; Asakura K; Nakagawa K; Watanabe SI
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 56 1 167 - 173 2019年07月 [査読有り]
  • Hiroaki Akamatsu; Shunsuke Teraoka; Satoshi Morita; Nobuyuki Katakami; Motoko Tachihara; Haruko Daga; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 4 e492-e494 - e494 2019年07月 [査読有り]
     
    Osimertinib is a standard treatment for epidermal growth factor receptor (EGFR)-mutated, T790M-positive patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. Osimertinib, a third-generation EGFR-TKI, allows progression-free survival of around 10 months, but its toxicity is well-tolerated compared with other EGFR-TKIs. Preclinical and clinical evidence suggests that EGFR-TKI may work synergistically with vascular endothelial growth factor inhibitors. We therefore plan a phase I/II study to investigate this possibility. In phase I, the primary endpoint is assessment of the tolerability of osimertinib and bevacizumab in 6 patients. Phase II then explores the efficacy of combined treatment compared with osimertinib monotherapy with progression-free survival as the primary endpoint. Secondary endpoints are overall response rate, time to treatment failure, overall survival, and safety. Eighty patients will be enrolled in phase II.
  • Satoshi Watanabe; Hiroshige Yoshioka; Hiroshi Sakai; Katsuyuki Hotta; Mitsuhiro Takenoyama; Kazuhiko Yamada; Shunichi Sugawara; Yuichi Takiguchi; Yukio Hosomi; Keisuke Tomii; Seiji Niho; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Terufumi Kato; Toshiaki Takahashi; Ami Kamada; Kazumi Suzukawa; Yukie Omori; Sotaro Enatsu; Kazuhiko Nakagawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 132 157 - 158 2019年06月 [査読有り]
  • Makoto Nishio; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Tomohiro Tanaka; Hiroshi Kuriki; Ali Zeaiter; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 132 160 - 160 2019年06月 [査読有り]
  • Keunchil Park; Jaafar Bennouna; Michael Boyer; Toyoaki Hida; Vera Hirsh; Terufumi Kato; Shun Lu; Tony Mok; Kazuhiko Nakagawa; Kenneth O'Byrne; Luis Paz-Ares; Martin Schuler; Denis Moro Sibilot; Eng-Huat Tan; Hiroshi Tanaka; Yi-Long Wu; James C-H Yang; Li Zhang; Caicun Zhou; Angela Märten; Wenbo Tang; Nobuyuki Yamamoto
    Lung cancer (Amsterdam, Netherlands) 132 126 - 131 2019年06月 [査読有り]
     
    OBJECTIVES: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. METHODS: Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates. RESULTS: Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. CONCLUSIONS: Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.
  • Masayuki Takeda; Kazuko Sakai; Takayuki Takahama; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    Cancers 11 6 2019年05月 [査読有り]
     
    : Recent progress in understanding the molecular basis of cancer-including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes-has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF and HER2 has already been successfully translated into clinical practice for individuals with solid tumor. Next-generation sequencing (NGS) technologies have led to the ability to test for multiple cancer-related genes at once with a small amount of cells and tissues. In Japan, several hospitals have started NGS-based mutational profiling screening in patients with solid tumor in order to guide patients to relevant clinical trials. The Ministry of Health, Labor, and Welfare of Japan has also approved several cancer gene panels for use in clinical practice. However, there is an urgent need to develop a medical curriculum of clinical variant interpretation and reporting. We review recent progress in the implementation of NGS in Japan.
  • Shunichi Sugawara; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Hiroshi Nokihara; Yuichiro Ohe; Makoto Nishio; Toshiaki Takahashi; Koichi Goto; Makoto Maemondo; Yukito Ichinose; Takashi Seto; Hiroshi Sakai; Akihiko Gemma; Fumio Imamura; Masato Shingyoji; Hideo Saka; Akira Inoue; Koji Takeda; Isamu Okamoto; Katsuyuki Kiura; Satoshi Morita; Tomohide Tamura
    International journal of clinical oncology 24 5 485 - 493 2019年05月 [査読有り]
     
    INTRODUCTION: The East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m2, the standard dosage in Japan. PATIENTS AND METHODS: Patients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety. RESULTS: Patient characteristics in the Japanese subgroup (n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group. CONCLUSIONS: This Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.
  • Qing Zhou; Yi-Long Wu; Jesus Corral; Kazuhiko Nakagawa; Edward B Garon; Eric I Sbar; Tao Wang; Rickard Sandin; Kay Noonan; Diana Gernhardt; Tony S Mok
    Future oncology (London, England) 15 13 1481 - 1491 2019年05月 [査読有り]
     
    Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.
  • Hiroaki Akamatsu; Yasuhiro Koh; Isamu Okamoto; Daichi Fujimoto; Akihiro Bessho; Koichi Azuma; Satoshi Morita; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 131 128 - 133 2019年05月 [査読有り]
     
    BACKGROUND: Liquid biopsy has been approved as an optional method to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). However, the clinical significance of its utility for monitoring the disease remains elusive. WJOG8114LTR is a prospective, multi-institutional study of liquid biopsy in EGFR mutated patients with NSCLC. PATIENTS AND METHODS: Chemotherapy naïve, advanced NSCLC patients with EGFR -sensitizing mutation received afatinib 40 mg/body until progressive disease (PD). Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFR mutations (exon 19 deletion, exon 20 T790 M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, digital PCR assay. This study was registered at UMIN 000015847. RESULTS: Fifty-seven patients were registered in the study. At baseline, 62.5% of patients were positive for EGFR mutation in plasma, and systemic spread of the tumor seemed to correlate with higher detection rate. After treatment, negative conversion of sensitive mutation within four weeks was observed among 87.5% of the patients. These patients demonstrated statistically significant longer progression-free survival than those who did not achieve negative conversion (13.6 months versus 5.1 months, p < 0.0001). Regarding progression, 35.7% of the patients showed recurrence in plasma DNA earlier than radiological progression. However, PFS curve based on plasma recurrence did not show significant difference than that based on RECIST. CONCLUSION: To predict durable efficacy and progression, liquid biopsy was useful in a part of EGFR mutated NSCLC patients.
  • Hiroaki Akamatsu; Shunsuke Teraoka; Yasuhiro Koh; Takeharu Yamanaka; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 2 139 - 141 2019年03月 [査読有り]
     
    Immune-checkpoint inhibitors (ICIs) play an important role in treatment for advanced non-small-cell lung cancer. Over one-half of patients, however, have relapse. Although rechallenge treatment of anti-cancer drugs that showed efficacy in prior lines of therapy has been broadly accepted in lung cancer, evidence of efficacy of rechallenge of ICIs has been limited to anecdotal case series. We therefore plan a phase II study. The primary endpoint is to assess the overall response rate of nivolumab in patients with advanced non-small-cell lung cancer who responded to prior ICIs. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Sixty patients will be enrolled in this trial. Programmed death-ligand 1 expression level in circulating tumor cells will be evaluated as a surrogate biomarker for the prediction of the efficacy.
  • Makoto Nishio; Toshiaki Takahashi; Hiroshige Yoshioka; Kazuhiko Nakagawa; Tatsuro Fukuhara; Kazuhiko Yamada; Masao Ichiki; Hiroshi Tanaka; Takashi Seto; Hiroshi Sakai; Kazuo Kasahara; Miyako Satouchi; Shi Rong Han; Kazuo Noguchi; Takashi Shimamoto; Terufumi Kato
    Cancer science 110 3 1012 - 1020 2019年03月 [査読有り]
     
    Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).
  • Hidetoshi Hayashi; Takayasu Kurata; Yuichi Takiguchi; Makoto Arai; Koji Takeda; Kohei Akiyoshi; Koji Matsumoto; Takuma Onoe; Hirofumi Mukai; Nobuaki Matsubara; Hironobu Minami; Masanori Toyoda; Yusuke Onozawa; Akira Ono; Yoshihiko Fujita; Kazuko Sakai; Yasuhiro Koh; Ayano Takeuchi; Yasuo Ohashi; Kazuto Nishio; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 7 570 - 579 2019年03月 [査読有り]
     
    PURPOSE: Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS: Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS: One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. CONCLUSION: Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.
  • Satomi Watanabe; Kimio Yonesaka; Junko Tanizaki; Yoshikane Nonagase; Naoki Takegawa; Koji Haratani; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Junji Tsurutani; Kazuhiko Nakagawa
    Cancer medicine 8 3 1258 - 1268 2019年03月 [査読有り]
     
    HER2-targeted therapy, especially the anti-HER2 antibody trastuzumab, is standard for HER2-positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)-dependent HER2-HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2-positive breast cancer. The anti-HER2 antibody pertuzumab and anti-HER3 antibody patritumab both target this heregulin-HER3-HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab-resistant HER2-positive breast cancer. HER2-positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3-HRG, BT474-HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474-HRG and an intrinsic heregulin-expressing and HER2-positive JIMT-1 xenograft models. SKBR3-HRG and BT474-HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin-expressing BT474-HRG and JIMT-1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin-expressing and HER2-positive breast cancer, which could be exploited clinically.
  • Shinichiro Suzuki; Koji Haratani; Takayuki Takahama; Satomi Watanabe; Naoki Takegawa; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 3 e50-e52 - e52 2019年03月 [査読有り]
  • Satoshi Watanabe; Hiroshige Yoshioka; Hiroshi Sakai; Katsuyuki Hotta; Mitsuhiro Takenoyama; Kazuhiko Yamada; Shunichi Sugawara; Yuichi Takiguchi; Yukio Hosomi; Keisuke Tomii; Seiji Niho; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Terufumi Kato; Toshiaki Takahashi; Ami Kamada; Kazumi Suzukawa; Yukie Omori; Sotaro Enatsu; Kazuhiko Nakagawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 129 55 - 62 2019年03月 [査読有り]
     
    OBJECTIVES: This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan. MATERIALS AND METHODS: The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m2 on days 1 and 8; cisplatin 75 mg/m2 on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival. RESULTS: In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio [HR] = 0.66, 95% CI: 0.47 - 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%). CONCLUSION: GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788.
  • Kimio Yonesaka; Naoki Takegawa; Satomi Watanabe; Koji Haratani; Hisato Kawakami; Kazuko Sakai; Yasutaka Chiba; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Kazuto Nishio; Kazuhiko Nakagawa
    Oncogene 38 9 1398 - 1409 2019年02月 [査読有り]
     
    EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
  • Hiroto Ueda; Hisato Kawakami; Yoshikane Nonagase; Naoki Takegawa; Tatsuya Okuno; Takayuki Takahama; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa
    The oncologist 24 2 163-e76 - e76 2019年02月 [査読有り]
     
    LESSONS LEARNED: The 5-fluorouracil, docetaxel, and nedaplatin (UDON) regimen was well tolerated and showed promising antitumor activity in terms of both objective response rate and survival for patients with advanced or recurrent esophageal squamous cell carcinoma in the first-line setting.UDON may be an optimal treatment option for patients with advanced esophageal cancer who are unfit for docetaxel, cisplatin, and 5-fluorouracil regimens.The high response rate as well as the rapid and marked tumor shrinkage associated with UDON suggest that further evaluation of this regimen in the neoadjuvant setting is warranted. BACKGROUND: A phase II study was performed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for untreated recurrent or metastatic esophageal cancer. METHODS: Patients received intravenous nedaplatin (90 mg/m2) on day 1, docetaxel (35 mg/m2) on days 1 and 15, and 5-fluorouracil (800 mg/m2) on days 1-5 of a 4-week cycle. The primary endpoint was response rate, with secondary endpoints including overall survival (OS), progression-free survival (PFS), dysphagia score, and adverse events. RESULTS: Between March 2015 and July 2017, 23 patients were enrolled. Of 22 evaluable patients, 16 and 4 individuals experienced a partial response and stable disease, respectively, yielding a response rate of 72.7% (95% confidence interval [CI], 49.8%-89.3%) and disease control rate of 90.9% (95% CI, 70.8%-98.9%). Median OS and PFS were 11.2 months (95% CI, 9.1 months to not reached) and 6.0 months (95% CI, 2.5-10.6 months), respectively. Eleven (64.7%) of the 17 patients with a primary lesion showed amelioration of dysphagia after treatment. Frequent adverse events of grade 3 or 4 included neutropenia (87.0%) and leukopenia (39.1%). Febrile neutropenia was observed in two patients (8.7%). CONCLUSION: This phase II study demonstrated promising antitumor activity and good tolerability of UDON.
  • Kimio Yonesaka; Yoshihisa Kobayashi; Hidetoshi Hayashi; Yasutaka Chiba; Tetsuya Mitsudomi; Kazuhiko Nakagawa
    Oncology reports 41 2 1059 - 1066 2019年02月 [査読有り]
     
    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) are efficacious drugs for non‑small cell lung cancers (NSCLCs) with EGFR‑activating mutations. Afatinib, a second‑generation EGFR‑TKI and osimertinib, a third‑generation EGFR‑TKI, are both standard therapies for patients with these types of cancer. Each drug possesses distinct binding sites for the tyrosine kinase domain of EGFR. The present study examined the efficacy of single and combination TKI therapy using in vitro growth inhibition assays of Ba/F3 cells with an EGFR‑activating Del19 mutation. Afatinib or osimertinib treatment alone markedly inhibited cell proliferation in Ba/F3 cells, although drug‑resistant cells eventually appeared with secondary EGFR mutations (either T790M or C797S, respectively) as determined by direct sequencing. Notably a combination of afatinib and osimertinib eradicated Ba/F3 cells with no development of resistance. We also evaluated the efficacy of afatinib, osimertinib, and a combination of the two, using drug‑resistant cells with T790M or C797S mutations. Osimertinib was effective for treating Ba/F3 cells with the T790M mutation, whereas afatinib was moderately effective against C797S Ba/F3 cells. However, subsequent treatment, even when both drugs were used in combination, could not completely eradicate the Ba/F3 population and doubly resistant cells with a variety of triple mutations were generated, including Del19/T790M/C797S. In conclusion, an initial treatment with a combination of osimertinib and afatinib is potentially more effective for eradicating mutant EGFR‑dependent cells than sequential drug use. This should be tested in future clinical trials to establish whether such a combination would be effective for the treatment of NSCLC.
  • Hayashi H; Kurata T; Takiguchi Y; Arai M; Takeda K; Akiyoshi K; Matsumoto K; Onoe T; Mukai H; Matsubara N; Minami H; Toyoda M; Onozawa Y; Ono A; Fujita Y; Sakai K; Koh Y; Takeuchi A; Ohashi Y; Nishio K; Nakagawa K
    Journal of Clinical Oncology 37 7 JCO1800771 - 579 Journal of Clinical Oncology 2019年01月 
    © 2019 by American Society of Clinical Oncology. PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (2
  • Masayuki Takeda; Kazuhiko Nakagawa
    International journal of molecular sciences 20 1 2019年01月 [査読有り]
     
    Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non⁻small cell lung cancer (NSCLC), selected based on the presence of EGFR mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with EGFR mutation⁻positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of EGFR-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment.
  • Shinsuke Uchida; Shun-Ichi Watanabe; Yukihiro Yoshida; Aki Kobayashi; Keisuke Asakura; Kazuo Nakagawa
    Journal of surgical case reports 2019 1 rjy359  2019年01月 [査読有り]
     
    Anatomic variations of the pulmonary artery (PA) cause vascular injuries and result in critical mistakes. Here we report the first case of lung cancer with a fissureless left upper lobectomy, an aberrant mediastinal trunk of the lingular and basal segments of the PA. A 65-year-old man was referred to our hospital with a solid mass on the left upper lobe. A fissureless left upper lobectomy was performed due to severe incomplete lobulation. Intraoperative findings showed an extremely rare anatomic variation (left A5+A8+A9b) that arose as a common trunk from the left main PA. To prevent intraoperative injury, it is essential to consider the unexpected mediastinal inferior branch and perform a surgical procedure such as fissureless lobectomy upon encountering incomplete lobulation.
  • Watanabe Satomi; Hayashi Hidetoshi; Haratani Koji; Shimizu Shigeki; Tanizaki Junko; Sakai Kazuko; Kawakami Hisato; Yonesaka Kimio; Tsurutani Junji; Togashi Yosuke; Nishio Kazuto; Ito Akihiko; Nakagawa Kazuhiko
    Cancer Science 110 1 52 - 60 2019年01月 
    非小細胞肺癌の細胞株や患者由来検体を実験材料とし、上皮成長因子受容体(EGFR)チロシンキナーゼ阻害薬(TKI)がMHCクラスIの発現に及ぼす影響について調査した。EGFR遺伝子にT790M二次的突然変異などの変異がある細胞株を適切なEGFR-TKIで処理するとMHCクラスIのmRNA/蛋白質発現は亢進した。細胞外シグナル調節キナーゼ(ERK)キナーゼであるMEKの阻害薬で処理した場合もMHCクラスI発現が亢進したことから、EGFR活性化に応答してみられるMHCクラスI発現の下方制御はMEK-ERK経路が媒介していることが示唆された。EGFR-TKI治療を施行したEGFR変異非小細胞肺癌患者から得た検体の免疫組織化学解析からも、疾患進行後においては、リン酸化EGFRやリン酸化ERKの下方制御が、MHC-Iの上方制御、CD8+浸潤T細胞の増加、およびPD-1リガンド1発現亢進と関連していることが明らかになった。これらの結果から、非小細胞癌においてEGFRが変異活性化するとMEK-ERK経路を通じてMHCクラスI発現が阻害され、免疫療法に不応となるのに寄与することが示唆された。
  • Arai S; Okabayashi A; Tohda R; Nakagawa K; Taniguchi M; Yanagihara S; Oiso N; Tsuruta D
    J Dermatol 46 1 e35 - e36 2019年01月 [査読有り]
  • Hiroaki Akamatsu; Hideyuki Harada; Shoji Tokunaga; Naruo Yoshimura; Hiroko Ikeda; Satoshi Oizumi; Naotoshi Sugimoto; Toshimi Takano; Haruyasu Murakami; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 1 e25-e27 - e27 2019年01月 [査読有り]
     
    Locally advanced non-small-cell lung cancer (NSCLC) is curable. Standard treatment is concurrent chemoradiotherapy, but its efficacy with cytotoxic agents seems to reach a plateau. Among patients with advanced NSCLC who have epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitor is the key drug. Thus, a similar strategy should be tested in patients with locally advanced NSCLC who have EGFR mutation. This single arm, phase II study aims to explore the efficacy and tolerability of gefitinib with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. The primary endpoint is progression-free survival rate at 2 years. The secondary endpoints are overall response rate, progression-free survival, overall survival, and safety. A total of 27 patients will be enrolled in this trial.
  • Naoyuki Nogami; Makoto Nishio; Isamu Okamoto; Sotaro Enatsu; Kazumi Suzukawa; Hiroki Takai; Kazuhiko Nakagawa; Tomohide Tamura
    Respiratory investigation 57 1 27 - 33 2019年01月 [査読有り]
     
    BACKGROUND: The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age). METHODS: The JMII study was a multicenter, post-marketing study that assessed the efficacy and safety of carboplatin (AUC6) and pemetrexed (500 mg/m2, given on Day 1 of a 21-day cycle, 4 cycles) followed by pemetrexed (500 mg/m2) maintenance in advanced non-squamous NSCLC patients (n = 109). Retrospective subgroup analyses were performed in elderly patients aged ≥70. RESULTS: The study includes younger (<70 years, n = 84) and elderly (≥70 years, n = 25) patients who received induction therapy. Median progression-free survival and overall survival from the start of the induction phase were 5.2 (95% CI: 3.5, 8.2) and 16.8 (95% CI: 10.3, NC) months for the elderly patients compared with 5.8 (95% CI: 4.3, 7.4) and 20.5 (95% CI: 16.7, NC) months for the younger patients, respectively. Grade 3/4 hematologic toxicities were more frequent in the elderly patients. Non-hematologic toxicities in the elderly patients were comparable to those in younger patients. Dose reduction was more common in the elderly (44% vs 23%), due to hematologic toxicities. CONCLUSIONS: There was no difference in efficacy (evaluated by progression-free survival) between elderly and younger patients. Although grade 3/4 hematologic toxicities were frequently observed in the elderly patients, they were easily managed with dose adjustment.
  • Satomi Watanabe; Hidetoshi Hayashi; Koji Haratani; Shigeki Shimizu; Junko Tanizaki; Kazuko Sakai; Hisato Kawakami; Kimio Yonesaka; Junji Tsurutani; Yosuke Togashi; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Cancer science 110 1 52 - 60 2019年01月 [査読有り]
     
    The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8+ T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC. .
  • Kazuma Kishi; Hiroshi Sakai; Takashi Seto; Toshiyuki Kozuki; Makoto Nishio; Fumio Imamura; Hiroshi Nokihara; Miyako Satouchi; Shintaro Nakagawa; Takashi Tahata; Kazuhiko Nakagawa
    Cancer treatment and research communications 18 100113 - 100113 2019年 [査読有り]
     
    INTRODUCTION: The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638. MATERIALS AND METHODS: Chemotherapy-naïve patients aged ≥ 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted. RESULTS: 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8-12.4); median OS was 15.6 months (95% CI 15.6-not evaluable); ORR was 68.9% (95% CI 55.7-80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8-95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes. CONCLUSION: The results presented are inconclusive due to the early termination of the study.
  • Yuichiro Ohe; Fumio Imamura; Naoyuki Nogami; Isamu Okamoto; Takayasu Kurata; Terufumi Kato; Shunichi Sugawara; Suresh S Ramalingam; Hirohiko Uchida; Rachel Hodge; Sarah L Vowler; Andrew Walding; Kazuhiko Nakagawa
    Japanese journal of clinical oncology 49 1 29 - 36 2019年01月 [査読有り]
     
    Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care. Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study. Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient). Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised. Clinical trial registration: NCT02296125 (ClinicalTrials.gov).
  • Hitomi Sakai; Masayuki Takeda; Kazuko Sakai; Yasushi Nakamura; Akihiko Ito; Hidetoshi Hayashi; Kaoru Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 127 59 - 65 2019年01月 [査読有り]
     
    OBJECTIVES: Immune-checkpoint inhibitors (ICIs) are now an established therapeutic option for advanced non-small cell lung cancer (NSCLC). It has remained unclear, however, whether cytotoxic chemotherapy affects the immune microenvironment in NSCLC wild type for EGFR and ALK. MATERIALS AND METHODS: We retrospectively evaluated changes in programmed cell death 1-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and CD8+ tumor-infiltrating lymphocyte (TIL) density in NSCLC patients who underwent rebiopsy at the site of recurrence after postoperative platinum-based adjuvant chemotherapy, or in those who underwent rebiopsy after one or more chemotherapeutic regimens at the advanced stage. The PD-L1 tumor proportion score (TPS) and CD8+ TIL density were determined by immunohistochemistry. TMB was estimated by next-generation sequencing with a cancer gene panel (409 genes). RESULTS: Seventeen patients with NSCLC wild type for EGFR and ALK were enrolled. Although PD-L1 TPS tended to be increased in rebiopsy samples compared with initial biopsy tissue, this difference was not significant (P =  0.113). Seven patients showed an increase in PD-L1 TPS, with this change being pronounced in four. Two cases in which PD-L1 TPS increased from 0 to 90% or from 0 to 95% after cytotoxic chemotherapy also showed a durable response to subsequent treatment with an ICI. No substantial correlation between PD-L1 TPS and TMB was apparent either before (R = 0.112) or after (R = 0.101) chemotherapy. A moderate correlation was detected between PD-L1 TPS and CD8+ TIL density before chemotherapy (R = 0.517) and a negligible correlation after (R = 0.0219). CONCLUSION: Cytotoxic chemotherapy may change the biological characteristics of tumors including PD-L1 expression level and TMB.
  • Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    OncoTargets and therapy 12 5355 - 5358 2019年 [査読有り]
     
    The discovery of RET rearrangement in non-small cell lung cancer (NSCLC) has prompted development of molecularly targeted therapy for such tumors, with several clinical trials being under way to evaluate the therapeutic effects of multitargeted tyrosine kinase inhibitors. The sensitivity of RET fusion-positive NSCLC to cytotoxic chemotherapy has remained unclear, however. We here report a case of NSCLC positive for the CCDC6-RET fusion gene that benefited from treatment with pemetrexed over a period of 30 months, suggesting that thymidylate synthase-targeted drugs such as pemetrexed may show efficacy for NSCLC harboring RET fusions.
  • Toshiharu Sakurai; Yoriaki Komeda; Tomoyuki Nagai; Ken Kamata; Kosuke Minaga; Kentarou Yamao; Mamoru Takenaka; Satoru Hagiwara; Tomohiro Watanabe; Naoshi Nishida; Hiroshi Kashida; Kazuhiko Nakagawa; Masatoshi Kudo
    Digestion 1 - 9 2018年12月 [査読有り]
  • Yutaka Kimura; Osamu Shiraishi; Hisato Kawakami; Hiroto Ueda; Tatsuya Okuno; Yoko Hiraki; Hiroaki Kato; Mitsuru Iwama; Atsushi Yasuda; Masayuki Shinkai; Takaaki Chikugo; Motohiro Imano; Haruhiko Imamoto; Kazuhiko Nakagawa; Takushi Yasuda
    Gan to kagaku ryoho. Cancer & chemotherapy 45 13 1812 - 1814 2018年12月 [査読有り]
     
    A 71-year-old man with a history of hypertension, diabetes mellitus, and cerebral infarction was admitted to our hospital with dysphagia. Gastroduodenoscopy, thoracoabdominal CT, and PET-CT findings showed type 2 advanced esophageal cancer( squamous cell carcinoma)with upper mediastinal and cervical lymph node(LN)metastasis: cT3N2M1(LYM #104L), cStage Ⅳ. Two courses of neoadjuvant UDONchemotherapy containing 5-FU(640mg/m / 2, days 1-5), docetaxel(28mg/m2, days 1 and 15), and nedaplatin(72mg/m2, day 1)were administered every 4 weeks. UDONtherapy caused grade(Gr)3 febrile neutropenia, Gr 2 diarrhea, and Gr 1 thrombopenia; the tumor and LNs partially responded to the therapy. After 2 courses of UDONtherapy, esophagectomy with right thoracotomy, 3-field LNdissection, and reconstruction of the gastric tube were performed. The postoperative course was almost uneventful besides recurrent nerve palsy, aspiration, pneumonia, and delirium, and the patient was discharged 60 days after surgery. The pathological diagnosis was ypT0N0M0, ypStage 0, and the histological response of the primary tumor and LNs were evaluated as Gr 3. Neoadjuvant UDON therapy is feasible for elderly patients with advanced esophageal cancer and renal failure or comorbidities, for whom CDDP could not be administered. We are planning a clinical trial to assess the effectiveness of neoadjuvant UDONtherapy.
  • Kato R; Hayashi H; Sano K; Handa K; Kumode T; Ueda H; Okuno T; Kawakami H; Matsumura I; Kudo M; Nakagawa K
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 12 e239 - e241 2018年12月 [査読有り]
  • 高用量CDDPの使用が困難な進行食道癌患者に対する術前化学療法の検討
    木村 豊; 白石 治; 川上 尚人; 植田 勲人; 奥野 達哉; 岩間 密; 加藤 寛章; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 今本 治彦; 中川 和彦; 安田 卓司
    日本消化器外科学会雑誌 51 Suppl.2 268 - 268 (一社)日本消化器外科学会 2018年11月
  • Hata A; Katakami N; Shimokawa M; Mitsudomi T; Yamamoto N; Nakagawa K
    Clinical lung cancer 19 6 e865 - e869 2018年11月 [査読有り]
     
    We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC.
  • 加藤 晃史; 岡田 守人; 木島 貴志; 青江 啓介; 藤本 伸一; 中川 和彦; 竹田 雄一郎; 樋田 豊明; 金井 一修; 今村 文生; 大泉 聡史; 高橋 利明; 竹之山 光広; 田中 洋史; 大江 裕一郎
    肺癌 58 6 461 - 461 (NPO)日本肺癌学会 2018年10月
  • Fumihiro Tanaka; Hiroyasu Yokomise; Toshinori Soejima; Hidetaka Uramoto; Takeharu Yamanaka; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yasumasa Nishimura; Hiroshi Niwa; Morihito Okada; Tatsuo Nakagawa; Motohiro Yamashita
    The Annals of thoracic surgery 106 4 1018 - 1024 2018年10月 [査読有り]
     
    BACKGROUND: The optimal therapeutic strategy for potentially resectable clinical (c-) stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. This phase II multiinstitutional study (West Japan Oncology Group 5308L) was designed to evaluate the feasibility of induction chemotherapy with concurrent thoracic radiotherapy (50 Gy), followed by resection and postoperative consolidation chemotherapy, in IIIA-N2 NSCLC. METHODS: Patients with resectable c-stage IIIA-N2 were eligible, and pathologic confirmation of N2 disease was mandatory. Patients received chemotherapy consisting of weekly carboplatin plus paclitaxel with concurrent radiotherapy (50 Gy in 25 fractions). Unless disease progression was documented, patients underwent surgical resection, and thereafter received two courses of consolidation chemotherapy with carboplatin plus paclitaxel. The primary end point was the proportion of patients who achieved complete resection after induction chemoradiotherapy (R0 rate). RESULTS: From December 2011 to November 2013, 40 eligible patients were enrolled. All patients completed induction chemoradiotherapy with an overall response rate of 58%, and 32 patients achieved complete resection (R0 rate, 80%) mostly with lobectomy (n = 27). Twenty patients (50%) completed the study treatment, including postoperative chemotherapy. After the median follow-up period of 38 months, the progression-free survival, overall survival, and recurrence-free survival rates at 2 years were 63%, 75%, and 62%, respectively. The 30-day and 90-day mortality were 0%. CONCLUSIONS: Induction chemotherapy with concurrent radiotherapy (50 Gy), followed by resection, was a feasible and promising treatment option for resectable c-stage IIIA-N2 NSCLC.
  • Yamamoto N; Kenmotsu H; Goto K; Takeda K; Kato T; Takeda M; Horinouchi H; Saito I; Sarashina A; Tanaka T; Morsli N; Nakagawa K
    Cancer chemotherapy and pharmacology 82 4 685 - 694 2018年10月 [査読有り]
  • Hiroaki Iwasa; Aradhan Sarkar; Takanobu Shimizu; Takeru Sawada; Shakhawoat Hossain; Xiaoyin Xu; Junichi Maruyama; Kyoko Arimoto-Matsuzaki; Kanchanamala Withanage; Kentaro Nakagawa; Hidetake Kurihara; Hidehito Kuroyanagi; Yutaka Hata
    Cancer Sci. 109 9 2767 - 2780 2018年09月 [査読有り]
     
    Ras-association domain family 6 (RASSF6) is a tumor suppressor that interacts with MDM2 and stabilizes p53. Caenorhabditis elegans unc-119 encodes a protein that is required for normal development of the nervous system. Humans have 2 unc-119 homologues, UNC119 and UNC119B. We have identified UNC119 as a RASSF6-interacting protein. UNC119 promotes the interaction between RASSF6 and MDM2 and stabilizes p53. Thus, UNC119 induces apoptosis by RASSF6 and p53. UNC119 depletion impairs DNA repair after DNA damage and results in polyploid cell generation. These findings support that UNC119 is a regulator of the RASSF6-MDM2-p53 axis and functions as a tumor suppressor.
  • Sakai Hitomi; Tsurutani Junji; Iwasa Tsutomu; Komoike Yoshifumi; Sakai Kazuko; Nishio Kazuto; Nakagawa Kazuhiko
    Breast Cancer 25 5 605 - 613 2018年09月 
    循環腫瘍DNA(ctDNA)のゲノム解析とその他のヒト上皮成長因子受容体2(HER2)陽性進行性乳癌(ABC)患者の臨床病理学的特徴を合わせて、trastuzumab emtasine(T-DM1)に対する初期耐性を予測した。T-DM1による治療を受けたHER2陽性ABC患者34例(年齢中央値62歳)を対象とした。患者の臨床病理学的特徴とT-DM1に対する初期耐性との相関関係を調べ、T-DM1を投与する前の患者16例から採取した血漿ctDNA検体を用いてHER2遺伝子コピー数とPIK3CA遺伝子突然変異を解析した。初回有効性解析の時点で疾患進行がみられた患者は9例で、これらの患者はT-DM1に対する初期耐性を有するとみなした。2群の間でT-DM1に対する初期耐性率の有意差は認められなかった。ctDNAを解析した16例のうち、4例がT-DM1に対する初期耐性を示した。これらの4例は、ctDNAにおけるHER2遺伝子増幅が陰性で、免疫組織化学検査ではエストロゲン受容体陽性および/またはプロゲステロン受容体陽性であった。
  • Murakami H; Nokihara H; Hayashi H; Seto T; Park K; Azuma K; Tsai CM; Yang JC; Nishio M; Kim SW; Kiura K; Inoue A; Takeda K; Kang JH; Nakagawa T; Takeda K; Akazawa R; Kaneko Y; Shimazaki M; Morita S; Fukuoka M; Nakagawa K
    Cancer science 109 9 2852 - 2862 2018年09月 [査読有り]
     
    Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations.
  • Junji Furuse; Takayasu Kurata; Naohiro Okano; Yasuhito Fujisaka; Daisuke Naruge; Toshio Shimizu; Hiroshi Kitamura; Tsutomu Iwasa; Fumio Nagashima; Kazuhiko Nakagawa
    Cancer chemotherapy and pharmacology 82 3 511 - 519 2018年09月 [査読有り]
     
    PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751.
  • Tomonari Sasaki; Takashi Seto; Takeharu Yamanaka; Naonobu Kunitake; Junichi Shimizu; Takeshi Kodaira; Makoto Nishio; Takuyo Kozuka; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Yukito Ichinose; Kazuhiko Nakagawa; Yasumasa Nishimura; Nobuyuki Yamamoto; Yoichi Nakanishi
    BRITISH JOURNAL OF CANCER 119 6 675 - 682 2018年09月 [査読有り]
     
    BACKGROUND: Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy.METHODS: Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UM1N000002420).RESULTS: From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm.CONCLUSIONS: The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.
  • Toshimi Takano; Junji Tsurutani; Masato Takahashi; Takeharu Yamanaka; Kazuko Sakai; Yoshinori Ito; Junya Fukuoka; Hideharu Kimura; Hidetaka Kawabata; Kenji Tamura; Koji Matsumoto; Kenjiro Aogi; Kazuhiko Sato; Kazuto Nishio; Kazuhiko Nakagawa; Toshiaki Saeki
    Breast (Edinburgh, Scotland) 40 67 - 75 2018年08月 [査読有り]
     
    BACKGROUND: For human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) with progression on trastuzumab-based therapy, continuing trastuzumab beyond progression and switching to lapatinib combined with chemotherapy are both valid options. We conducted an open-label, randomized phase II trial to compare the efficacy of these strategies. PATIENTS AND METHODS: Women with HER2-positive MBC previously treated with trastuzumab and taxanes were randomly assigned to receive trastuzumab plus capecitabine (HX) or lapatinib plus capecitabine (LX). The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and the objective response rate (ORR). To explore the predictive value of the differential benefit of anti-HER2 drugs, PIK3CA mutations were assessed using circulating tumor DNA. RESULTS: Eighty-six patients (43 in each arm) were enrolled. The median PFS was 6.1 months in the HX arm and 7.1 months in the LX arm (hazard ratio, 0.81; 90% CI, 0.55-1.21; p = 0.39); the median OS was 31.0 months in the HX arm and was not reached in the LX arm (hazard ratio, 0.58; 95% CI, 0.26-1.31; p = 0.18). The ORR was 40% in the HX arm and 41% in the LX arm. PIK3CA mutations were detected in 23% of the 35 analyzed patients, and in patients without PIK3CA mutations, LX yielded relatively longer PFS and OS than HX. CONCLUSION: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, no significant differences in PFS and OS were observed between patients treated with LX and HX. TRIAL REGISTRATION NUMBER: UMIN000005219.
  • Solomon BJ; Kim DW; Wu YL; Nakagawa K; Mekhail T; Felip E; Cappuzzo F; Paolini J; Usari T; Tang Y; Wilner KD; Blackhall F; Mok TS
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36 22 2251 - 2258 2018年08月 [査読有り]
  • Azuma K; Nishio M; Hayashi H; Kiura K; Satouchi M; Sugawara S; Hida T; Iwamoto Y; Inoue A; Takeda K; Ikeda S; Nakagawa T; Takeda K; Asahina S; Komatsu K; Morita S; Fukuoka M; Nakagawa K
    Cancer science 109 8 2532 - 2538 2018年08月 [査読有り]
     
    Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non-small-cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR-TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation-positive NSCLC. Epidermal growth factor receptor-TKI-naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end-point was to determine the safety of ASP8273 300 mg; the secondary end-point was antitumor activity defined by RECIST version 1.1. Thirty-one patients (12 men and 19 women; median age, 64 years [range, 31-82 years]) with EGFR mutation-positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment-emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post-baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once-daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI-naïve Japanese patients with EGFR mutation-positive NSCLC.
  • Mok TS; Cheng Y; Zhou X; Lee KH; Nakagawa K; Niho S; Lee M; Linke R; Rosell R; Corral J; Migliorino MR; Pluzanski A; Sbar EI; Wang T; White JL; Wu YL
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36 22 2244 - 2250 2018年08月 [査読有り]
  • Reungwetwattana T; Nakagawa K; Cho BC; Cobo M; Cho EK; Bertolini A; Bohnet S; Zhou C; Lee KH; Nogami N; Okamoto I; Leighl N; Hodge R; McKeown A; Brown AP; Rukazenkov Y; Ramalingam SS; Vansteenkiste J
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2018783118  2018年08月 [査読有り]
     
    Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.
  • 【分子標的薬の新しいバイオマーカー】 バイオマーカーの最近のtopics
    中川 和彦; 各務 博; 松村 到; 岩田 広治
    がん分子標的治療 16 2 146 - 153 (株)メディカルレビュー社 2018年07月 
    分子標的薬や免疫チェックポイント阻害薬ががん治療に浸透していくなかで、より適切で効果的な治療開発に向け、バイオマーカーの研究も進んでいる。たとえば、免疫チェックポイント阻害薬においては、腫瘍細胞におけるPD-L1発現が進行非小細胞肺がんに対するペムブロリズマブのコンパニオン診断として使われている。しかしながら、がん種によってPD-L1発現のバイオマーカーとしての臨床的意義が異なっていたり、腫瘍細胞に発現するPD-L1が重要なのか、それとも腫瘍組織に浸潤した細胞傷害性Tリンパ球(CTL)に発現されるPD-L1か、どちらをみるべきかといった議論もあり、今後解決すべき課題は多い。一方で、腫瘍細胞のtumor mutation burdenやCD62Lが新たなバイオマーカーとして注目されている。一方、分子標的薬のバイオマーカーとしては、肺がん領域において上皮成長因子受容体(EGFR)の遺伝子変異やALK、ROS1、BRAFの融合遺伝子の有無が治療方針の決定に用いられている。最近では第3世代のEGFRチロシンキナーゼ阻害薬(TKI)であるオシメルチニブのコンパニオン診断としてEGFR遺伝子変異T790Mの臨床導入も行われている。血液がんでは慢性骨髄性白血病(CML)のBCR-ABL融合遺伝子がイマチニブ治療の診断薬ならびに効果判定の指標として使用されている。乳がんでは古くからエストロゲン受容体(ER)やプロゲステロン(PG)の蛋白発現の有無がホルモン療法の有効性のバイオマーカーとして用いられてきた。トラスツズマブ治療の診断薬の指標としてのヒト上皮成長因子受容体(HER)2蛋白の過剰発現は固形がんの分子標的治療の先駆けとして有名である。近年はPI3Kの遺伝子変異や生殖細胞のBRCA変異による患者選択が臨床開発されている。本座談会では、がん治療各領域におけるトップリーダーをお招きしてバイオマーカー研究の最近のtopicsを総括した。(著者抄録)
  • Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer research and treatment : official journal of Korean Cancer Association 50 3 691 - 700 2018年07月 [査読有り]
  • Haratani K; Hayashi H; Nakagawa K
    JAMA oncology 4 7 1017 - 1018 2018年07月 [査読有り]
  • Makoto Nishio; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Tomohiro Tanaka; Hiroshi Kuriki; Ali Zeaiter; Tomohide Tamura
    Lung Cancer 121 37 - 40 2018年07月 [査読有り]
     
    Objectives: We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study. Materials and methods: Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method. Results: The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16–1.64 P = 0.2502) and 0.19 (95% CI: 0.07–0.53 P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases. Conclusion: Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.
  • Kimio Yonesaka; Koji Haratani; Shiki Takamura; Hitomi Sakai; Ryoji Kato; Naoki Takegawa; Takayuki Takahama; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Sigeki Kato; Osamu Maenishi; Kazuko Sakai; Yasutaka Chiba; Takafumi Okabe; Keita Kudo; Yoshikazu Hasegawa; Hiroyasu Kaneda; Michiko Yamato; Kenji Hirotani; Masaaki Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical Cancer Research 24 11 2653 - 2664 2018年06月 [査読有り]
  • Nonagase Y; Takeda M; Tanaka K; Hayashi H; Iwasa T; Nakagawa K
    Oncotarget 9 50 29532 - 29535 2018年06月 [査読有り]
     
    © Nonagase et al. Malignant tumors can induce a hypercoagulable state known as Trousseau syndrome that increases the risk for venous thromboembolism including disabling cerebral infarction. Anticoagulant therapy without anticancer treatment is not effective for amelioration of this coagulation abnormality. Most patients with lung cancer positive for activating mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR tyrosine kinase inhibitors (TKIs), but the efficacy and safety of EGFR-TKIs in such patients with a poor performance status (PS) due to Trousseau syndrome has been unclear. We here describe a patient with EGFR mutation-positive lung cancer who developed disabling cerebral infarction due to Trousseau syndrome. Administration of the EGFR-TKI gefitinib and anticoagulant therapy resulted in a partial tumor response and recovery from both the coagulation abnormality and the severe neurological symptoms. After the development of resistance to gefitinib, the EGFR-TKI osimertinib was safely administered until disease progression without recurrence of the coagulation abnormality. This case suggests that gefitinib followed by osimertinib may be a safe and effective treatment option for patients with EGFR mutation-positive lung cancer who experience disabling cerebral infarction due to Trousseau syndrome.
  • 進行性/再発性乳癌に対するeribulin/S-1併用療法の第II相試験(Phase II trial of Eribulin/S-1 combination therapy for advanced/recurrent breast cancer)
    鶴谷 純司; 岩朝 勤; 水野 豊; 小島 康幸; 高島 勉; 松並 展輝; 森本 卓; 山村 順; 大谷 彰一郎; 田辺 裕子; 渡邉 諭美; 加藤 了資; 高野 利美; 菰池 佳史; 中川 和彦
    日本乳癌学会総会プログラム抄録集 26回 334 - 334 2018年05月
  • Martin Reck; Edward B. Garon; Luis Paz-Ares; Santiago Ponce; Jesus Corral Jaime; Oscar Juan; Ernest Nadal; Katsuyuki Kiura; Ryan C. Widau; Shuang He; Rita Dalal; Pablo Lee; Kazuhiko Nakagawa
    Clinical Lung Cancer 19 3 213 - 220.e4 2018年05月 [査読有り]
     
    We conducted safety, exposure, and progression-free survival analyses of patients in part A (phase 1b) of RELAY, a randomized, double-blind, phase Ib/III study investigating ramucirumab-erlotinib in treatment-naive epidermal growth factor receptor-mutant stage IV non–small-cell lung cancer. Overall, ramucirumab-erlotinib showed no unexpected safety concerns and encouraging clinical activity. Phase III enrollment was initiated, maintaining ramucirumab at 10 mg/kg every 2 weeks with erlotinib at 150 mg/d. Background: Despite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non–small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC. Patients and Methods: Eligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles. Results: Fourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment. Conclusion: Ramucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.
  • Junko Tanizaki; Yasutaka Chiba; Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 13 5 e86 - e87 2018年05月 [査読有り]
  • Yosuke Makuuchi; Hidetoshi Hayashi; Koji Haratani; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Shigeki Shimizu; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 33 23315 - 23319 2018年05月 [査読有り]
     
    The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and ceritinib are standard treatment options for patients with non-small cell lung cancer (NSCLC) positive for ALK fusion genes. However, almost all patients eventually develop resistance to these drugs. We here report a case of ALK-rearranged NSCLC that developed resistance to alectinib but remained sensitive to ceritinib. The L1196M mutation within the ALK fusion gene was detected after failure of consecutive treatment with crizotinib and alectinib, but no other mechanism underlying acquired resistance to ALK-TKIs was found to be operative. Given the increasing application of ALK-TKIs to the treatment of patients with ALK-rearranged NSCLC, further clinical evaluation is warranted to provide a better understanding of the mechanisms of acquired resistance to these agents and to inform treatment strategies for such tumors harboring secondary mutations.
  • Yutaka Fujiwara; Masayuki Takeda; Noboru Yamamoto; Kazuhiko Nakagawa; Kaname Nosaki; Ryo Toyozawa; Chihiro Abe; Ryota Shiga; Kenji Nakamaru; Takashi Seto
    Oncotarget 9 34 23729 - 23737 2018年05月 [査読有り]
     
    Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6 600 mg n = 6 or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS- 6051a increased with dose. Compared with a US phase I study, AUC0-24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.
  • Hitomi Sakai; Junji Tsurutani; Tsutomu Iwasa; Yoshifumi Komoike; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Breast Cancer 25 5 1 - 9 2018年04月 [査読有り]
     
    Background: Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC. Methods: The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration. Results: Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry. Conclusions: HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Junko Tanizaki; Takayuki Takahama; Koji Haratani; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 30 21132 - 21140 2018年04月 [査読有り]
     
    Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited. Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon- 20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel. Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon- 20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2. Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.
  • Yoshihisa Nakatani; Hisato Kawakami; Masashi Ichikawa; Sachiyo Yamamoto; Yasuo Otsuka; Akiko Mashiko; Yasutoshi Takashima; Akihiko Ito; Kazuhiko Nakagawa; Shuji Arima
    Investigational New Drugs 36 4 1 - 6 2018年04月 [査読有り]
     
    Summary: We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death–ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules. Among infiltrating immune cells, aggregation of T cells was more extensive than that of B cells, with CD4+ T cells outnumbering CD8+ T cells, consistent with the relative numbers of these cells in the circulation. Treatment with methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function and reduction in the number of circulating CD4+ T cells. Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy.
  • Kodaira T; Kagami Y; Shibata T; Shikama N; Nishimura Y; Ishikura S; Nakamura K; Saito Y; Matsumoto Y; Teshima T; Ito Y; Akimoto T; Nakata K; Toshiyasu T; Nakagawa K; Nagata Y; Nishimura T; Uno T; Kataoka M; Yorozu A; Hiraoka M
    Annals of oncology : official journal of the European Society for Medical Oncology 29 4 992 - 997 2018年04月 [査読有り]
     
    Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8% onesided P=0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC.
  • Katsuyuki Kiura; Fumio Imamura; Hiroshi Kagamu; Shingo Matsumoto; Toyoaki Hida; Kazuhiko Nakagawa; Miyako Satouchi; Isamu Okamoto; Mitsuhiro Takenoyama; Yasuhito Fujisaka; Takayasu Kurata; Masayuki Ito; Kota Tokushige; Ben Hatano; Makoto Nishio
    Japanese journal of clinical oncology 48 4 367 - 375 2018年04月 [査読有り]
     
    Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days). Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. ClinicalTrials.gov identifier: NCT01828112.
  • Hideo Saka; Masahide Oki; Chiyoe Kitagawa; Yoshihito Kogure; Yuki Kojima; Akiko M. Saito; Atsuko Ishida; Teruomi Miyazawa; Koji Takeda; Kazuhiko Nakagawa; Shinji Sasada; Shunichi Negoro
    Japanese Journal of Clinical Oncology 48 4 376 - 381 2018年04月 [査読有り]
     
    Background: Malignant pleural effusion is a commonly seen complication of malignancies such as lung and breast cancers. In Western countries, talc is frequently used as a standard therapeutic agent (pleurodesis agent) with the aim of alleviating symptoms including dyspnea and chest pain. Talc is not recognized as a pleurodesis agent in Japan. The aim of this study was to verify the efficacy and safety of sterilized talc (NPC-05) for the introduction of talc in Japan. Methods: The study was a single-arm, open-label, investigator-initiated trial conducted jointly at six institutions. The subjects were 30 patients with malignant pleural effusions. A solution of 4 g NPC-05 suspended in 50 ml physiological saline was instilled into the pleural space to perform pleurodesis. Results: The efficacy of NPC-05 for pleural adhesion 30 days after pleurodesis was 83.3% (25/30 cases). Amelioration of dyspnea and pain (chest pain) was seen. Commonly seen adverse effects were increased C-reactive protein (CRP) and fever. Nearly all adverse events were phenomena previously reported as adverse effects of talc. No acute respiratory distress syndrome (ARDS) or other serious side effects occurred. Conclusion: The efficacy and safety of NPC-05 for malignant pleural effusion in Japanese patients was verified, and the clinical outcomes with talc were confirmed to be the same as previously reported in other countries. There is thought to be a high level of need for this agent in the treatment of malignant pleural effusion in Japan.
  • 木村 達郎; 川口 知哉; 工藤 新三; 千葉 康敬; 丹羽 崇; 渡部 克也; 木島 貴志; 小暮 啓人; 小栗 鉄也; 笠井 尚; 林 秀敏; 小野 哲; 田中 洋史; 吉岡 弘鎮; 矢野 聖二; 山本 信之; 中西 洋一; 中川 和彦
    日本呼吸器学会誌 7 増刊 149 - 149 (一社)日本呼吸器学会 2018年03月
  • 渡邉 諭美; 中川 和彦
    薬局 69 4 2104 - 2107 (株)南山堂 2018年03月
  • 悪性リンパ腫放射線治療後、2次発癌として進行食道癌を併発した1例
    奥野 達哉; 植田 勲人; 武川 直樹; 野長瀬 祥兼; 川上 尚人; 谷崎 潤子; 林 秀敏; 田中 薫; 武田 真幸; 鶴谷 純司; 中川 和彦
    日本消化器病学会雑誌 115 臨増総会 A328 - A328 (一財)日本消化器病学会 2018年03月
  • Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Keita Kudo; Kimio Yonesaka; Ryoji Kato; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    JAMA Oncology 4 3 374 - 378 2018年03月 [査読有り]
     
    IMPORTANCE Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non-small cell lung cancer (NSCLC) has remained unknown. OBJECTIVE To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. EXPOSURES The absence or presence of any irAE before the landmark date. MAIN OUTCOMES AND MEASURES Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. RESULTS In a cohort of 134 patients (median [range] age, 68 [33-85] years 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937 P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667 P = .003) for OS. CONCLUSIONS AND RELEVANCE Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.
  • Isamu Okamoto; Satoshi Morita; Naoki Tashiro; Fumio Imamura; Akira Inoue; Takashi Seto; Nobuyuki Yamamoto; Yuichiro Ohe; Kazuhiko Nakagawa; Masahiro Fukuoka
    Lung Cancer 117 14 - 19 2018年03月 [査読有り]
     
    Objectives Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting. Materials and methods Clinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived > 5 years from initiation of first-line treatment. Results The full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs. Conclusions This large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies.
  • Junichi Maruyama; Kazutoshi Inami; Fumiyoshi Michishita; Xinliang Jiang; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Norio Miyamura; Jun Hirayama; Hiroshi Nishina; Daichi Nogawa; Kouhei Yamamoto; Yutaka Hata
    Molecular Cancer Research 16 2 197 - 211 2018年02月 [査読有り]
     
    Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial–mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n ¼ 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells. Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers.
  • Miyako Satouchi; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa
    Japanese Journal of Cancer and Chemotherapy 45 2 257 - 264 2018年02月 [査読有り]
     
    The advent of anaplastic lymphoma kinase (ALK) inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer (NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib (Zykadia® capsules) is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events.
  • Treatment of EGFR mutation-positive non-small cell lung cancer complicated by Trousseau syndrome with gefitinib followed by osimertinib: a case report.
    Nonagase Y; Takeda M; Tanaka K; Hayashi H; Iwasa T; Nakagawa K
    Oncotarget. 9 50 29532 - 29535 2018年 [査読有り]
  • Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study.
    Fujiwara Y; Takeda M; Yamamoto N; Nakagawa K; Nosaki K; Toyozawa R; Abe C; Shiga R; Nakamaru K; Seto T
    Oncotarget. 9 34 23729 - 23737 2018年 [査読有り]
  • Clinical characteristics of non-small cell lung cancer harboring mutations in exon 20 of EGFR or HER2.
    Takeda M; Sakai K; Hayashi H; Tanaka K; Tanizaki J; Takahama T; Haratani K; Nishio K; Nakagawa K
    Oncotarget. 9 30 21132 - 21140 2018年 [査読有り]
  • Saka H; Oki M; Kitagawa C; Kogure Y; Kojima Y; Saito AM; Ishida A; Miyazawa T; Takeda K; Nakagawa K; Sasada S; Negoro S
    Jpn J Clin Oncol. 48 4 376 - 381 2018年 [査読有り]
  • Garassino MC; Cho BC; Kim JH; Mazi?res J; Vansteenkiste J; Lena H; Corral Jaime J; Gray JE; Powderly J; Chouaid C; Bidoli P; Wheatley-Price P; Park K; Soo RA; Huang Y; Wadsworth C; Dennis PA; Rizvi NA; ATLANTIC Investigators
    Lancet Oncol. 19 4 521 - 536 2018年 [査読有り]
  • Crizotinib Versus Chemotherapy in Asian Patients with Advanced ALK-positive Non-small Cell Lung Cancer.
    Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer Res Treat. 50 3 691 - 700 2018年 [査読有り]
  • Noma D; Inamura K; Matsuura Y; Hirata Y; Nakajima T; Yamazaki H; Hirai Y; Ichinose J; Nakao M; Ninomiya H; Mun M; Nakagawa K; Masuda M; Ishikawa Y; Okumura S
    Clinical lung cancer 19 1 e109 - e122 2018年01月 [査読有り]
     
    INTRODUCTION: Lymphovascular invasion (LVI) is a known adverse prognostic factor for early-stage non-small-cell lung cancer (NSCLC). Nonetheless, the prognostic effect of LVI on TNM staging of stage I NSCLC remains inconclusive. We thus hypothesized that it might be better to upstage pathologic stage IA NSCLC with LVI to pathologic stage IB NSCLC. PATIENTS AND METHODS: Using a Cox proportional hazards model, we examined the effect of LVI on disease-specific survival (DSS) in stage IA versus stage IB disease in 660 consecutive patients with stage I NSCLC (598 with adenocarcinoma, 62 with squamous cell carcinoma) who had undergone complete resection. RESULTS: On univariable analysis of stage IA cases, vascular invasion (VI) was significantly associated with inferior DSS (univariable hazard ratio [HR], 3.39; 95% confidence interval [CI], 1.46-7.89; P = .005). In contrast, lymphatic invasion exhibited a tendency toward inferior DSS (univariable HR, 2.90; 95% CI, 0.97-8.66; P = .056). Multivariable analysis of DSS in stage IA cases identified VI as an independent significant prognostic factor (multivariable HR, 2.86; 95% CI, 1.58-5.18; P = .007). With VI, DSS was significantly poorer for stage IB than for stage IA patients without VI (univariable HR, 3.44; 95% CI, 1.67-7.09; P < .001). In contrast, no difference was observed between patients with stage IA and VI and stage IB patients (P = .97). CONCLUSION: The presence of VI independently and significantly affects DSS in patients with stage IA NSCLC. We found that stage IA with VI and stage IB disease had equivalent prognostic outcomes. Our results suggest that stage IA with VI should be upstaged to IB in the TNM classification of NSCLC.
  • Takahama, T.; Azuma, K.; Shimokawa, M.; Kato, T.; Daga, H.; Okamoto, I.; Akamatsu, H.; Takahashi, T.; Ohira, T.; Yokoyama, T.; Hirano, K.; Shiraishi, Y.; Himeji, D.; Yamamoto, N.; Nishio, K.; Nakagawa, K.
    Annals of Oncology 29 2018年 [査読有り]
  • Junko Tanizaki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Yasushi Nakamura; Kimio Yonesaka; Keita Kudo; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Akihiko Ito; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 13 1 97 - 105 2018年01月 [査読有り]
     
    Objective The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab. Methods Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined. Results Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors. Conclusions A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.
  • Tomonori Mizutani; Masahiko Ando; Junki Mizusawa; Kenichi Nakamura; Haruhiko Fukuda; Hiroko Tsukada; Tetsuya Abe; Koji Takeda; Akira Yokoyama; Shinichiro Nakamura; Kazuhiko Nakagawa; Noboru Yamamoto; Yuichiro Ohe
    Journal of Geriatric Oncology 9 6 583 - 588 2018年 [査読有り]
     
    Objective: The Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire is commonly used for evaluating lung cancer-specific symptoms. The objective of this study was to elucidate the prognostic value of the LCS in older patients with advanced non-small cell lung cancer (NSCLC). Material and Methods: We conducted an integrated analysis of data from two randomized phase III trials (JCOG0207, JCOG0803/WJOG4307L) including patients aged 70 years or older with advanced NSCLC to evaluate the prognostic value of LCS scores at baseline (Aim 1) and for symptom improvement (an increase in LCS of two points or more during treatment) (Aim 2). Multivariable analyses for survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as a stratum. Results: A total of 327 patients were included in the analysis for Aim 1 and 373 patients for Aim 2. Approximately 70% of patients were aged 75 or older. In Aim 1, use of descriptive statistics determined a cutoff point for baseline LCS score of 21. Multivariable analysis showed that higher baseline LCS was associated with favorable overall survival (OS) (hazard ratio [HR]: 0.68 95% confidence interval [CI]: 0.52–0.89) and progression-free survival (HR: 0.68 95% CI: 0.52–0.89). In Aim 2, symptom improvement was not associated with favorable OS (HR: 0.97 95% CI: 0.72–1.23). Conclusion: It is recommended to consider baseline LCS scores while determining treatment strategies for older patients with advanced NSCLC.
  • Shinji Atagi; Junki Mizusawa; Satoshi Ishikura; Toshiaki Takahashi; Hiroaki Okamoto; Hiroshi Tanaka; Koichi Goto; Kazuhiko Nakagawa; Masao Harada; Yuichiro Takeda; Naoyuki Nogami; Yuka Fujita; Takashi Kasai; Kazuma Kishi; Toshiyuki Sawa; Koji Takeda; Keisuke Tomii; Miyako Satouchi; Takashi Seto; Yuichiro Ohe
    Clinical Lung Cancer 19 5 e619 - e627 2018年 [査読有り]
     
    We have previously reported on the superiority of combined chemoradiotherapy over radiotherapy alone in elderly patients with locally advanced non–small-cell lung cancer. The current long-term follow-up results reconfirmed that the significant survival benefit of combined chemoradiotherapy, previously observed, remained unchanged. There was no observed increase in late toxicity with chemoradiotherapy compared with radiotherapy alone. Introduction: In the phase III JCOG0301 trial, chemoradiotherapy (CRT) with daily low-dose carboplatin showed significant benefits in elderly patients with locally advanced non–small-cell lung cancer (NSCLC) compared with radiotherapy (RT) alone. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT in elderly patients are not well elucidated. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. Patients and Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT or CRT. Prognosis and adverse events data were collected beyond those in the initial report. Late toxicities were defined as occurring more than 90 days after RT initiation. Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100 CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better overall survival than the RT arm (hazard ratio, 0.743 95% confidence interval, 0.552-0.998 1-sided P =.0239). The proportion of Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) and treatment-related death have been seen since the initial report that was published. Conclusion: Long-term follow-up confirmed the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT compared with RT alone.
  • Tony S. K. Mok; Sang-We Kim; Yi-Long Wu; Kazuhiko Nakagawa; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Xiaojin Shi; Yuri Rukazenkov; Vincent Haddad; Kenneth S. Thress; Jean-Charles Soria
    JOURNAL OF CLINICAL ONCOLOGY 35 36 4027 - + 2017年12月 [査読有り]
     
    Purpose The Iressa Mutation-Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS) compared the continuation of gefitinib plus chemotherapy with placebo plus chemotherapy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer with progression (Response Evaluation Criteria in Solid Tumors 1.1) after first-line gefitinib. Primary results indicated no difference between treatments in terms of progression-free survival (PFS). The current analysis presents final, mature, overall survival (OS) data, together with exploratory analyses that examined whether specific biomarkers, including T790M mutation status, were able to differentiate a relative treatment effect. Patients and Methods Patients were randomly assigned to gefitinib 250 mg or placebo, in addition to cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) (maximum of six cycles of chemotherapy). EGFR mutation status was determined from plasma-derived circulating free tumor-derived DNA samples (beads, emulsification, amplification, and magnetics digital polymerase chain reaction assay, allelic fraction analysis). Results A total of 265 patients with non-small-cell lung cancer were randomly assigned, and overall data maturity was 66%. Continuation of gefitinib plus cisplatin and pemetrexed was detrimental to OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio [HR], 1.44; 95% CI, 1.07 to 1.94; P = .016; median OS, 13.4 v 19.5 months). The detriment was statistically significant in patients with T790M mutation-positive plasma samples (HR, 1.49; 95% CI, 1.02 to 2.21), whereas statistical significance was not reached in T790M mutation-negative patients (HR, 1.15; 95% CI, 0.68 to 1.94). PFS in T790M mutation-positive patients was similar between treatments, and the difference observed in T790M mutation-negative patients did not reach statistical significance (HR, 0.67; 95% CI, 0.43 to 1.03; P = .0745). Conclusion Final OS data from IMPRESS are supportive of earlier PFS results and are sufficient to warn physicians against the continuation of treatment with first-generation EGFR tyrosine kinase inhibitors beyond radiologic disease progression when chemotherapy is initiated. Plasma biomarker analyses suggest that this effect may be driven by T790M-positive status. (c) 2017 by American Society of Clinical Oncology
  • H. Nokihara; S. Lu; T. S. K. Mok; K. Nakagawa; N. Yamamoto; Y. K. Shi; L. Zhang; R. A. Soo; J. C. Yang; S. Sugawara; M. Nishio; T. Takahashi; K. Goto; J. Chang; M. Maemondo; Y. Ichinose; Y. Cheng; W. T. Lim; S. Morita; T. Tamura
    ANNALS OF ONCOLOGY 28 11 2698 - 2706 2017年11月 [査読有り]
     
    Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients with advanced NSCLC previously treated with >= 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m(2) in Japan, 75 mg/m(2) at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Japan Pharmaceutical Information Center, JapicCTI-101155.
  • Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 6 E449 - E455 2017年11月 [査読有り]
     
    Minimal (< 10 mm in thickness) pericardial effusion can be incidentally detected by computed tomography at diagnosis in patients with lung cancer. We retrospectively analyzed 428 patients diagnosed with advanced nonesmall-cell lung cancer. Our study found that 14.3% of patients presented with minimal pericardial effusion at first diagnosis, and its presence was an independent prognostic factor for reduced survival in patients with advanced nonesmall-cell lung cancer. Introduction: Minimal (< 10 mm in thickness) pericardial effusion (PCE) can be incidentally detected by computed tomography at the time of diagnosis in patients with lung cancer. Although malignant PCE is known to be associated with poor prognosis, the impact of minimal PCE on outcome has remained unclear. We therefore examined the prognostic relevance of minimal PCE in patients with advanced nonesmall-cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed consecutive patients diagnosed with stage IV NSCLC at Kindai University Hospital between April 2009 and March 2015. The patients were classified into 3 groups on the basis of the presence and thickness of PCE: no PCE, minimal (< 10 mm) PCE, and malignant (< 10 mm) PCE. The relation between overall survival and PCE status was examined with a Cox proportional hazards model. Results: The total of 428 enrolled patients included 327 (76.4%) in the no PCE group, 61 (14.3%) in the minimal PCE group, and 40 (9.3%) in the malignant PCE group. Median overall survival was 15.0, 10.1, and 7.6 months in the no PCE, minimal PCE, and malignant PCE groups, respectively, with the survival of patients with minimal PCE thus being intermediate between that of the other 2 groups (P = .003). Multivariable analysis revealed that minimal PCE was independently associated with reduced survival (hazard ratio, 1.46; 95% confidence interval, 1.07-1.96; P = .019). Conclusions: The presence of minimal PCE was an independent prognostic factor for reduced survival in patients with advanced NSCLC. (C) 2017 Elsevier Inc. All rights reserved.
  • Hidetoshi Hayashi; Yasutaka Chiba; Kazuko Sakai; Tomonobu Fujita; Hiroshige Yoshioka; Daisuke Sakai; Chiyoe Kitagawa; Tateaki Naito; Koji Takeda; Isamu Okamoto; Tetsuya Mitsudomi; Yutaka Kawakami; Kazuto Nishio; Shinichiro Nakamura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 6 719 - 723 2017年11月 [査読有り]
     
    Antibodies to programmed cell death-1 (PD-1), such as nivolumab, have shown promising clinical activity in patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy appears to be less pronounced in patients with such tumors harboring epidermal growth factor receptor gene (EGFR) mutations. Recent findings suggest that patients with EGFR mutation-positive NSCLC who develop resistance to tyrosine kinase inhibitors (TKIs) due to mechanisms other than acquisition of the secondary T790M mutation of EGFR are more likely to benefit from nivolumab treatment, possibly as a result of a higher level of expression of the PD-1 ligand PD-L1, than are patients who are T790M-positive. The WJOG8515L study (UMIN ID: 000021133) is a randomized phase II trial to compare nivolumab with the combination of carboplatin and pemetrexed in patients with EGFR mutation-positive nonsquamous NSCLC who have developed resistance to EGFR-TKIs due to mechanisms other than T790M. Eligible patients are those with stage IV or recurrent EGFR mutation-positive NSCLC who experience disease progression after therapy with more than 1 EGFR-TKI, including gefitinib, erlotinib, or afatinib; they must show no evidence of the T790M mutation on analysis of a tumor biopsy specimen obtained after progression on such EGFR-TKI therapy, or, if T790M is detected, they must again experience progression on subsequent treatment with a third-generation EGFR-TKI. The primary endpoint is progression-free survival (PFS), and secondary end points include overall survival (OS), objective response rate, duration of response, safety, and OS and PFS according to PD-L1 expression level. Recruitment started in May 2016 and is ongoing.
  • Satomi Watanabe; Takeshi Yoshida; Hisato Kawakami; Naoki Takegawa; Junko Tanizaki; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Junji Tsurutani; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 16 11 2563 - 2571 2017年11月 [査読有り]
     
    T790M mutation-selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with down-regulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFRTKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. (C) 2017 AACR.
  • Kaoru Kubota; Hiroshige Yoshioka; Fumihiro Oshita; Toyoaki Hida; Kiyotaka Yoh; Hidetoshi Hayashi; Terufumi Kato; Hiroyasu Kaneda; Kazuhiko Yamada; Hiroshi Tanaka; Yukito Ichinose; Keunchil Park; Eun Kyung Cho; Kyung-Hee Lee; Chih-Bin Lin; James Chih-Hsin Yang; Kaori Hara; Takayuki Asato; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 35 32 3662 - + 2017年11月 [査読有り]
     
    Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1: 1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m(2) IV and carboplatin area under the concentration-time curve 6 mg/mL . min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months (P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% (P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade >= 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. (C) 2017 by American Society of Clinical Oncology
  • Yi-Long Wu; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Fumito Tsuji; Rolf Linke; Rafael Rosell; Jesus Corral; Maria Rita Migliorino; Adam Pluzanski; Eric I. Sbar; Tao Wang; Jane Liang White; Sashi Nadanaciva; Rickard Sandin; Tony S. Mok
    LANCET ONCOLOGY 18 11 1454 - 1466 2017年11月 [査読有り]
     
    Background Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). Methods In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged >= 18 years or >= 20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1: 1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. Findings Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22.1 months (95% CI 20.3-23.9). Median progression-free survival according to masked independent review was 14.7 months (95% CI 11.1-16.6) in the dacomitinib group and 9.2 months (9.1-11.0) in the gefitinib group (hazard ratio 0.59, 95% CI 0.47-0.74; p<0.0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Interpretation Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.
  • Naoki Takegawa; Yoshikane Nonagase; Kimio Yonesaka; Kazuko Sakai; Osamu Maenishi; Yusuke Ogitani; Takao Tamura; Kazuto Nishio; Kazuhiko Nakagawa; Junji Tsurutani
    INTERNATIONAL JOURNAL OF CANCER 141 8 1682 - 1689 2017年10月 [査読有り]
     
    Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
  • Hiromichi Matsuoka; Chihiro Makimura; Atsuko Koyama; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa
    Biomedical Reports 7 4 380 - 384 2017年10月 [査読有り]
     
    Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680 p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naïve patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naïve and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.
  • Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Masato Terashima; Takeshi Yoshida; Kiyohiro Sakai; Yoichi Otake; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    BMC CANCER 17 1 674  2017年10月 [査読有り]
     
    Background: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief. Methods: The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS = >= 3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups. Discussion: A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain.
  • Hiroto Ueda; Masayuki Takeda; Shinya Ueda; Hisato Kawakami; Tatsuya Okuno; Naoki Takegawa; Hidetoshi Hayashi; Junji Tsurutani; Takao Tamura; Kazuki Ishikawa; Yasumasa Nishimura; Kazuhiko Nakagawa
    ONCOTARGET 8 46 80286 - 80294 2017年10月 [査読有り]
     
    Platinum-based chemotherapy is considered a standard treatment option for patients with metastatic esophageal carcinoma. However, the overall survival of patients receiving such treatment is <1 year. A common presenting symptom of esophageal cancer is dysphagia, which has a substantial impact on quality of life. We have now retrospectively evaluated the efficacy and safety of palliative chemoradiotherapy for patients with stage IV esophageal cancer, most of whom are unfit for curative chemoradiotherapy. Fifty consecutive patients diagnosed with stage IV esophageal cancer were treated with concurrent chemoradiotherapy at Kindai University Hospital between April 2008 and December 2014. Most (90%) patients received a total radiation dose of at least 50 Gy, and the median number of treatment cycles per patient was four for the combination of 5-fluorouracil and cisplatin. The response of the primary tumor and the overall response were 80% and 44%, respectively. The dysphagia score was improved after chemoradiotherapy in 36 (72%) patients and did not change between before and after treatment in 14 (28%) patients. With a median follow-up time of 9.4 months from the start of chemoradiotherapy, the median progression-free survival and overall survival were 4.7 and 12.3 months, respectively. Three patients (T4b in two, T3 in one) developed esophagobronchial fistula after completion of chemoradiotherapy (n = 2) or after disease progression (n = 1), resulting in death in each case. Our results suggest that palliative chemoradioiotherapy was safe and contributed the improvement of dysphagia in patients with stage IV esophageal cancer.
  • 吉田 健史; 渡邉 諭美; 武川 直樹; 川上 尚人; 中川 和彦
    肺癌 57 5 377 - 377 (NPO)日本肺癌学会 2017年09月
  • Masashi Yanae; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    Journal of Bone Oncology 8 18 - 22 2017年09月 [査読有り]
     
    Background Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. Methods We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. Results The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30–87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647–9.481 p = 0.002). Conclusions Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Nagashima Y; Yoshino S; Yamamoto S; Maeda N; Azumi T; Komoike Y; Okuno K; Iwasa T; Tsurutani J; Nakagawa K; Masaaki O; Hiroaki N
    Molecular and clinical oncology 7 3 359 - 366 2017年09月 [査読有り]
     
    Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of Lentinula edodes mycelia extract (LEM), which is an oral biological response modifier (BRM) medicine for cancer patients as such an adjuvant. A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, i.e., 5-fluorouracil (5-FU) + cyclophosphamide + epirubicin (FEC regimen), 5-FU + cyclophosphamide + doxorubicin/pirarubicin (FAC regimen), cyclophosphamide + doxorubicin/pirarubicin (AC regimen) and cyclophosphamide + epirubicin (EC regimen), were entered in the study. The patients were randomly divided into either an LEM or a placebo tablet group; the tablets were orally ingested daily over 2 courses of each therapy. In the placebo group, the total scores for QOL were lower on day 8 of the second course of chemotherapy compared with the baseline scores, whereas in the LEM group the scores had not decreased. In the placebo group, the QOL functional well-being score was lower on day 8 after both the first and second courses of chemotherapy compared with the baseline score, but it had not decreased in the LEM group. Evaluation of immunological parameters indicated that an increase in the proportion of regulatory T cells to peripheral blood CD4+ cells tended to be inhibited in the LEM group compared with the placebo group. Oral LEM that was coadministered with anthracycline-based chemotherapies was useful for maintaining patients' QOL and immune function. Thus, LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy.
  • Masashi Yanaea; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    JOURNAL OF BONE ONCOLOGY 8 18 - 22 2017年09月 [査読有り]
     
    Background: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. Methods: We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. Results: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged >= 60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Conclusions: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Chihiro Makimura; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE 24 4 535 - 541 2017年08月 [査読有り]
     
    Purpose Cancer pain is a multidimensional experience that includes physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Few prospective studies have examined the relationship between a patient's expectation of pain improvement and the pain prognosis. The aim of this prospective study was to investigate whether patients' expectation to pain reduction was associated with pain intensity after morphine treatment in opioid treatment-na < ve patients with various types of cancer. The subjects were patients scheduled for cancer pain treatment with morphine who were taking nonsteroidal anti-inflammatory drugs daily. Morphine treatment was performed according to the standard method, including titration (NCCN Guidelines (TM), Adult Cancer Pain). Simple regression analysis was performed between pain intensity numerical rating scale (NRS) (day 8) as the dependent variable, expectation of pain decrease NRS (day 1), tumor types, and the following covariates as independent variables: patients' characteristics such as age, gender, PS (day 1), genotype of catechol-O-methyltransferase, total scores of Hospital Anxiety and Depression Scale (day 1), and pain intensity NRS (day 1). Multiple regression analysis was performed using forced entry methods with pain intensity NRS (day 8) as the dependent variable, and expectation of pain decrease NRS (day 1) and the covariates as independent variables that had a p value < 0.05 in the simple regression models. A total of 100 patients with baseline data were included, and 97 patients (51% female) met the inclusion criteria. Patients with a high expectation of pain decrease NRS had a significantly lower pain intensity NRS (day 8) (p = 0.001). Non-pharmacological factors such as expectations for pain treatment could also be important factors to treat cancer pain, which might be associated with communication skills in physicians.
  • Hisato Kawakami; Junko Tanizaki; Kaoru Tanaka; Koji Haratani; Hidetoshi Hayashi; Masayuki Takeda; Ken Kamata; Mamoru Takenaka; Masatomo Kimura; Takaaki Chikugo; Takao Sato; Masatoshi Kudo; Akihiko Ito; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 35 4 529 - 536 2017年08月 [査読有り]
     
    Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with in-travenous nivolumab monotherapy (3.0 mg/kg) every 2 weeks until disease progression or irAEs occurred. Clinical data regarding the duration of nivolumab treatment, symptoms, laboratory abnormalities, pathological findings of liver parenchyma biopsy specimens, and management of nivolumab-related cholangitis were analyzed. Results Our analysis revealed that nivolumab-related cholangitis was characterized by (1) localized extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) a dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to the hepatic enzymes aspartate and alanine aminotransferase; (4) normal or reduced levels of the serum immunological markers antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and immunoglobulin G4; (5) the pathological finding of biliary tract cluster of differentiation 8-positive T cell infiltration from liver biopsy; and (6) amoderate to poor response to steroid therapy. Conclusions Nivolumab-related cholangitis is associated with distinct imaging and clinicopathological features that distinguish it from acute cholangitis of common etiologies and other immune-related cholangitis. Further studies are warranted to establish the optimal management of patients with this irAE.
  • Toyoaki Hida; Miyako Satouchi; Kazuhiko Nakagawa; Takashi Seto; Shingo Matsumoto; Katsuyuki Kiura; Hiroshi Nokihara; Haruyasu Murakami; Kota Tokushige; Ben Hatano; Makoto Nishio
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 7 618 - 624 2017年07月 [査読有り]
     
    ClinicalTrials.gov identifier: NCT01685060.Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. All 24 Japanese patients had received a parts per thousand<yen>2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.
  • Toyoaki Hida; Hiroshi Nokihara; Masashi Kondo; Young Hak Kim; Koichi Azuma; Takashi Seto; Yuichi Takiguchi; Makoto Nishio; Hiroshige Yoshioka; Fumio Imamura; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Takehito Shukuya; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takashi Asakawa; Ryoichi Asabe; Tomohiro Tanaka; Tomohide Tamura
    LANCET 390 10089 29 - 39 2017年07月 [査読有り]
     
    Background Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. Methods J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1: 1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). Findings Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0.34 [99.7% CI 0.17-0.71], stratified log-rank p< 0.0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20.3-not estimated) and was 10.2 months (8.2-12.0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. Interpretation These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.
  • 大学病院における早期からの緩和ケア・地域連携の実践
    吉田 健史; 松岡 弘道; 小山 敦子; 鶴谷 純司; 中川 和彦; 三瀬 博之; 尾崎 公俊; 前田 宗之; 新田 隆
    肺癌 57 3 251 - 251 (NPO)日本肺癌学会 2017年06月
  • Masayuki Takeda; Kazuko Sakai; Kazuhiko Nakagawa; Kazuto Nishio
    Transl Cancer Res 6 3 633 - 638 2017年06月 [査読有り]
     
    The development of targeted therapies for lung cancer based on the presence of corresponding specific biomarkers has highlighted the need for molecular diagnostic tests capable of the analysis of multiple actionable genetic alterations in a single tumor sample. Amplicon-based next-generation sequencing (NGS)- as opposed to conventional Sanger-based sequencing-has been introduced to facilitate the performance of multiple genomic tests with small amounts of tissue. In Japan, several institutions including the National Cancer Center and university hospitals have initiated NGS-based clinical testing for cancer patients and are able to provide access to investigational drugs or approved targeted agents matched to detected molecular alterations. However, no NGS system has yet been approved for the detection of somatic mutations by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. Further development of precision medicine in clinical practice in Japan will require changes to the medical curriculum to support the interpretation and annotation of NGS data. In this review, we introduce NGS-based clinical sequencing projects that are ongoing in Japan-in particular, those focusing on lung cancer-and we discuss issues relating to the integration of NGS into clinical practice.
  • Chee Khoon Lee; Lucy Davies; Yi-Long Wu; Tetsuya Mitsudomi; Akira Inoue; Rafael Rosell; Caicun Zhou; Kazuhiko Nakagawa; Sumitra Thongprasert; Masahiro Fukuoka; Sally Lord; Ian Marschner; Yu-Kang Tu; Richard J. Gralla; Val Gebski; Tony Mok; James Chih-Hsin Yang
    JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 109 6 2017年06月 [査読有り]
     
    Background: We performed an individual patient data meta-analysis to examine the impact of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: Data from trials comparing EGFR-TKI against chemotherapy in exon 19 deletion (del19) or exon 21 L858R (L858R) EGFR mutations patients were used. We performed Cox regression to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Impact of postprogression therapies was examined in exploratory analyses. All statistical tests were two-sided. Results: Six eligible trials (gefitinib = 3, erlotinib = 3) included 1231 patients; 632 received EGFR-TKI and 599 received chemotherapy. At a median 35.0 months follow-up, there were 780 deaths and 1004 progressions. There was no difference in OS between EGFR-TKI and chemotherapy (HR = 1.01, 95% CI = 0.88 to 1.17, P = .84). There was also no difference in OS for Del19 (n = 682, HR = 0.96, 95% CI = 0.79 to 1.16, P = .68) and L858R (n = 540, HR = 1.06, 95% CI = 0.86 to 1.32, P = .59) subgroups (Pinteraction = .47), or according to smoking status, sex, performance status, age, ethnicity, or histology. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P < .001) and in all subgroups. Following progression, 73.8% from the chemotherapy arm received EGFR-TKI, and 65.9% from the EGFR-TKI arm received chemotherapy. Nine percent from the EGFR-TKI arm received no further treatment vs 0.6% from the chemotherapy arm. Following disease progression, patients randomly assigned to EGFR-TKI had shorter OS than those randomly assigned to chemotherapy (12.8 months, 95% CI = 11.4 to 14.3, vs 19.8 months, 95% CI = 17.6 to 21.7). Conclusions: Despite statistically significant PFS benefit, there is no relative OS advantage with frontline gefitinib or erlotinib vs chemotherapy in EGFR-mutated NSCLC. This finding is likely due to the high rate of crossover at progression.
  • 西山 理; 山崎 亮; 西川 祐作; 佐野 安希子; 山縣 俊之; 佐野 博幸; 岩永 賢司; 東本 有司; 東田 有智; 中川 和彦
    気管支学 39 Suppl. S191 - S191 (NPO)日本呼吸器内視鏡学会 2017年05月
  • Toyoaki Hida; Makoto Nishio; Naoyuki Nogami; Yuichiro Ohe; Hiroshi Nokihara; Hiroshi Sakai; Miyako Satouchi; Kazuhiko Nakagawa; Mitsuhiro Takenoyama; Hiroshi Isobe; Shiro Fujita; Hiroshi Tanaka; Koichi Minato; Toshiaki Takahashi; Makoto Maemondo; Koji Takeda; Hideo Saka; Koichi Goto; Shinji Atagi; Tomonori Hirashima; Naoki Sumiyoshi; Tomohide Tamura
    CANCER SCIENCE 108 5 1000 - 1006 2017年05月 [査読有り]
     
    Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum- containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.
  • Masayuki Nakao; Yosuke Matsuura; Hirofumi Uehara; Mingyon Mun; Ken Nakagawa; Makoto Nishio; Yuichi Ishikawa; Sakae Okumura
    Asian Cardiovascular and Thoracic Annals 25 4 281 - 286 2017年05月 [査読有り]
     
    Background Systemic examination for distant metastases is generally recommended for all lung cancer patients. However, this approach rarely detects distant metastases in typically resectable cT1-2N0 non-small-cell lung cancer. The aim of this study was to identify factors associated with distant metastases and develop indication criteria for preoperative systemic examination in patients with cT1-2N0 non-small-cell lung cancer, with a particular focus on computed tomography imaging of primary lesions. Methods We retrospectively reviewed non-small-cell lung cancer patients treated at our institute between 2005 and 2013. Data were extracted and compared between two groups: patients diagnosed as cT1-2N0M0 who underwent complete resection (M0 group, n = 1530) and those diagnosed as cT1-2N0M1b who received systemic chemotherapy (M1 group, n = 26). Results The median age at diagnosis was significantly lower in the M1 group (p = 0.015). Although carcinoembryonic antigen levels were significantly higher in the M1 group (p < 0.001), 42% had normal levels. Tumor diameters in lung and mediastinal windows on chest computed tomography were significantly larger, and the proportion (mediastinal/lung window tumor diameter ratio) was higher in the M1 group (p < 0.001). All 26 patients in the M1 group had a tumor diameter > 15 mm and mediastinal/lung window ratio > 0.75. Conclusions Preoperative systemic examination is not necessary in cT1-2N0 non-small-cell lung cancer patients when tumor diameters are ≤15 mm and mediastinal/lung window ratios are ≤0.75. According to these criteria, systemic examinations would have been reduced by 40% in our cohort.
  • Toyoaki Hida; Makoto Nishio; Naoyuki Nogami; Yuichiro Ohe; Hiroshi Nokihara; Hiroshi Sakai; Miyako Satouchi; Kazuhiko Nakagawa; Mitsuhiro Takenoyama; Hiroshi Isobe; Shiro Fujita; Hiroshi Tanaka; Koichi Minato; Toshiaki Takahashi; Makoto Maemondo; Koji Takeda; Hideo Saka; Koichi Goto; Shinji Atagi; Tomonori Hirashima; Naoki Sumiyoshi; Tomohide Tamura
    Cancer Science 108 5 1000 - 1006 2017年05月 [査読有り]
     
    Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. Clinical trial registration number: JapicCTI-132072.
  • Tomohide Tamura; Katsuyuki Kiura; Takashi Seto; Kazuhiko Nakagawa; Makoto Maemondo; Akira Inoue; Toyoaki Hida; Hiroshige Yoshioka; Masao Harada; Yuichiro Ohe; Naoyuki Nogami; Haruyasu Murakami; Hiroshi Kuriki; Tadashi Shimada; Tomohiro Tanaka; Kengo Takeuchi; Makoto Nishio
    JOURNAL OF CLINICAL ONCOLOGY 35 14 1515 - + 2017年05月 [査読有り]
     
    Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naive, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment. (C) 2017 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/
  • Yuichi Tambo; Yukio Hosomi; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Yasutsuna Sasaki; Terufumi Kato; Toshiaki Takahashi; Takashi Seto; Makoto Maemondo; Hiroshi Nokihara; Ryo Koyama; Kazuhiko Nakagawa; Tomoya Kawaguchi; Yuta Okamura; Osamu Nakamura; Makoto Nishio; Tomohide Tamura
    INVESTIGATIONAL NEW DRUGS 35 2 217 - 226 2017年04月 [査読有り]
     
    Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m2. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m2) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1- 5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8- 5.7) months with docetaxel group and 4.1 (1.5- 5.4) months with DR group (hazard ratio HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade >= 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.
  • Naoya Yamazaki; Tatsuya Takenouchi; Manabu Fujimoto; Hironobu Ihn; Hiroshi Uchi; Takashi Inozume; Yoshio Kiyohara; Hisashi Uhara; Kazuhiko Nakagawa; Hiroshi Furukawa; Hidefumi Wada; Kazuo Noguchi; Takashi Shimamoto; Kenji Yokota
    Cancer chemotherapy and pharmacology 79 4 651 - 660 2017年04月 [査読有り]
     
    PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.
  • Toshio Shimizu; Kimio Yonesaka; Hidetoshi Hayashi; Tsutomu Iwasa; Koji Haratani; Hironori Yamada; Shoichi Ohwada; Emi Kamiyama; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 79 3 489 - 495 2017年03月 [査読有り]
     
    This phase 1 study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287) Process 2, a new formulation of fully human anti-HER3 monoclonal antibody in combination with erlotinib, an epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) in prior chemotherapy treated Japanese patients with advanced non-small cell lung cancer (NSCLC). Patients received intravenous patritumab Process 2 formulation at 9 mg/kg every 3 weeks after initiation of 18 mg/kg loading dose combined with continuous daily dose of erlotinib (150 mg QD) until any of the withdrawal criteria are met. Adverse events (AEs) were assessed using CTCAE v4.0 and tumor response was assessed using RECIST v1.1. Full pharmacokinetic sampling and serum biomarker analyses were mainly performed during cycle 1 and 2. Total of six EGFR-mutant NSCLC patients including one EGFR-TKI na < ve patient received patritumab Process 2 formulation combined with erlotinib. No dose-limiting toxicities were observed. The most frequent AEs were gastrointestinal or skin toxicities, which were generally mild and manageable. One patient discontinued from study due to reversible grade 3 interstitial lung disease. The mean area under the curve (AUC) value was 2640 mu g/day/mL; the Cmax value was 434 mu g/mL, respectively. The median progression-free survival (95% confidence interval) was 220.0 (100.0-363.0) days. HER3 ligand heregulin was detected in serum from only a patient that maintained most durable stable disease. Patritumab Process 2 formulation in combination with erlotinib was well tolerated compatible with favorable PK profile in Japanese patients with advanced NSCLC.
  • Kimio Yonesaka; Kenji Hirotani; Joachim von Pawel; Mircea Dediu; Shuquan Chen; Catherine Copigneaux; Kazuhiko Nakagawa
    LUNG CANCER 105 1 - 6 2017年03月 [査読有り]
     
    Objectives: Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n = 212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib. Materials and methods: Serum was obtained from participants prior to treatment (n = 202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed. Results: sHRG level was various (-1346-11,772 pg/mL). Participants were divided into the sHRG-high or-low subgroups at the concentration defining near the third quartile, 980 pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n = 46, hazard ratio 0.42 [0.19-0.96], p = 0.0327). In contrast, the HRG-low subgroup (n = 148) had no improvement in PFS with patritumab. Conclusion: sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Sakai K; Matsuoka H; Ohtake Y; Makimura C; Izumi H; Fujita Y; Otsuka M; Tsurutani J; Nishio K; Nakagawa K; Koyama A
    Molecular and clinical oncology 6 3 331 - 333 2017年03月 [査読有り]
     
    Carnitine deficiency is reportedly associated with increased pain sensation in diabetes mellitus and fibromyalgia, but the association between serum carnitine concentration and cancer pain has not been fully elucidated. We investigated the incidence of carnitine deficiency in patients with cancer pain, and examined the effect of the patients' demographic and clinical characteristics on pain intensity and carnitine deficiency. The serum carnitine concentration was measured in 50 patients with cancer pain receiving non-steroidal anti-inflammatory drugs, but not opioids. Multivariate regression analysis was used to determine the association of carnitine concentration, pain intensity, age and gender with hemoglobin and C-reactive protein (CRP) concentrations. Carnitine deficiency was detected in 9 of the patients (18.0%) and found to be significantly correlated with an elevated CRP concentration (P=0.039). In conclusion, although there does not appear to be an association between carnitine deficiency and cancer pain, it may be affected by inflammation or infection.
  • H. Yoshioka; N. Katakami; H. Okamoto; Y. Iwamoto; T. Seto; T. Takahashi; N. Sunaga; S. Kudoh; K. Chikamori; M. Harada; H. Tanaka; H. Saito; H. Saka; K. Takeda; N. Nogami; N. Masuda; T. Harada; H. Kitagawa; H. Horio; T. Yamanaka; M. Fukuoka; N. Yamamoto; K. Nakagawa
    ANNALS OF ONCOLOGY 28 2 285 - 291 2017年02月 [査読有り]
     
    Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35mg/m(2) on days 1-3 every 3 weeks) or docetaxel (60mg/m(2) on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade >= 3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade >= 3 leukopenia occurred in 63.3% and 70.7%, and grade >= 3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel.
  • Christian Manegold; Anne-Marie C. Dingemans; Jhanelle E. Gray; Kazuhiko Nakagawa; Marianne Nicolson; Solange Peters; Martin Reck; Yi-Long Wu; Odd Terje Brustugun; Lucio Crino; Enriqueta Felip; Dean Fennell; Pilar Garrido; Rudolf M. Huber; Aurelien Marabelle; Marcin Moniuszko; Francoise Mornex; Silvia Novello; Mauro Papotti; Maurice Perol; Egbert F. Smit; Kostas Syrigos; Jan P. van Meerbeeck; Nico van Zandwijk; James Chih-Hsin Yang; Caicun Zhou; Everett Vokes
    JOURNAL OF THORACIC ONCOLOGY 12 2 194 - 207 2017年02月 [査読有り]
     
    Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
  • Taniguchi H; Takeuchi S; Fukuda K; Nakagawa T; Arai S; Nanjo S; Yamada T; Yamaguchi H; Mukae H; Yano S
    Cancer science 108 1 53 - 60 2017年01月 [査読有り]
     
    Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.
  • Takashi Satoh; Katsuhiro Nakagawa; Fuminori Sugihara; Ryusuke Kuwahara; Motooki Ashihara; Fumihiro Yamane; Yosuke Minowa; Kiyoharu Fukushima; Isao Ebina; Yoshichika Yoshioka; Atsushi Kumanogoh; Shizuo Akira
    NATURE 541 7635 96 - + 2017年01月 [査読有り]
     
    Monocytes and macrophages comprise a variety of subsets with diverse functions(1-5). It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages(6-8). However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1(+)Msr1(+)Ly6C(-)F4/80(-)Mac1(+) monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein beta (C/EBP beta), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb(-/-) haematopoietic cells. Adoptive transfer of SatM into Cebpb(-/-) mice resulted in fibrosis. Notably, SatM are derived from Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBP beta licenses differentiation of SatM from their committed progenitor.
  • Masaya Yotsukura; Akihiko Yoshida; Aoi Sukeda; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Hisao Asamura; Noriko Motoi
    JOURNAL OF THORACIC ONCOLOGY 12 1 S1127 - S1128 2017年01月 [査読有り]
  • Kyohei Masai; Aoi Sukeda; Akihiko Yoshida; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Hisao Asamura; Noriko Motoi
    JOURNAL OF THORACIC ONCOLOGY 12 1 S1122 - S1122 2017年01月 [査読有り]
  • Takuro Mizukami; Yosuke Togashi; Saeko Naruki; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Azusa Yoneshige; Hidetoshi Hayashi; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Takashi Fujino; Narikazu Boku; Akihiko Ito; Kazuhiko Nakagawa; Kazuto Nishio
    Molecular Carcinogenesis 56 1 106 - 117 2017年01月 [査読有り]
     
    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of > 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.
  • Haratani K; Hayashi H; Tanaka T; Kaneda H; Togashi Y; Sakai K; Hayashi K; Tomida S; Chiba Y; Yonesaka K; Nonagase Y; Takahama T; Tanizaki J; Tanaka K; Yoshida T; Tanimura K; Takeda M; Yoshioka H; Ishida T; Mitsudomi T; Nishio K; Nakagawa K
    Ann Oncol 28 7 1532 - 1539 2017年 [査読有り]
     
    Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
  • Tomoko Funazo; Kyohei Morita; Naoya Ikegami; Chisato Konishi; Satoshi Nakao; Ryo Ariyasu; Masato Taki; Kazuhiko Nakagawa; Moon Hee Hwang; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka
    Internal Medicine 56 17 2317 - 2320 2017年 [査読有り]
     
    Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.
  • Chisato Konishi; Kazuhiko Nakagawa; Erika Nakai; Kenta Nishi; Ryoichi Ishikawa; Shinya Uematsu; Satoshi Nakao; Masato Taki; Kyohei Morita; Hwang Moon Hee; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka
    Internal Medicine 56 19 2633 - 2637 2017年 [査読有り]
     
    Interstitial lung disease (ILD) has rarely been reported as a manifestation of giant cell arteritis (GCA). We herein report a unique case of GCA in a 76-year-old woman who presented with ILD as an initial manifestation of GCA. Ten years before admission, she had been diagnosed with granulomatous ILD of unknown etiology. Corticosteroid therapy induced remission. One year after the cessation of corticosteroid therapy, she was admitted with a persistent fever. After admission, she developed left oculomotor paralysis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) proved extremely useful in establishing the diagnosis. Our case promotes awareness of GCA as a possible diagnosis for granulomatous ILD with unknown etiology.
  • Takuro Mizukami; Yosuke Togashi; Saeko Naruki; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Azusa Yoneshige; Hidetoshi Hayashi; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Takashi Fujino; Narikazu Boku; Akihiko Ito; Kazuhiko Nakagawa; Kazuto Nishio
    MOLECULAR CARCINOGENESIS 56 1 106 - 117 2017年01月 [査読有り]
     
    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. (c) 2016 Wiley Periodicals, Inc.
  • Edward B. Garon; Martin Reck; Luis Paz-Ares; Santiago Ponce; Jesus Corral Jaime; Oscar Juan; Ernest Nadal; Pablo Lee; Rita Dalal; Jingyi Liu; Shuang He; Joseph Treat; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 1 96 - 99 2017年01月 [査読有り]
     
    Introduction: We present the treatment rationale and study design for the RELAY study (NCT02411448). This phase lb/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation. Patients and Methods: The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase lb), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose -limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life. Conclusion: Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations. (C) 2016 Elsevier Inc. All rights reserved.
  • Hiromichi Matsuoka; Hiroyasu Kaneda; Kazuko Sakai; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical Lung Cancer 18 1 e85 - e87 2017年01月 [査読有り]
  • Kato R; Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO open 2 1 e000145  2017年 [査読有り]
  • Sakai H; Hayashi H; Iwasa T; Hasegawa Y; Takeda M; Nakagawa K
    ESMO open 2 Suppl 1 e000104  2017年 [査読有り]
  • Crizotinib Versus Chemotherapy in Asian Patients with Advanced ALK-positive Non-small Cell Lung Cancer.
    Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer Res Treat. 2017年 [査読有り]
  • Peritumoral ground-glass opacity associated with tumor pseudoprogression in a patient with non?small cell lung cancer treated with nivolumab.
    Kato R; ※Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO Open 2 1 e000145.  2017年 [査読有り]
  • ALK融合遺伝子陽性NSCLCに対するクリゾチニブ、アレクチニブ逐次療法の生存解析
    渡邉 諭美; 林 秀敏; 岡本 邦男; 田中 薫; 武田 真幸; 中川 和彦; 金田 裕靖; 藤原 季美子; 長谷川 喜一
    肺癌 56 7 1064 - 1064 (NPO)日本肺癌学会 2016年12月
  • Kyohei Masai; Koji Tsuta; Noriko Motoi; Kouya Shiraishi; Koh Furuta; Shigeki Suzuki; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Nobuyoshi Hiraoka; Hisao Asamura
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 11 12 2141 - 2149 2016年12月 [査読有り]
     
    INTRODUCTION: An association between usual interstitial pneumonia (UIP) and carcinogenesis has been well established. However, few detailed analyses have investigated the clinicopathological, immunohistochemical, and genetic features of patients with primary lung adenocarcinoma (ADC) with UIP (UIP-ADC). METHODS: We identified 44 patients with ADC in the setting of UIP (the UIP-ADC group) (1.9%) from 2309 patients with primary ADC and compared clinicopathological, immunohistochemical, and genetic features between the UIP-ADC group and patients with ADC without UIP (the non-UIP-ADC group). RESULTS: Clinicopathological features of UIP-ADC included an older age at occurrence; male predominance; smoking history; predilection for the lower lobe; large tumor size; high incidence of lymph vessel invasion, pleural invasion, and lymph node metastasis; and poor survival rate. However, the cause of death of patients with UIP-ADC was largely influenced by respiratory complications. Histologically, patients in the UIP-ADC group could be stratified according to invasive mucinous-predominant subtype. Genetically, patients in the UIP-ADC group had lower EGFR and higher KRAS mutation rates compared with patients in the non-UIP-ADC group. CONCLUSIONS: UIP-ADC was associated with a poor prognosis owing to the high frequency of perioperative complications rather than the malignancy of the tumor itself. There was a high prevalence of the invasive mucinous-predominant subtype in cases of UIP-ADC. UIP-ADC also had a low prevalence of EGFR mutations and a high prevalence of KRAS mutations. These findings suggest that UIP-ADC should be distinct from non-UIP-ADC.
  • Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani
    ONCOTARGET 7 51 84860 - 84871 2016年12月 [査読有り]
     
    Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
  • Hiroto Ueda; Hidetoshi Hayashi; Keita Kudo; Masayuki Takeda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 6 797 - 799 2016年12月 [査読有り]
     
    Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
  • Hiroto Ueda; Hidetoshi Hayashi; Keita Kudo; Masayuki Takeda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 6 797 - 799 2016年12月 [査読有り]
     
    Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
  • Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani
    ONCOTARGET 7 51 84860 - 84871 2016年12月 [査読有り]
     
    Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
  • Junko Tanizaki; Hidetoshi Hayashi; Masatomo Kimura; Kaoru Tanaka; Masayuki Takeda; Shigeki Shimizu; Akihiko Ito; Kazuhiko Nakagawa
    LUNG CANCER 102 44 - 48 2016年12月 [査読有り]
     
    The recent approval of nivolumab and other immune-checkpoint inhibitors for the treatment of certain solid tumors including non small cell lung cancer (NSCLC) has transformed cancer therapy. However, it will be important to characterize effects of such agents not seen with classical cytotoxic drugs or other targeted therapeutics. We here report two cases of NSCLC showing so-called pseudoprogression during nivolumab treatment. In both cases, imaging assessment revealed that liver metastatic lesions initially progressed but subsequently shrank during continuous nivolumab administration, with treatment also resulting in a decline in serum levels of carcinoembryonic antigen. Histological evaluation of the liver metastatic lesion of one case after regression revealed fibrotic tissue containing infiltrated lymphocytes positive for CD3, CD4, or CD8 but no viable tumor cells, suggestive of a durable immune reaction even after a pathological complete response. Given the increasing use of immune-checkpoint inhibitors in patients with NSCLC or other solid tumors, further clinical evaluation and pathological assessment are warranted to provide a better understanding of such pseudoprogression. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Joji Samejima; Mingyon Mun; Yosuke Matsuura; Masayuki Nakao; Hirofumi Uehara; Ken Nakagawa; Munetaka Masuda; Sakae Okumura
    JOURNAL OF THORACIC DISEASE 8 11 3105 - 3111 2016年11月 [査読有り]
     
    Background: Dealing with incomplete lung fissures during thoracoscopic surgery is difficult. Our objective was to evaluate the efficacy and safety of a thoracoscopic anterior 'fissure first' technique for dealing with incomplete left lung fissures. Methods: One hundred and seventy patients underwent left upper lobectomy or left lower lobectomy between April 2008 and July 2014. Of these, 34 patients underwent surgery using a thoracoscopic anterior 'fissure first' technique for incomplete fissures (group A) and 136 underwent surgery using a conventional thoracoscopic method for unfused fissures (group B). A four-port complete thoracoscopic approach was used in all patients. After completion of the fissure, hilar lymphadenectomy was performed in the conventional manner. Results: There were no significant differences between the two groups in operating time, blood loss, or duration of chest tube drainage. Patients in group A required more staple cartridges than those in group B (mean number of cartridges, 2.4 vs. 1.1; P<0.01). The two groups did not significantly differ with regard to the prevalence of air leaks (12% vs. 4%; P=0.11), either prolonged or delayed. Conclusions: We found that a thoracoscopic anterior 'fissure first' technique for left lung cancer with an incomplete fissure enabled hilar lymphadenectomy to be performed in the conventional manner without any increase in the prevalence of air leaks, operating time, or duration of chest tube drainage. This technique should be considered for use in left upper lobectomy or left lower lobectomy in patients with an incomplete fissure.
  • 米阪 仁雄; 前西 修; 廣谷 賢志; 金田 裕靖; 西尾 和人; 中川 和彦
    肺癌 56 6 530 - 530 (NPO)日本肺癌学会 2016年11月
  • Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    LUNG CANCER 101 11 - 15 2016年11月 [査読有り]
     
    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Masaaki Hibi; Hiroyasu Kaneda; Junko Tanizaki; Kazuko Sakai; Yosuke Togashi; Masato Terashima; Marco Antonio De Velasco; Yoshihiko Fujita; Eri Banno; Yu Nakamura; Masayuki Takeda; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Isamu Okamoto; Kazuto Nishio
    CANCER SCIENCE 107 11 1667 - 1676 2016年11月 [査読有り]
     
    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
  • Toyoaki Hida; Kazuhiko Nakagawa; Takashi Seto; Miyako Satouchi; Makoto Nishio; Katsuyuki Hotta; Toshiaki Takahashi; Yuichiro Ohe; Koji Takeda; Masahiro Tatsuno; Takashi Asakawa; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    CANCER SCIENCE 107 11 1642 - 1646 2016年11月 [査読有り]
     
    We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (20years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40mg vs 150mg; food effect with 150mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC(last)+/- standard deviation 3230 +/- 914h<bold>ng</bold>/mL vs 3710 +/- 1040h<bold>ng</bold>/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2months (95% CI 1.1-2.1). For the full analysis set (n=35) and crizotinib-failure subpopulations (n=23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9months (95% CI 11.1-not reached) and 12.9months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.
  • Martin Reck; Alexander Luft; Aleksandra Szczesna; Libor Havel; Sang-We Kim; Wallace Akerley; Maria Catherine Pietanza; Yi-long Wu; Christoph Zielinski; Michael Thomas; Enriqueta Felip; Kathryn Gold; Leora Horn; Joachim Aerts; Kazuhiko Nakagawa; Paul Lorigan; Anne Pieters; Teresa Kong Sanchez; Justin Fairchild; David Spigel
    JOURNAL OF CLINICAL ONCOLOGY 34 31 3740 - + 2016年11月 [査読有り]
     
    Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum(cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC. (C) 2016 by American Society of Clinical Oncology
  • Toyoaki Hida; Kazuhiko Nakagawa; Takashi Seto; Miyako Satouchi; Makoto Nishio; Katsuyuki Hotta; Toshiaki Takahashi; Yuichiro Ohe; Koji Takeda; Masahiro Tatsuno; Takashi Asakawa; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    CANCER SCIENCE 107 11 1642 - 1646 2016年11月 [査読有り]
     
    We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (20years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40mg vs 150mg; food effect with 150mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC(last)+/- standard deviation 3230 +/- 914h<bold>ng</bold>/mL vs 3710 +/- 1040h<bold>ng</bold>/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2months (95% CI 1.1-2.1). For the full analysis set (n=35) and crizotinib-failure subpopulations (n=23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9months (95% CI 11.1-not reached) and 12.9months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.
  • Masaaki Hibi; Hiroyasu Kaneda; Junko Tanizaki; Kazuko Sakai; Yosuke Togashi; Masato Terashima; Marco Antonio De Velasco; Yoshihiko Fujita; Eri Banno; Yu Nakamura; Masayuki Takeda; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Isamu Okamoto; Kazuto Nishio
    CANCER SCIENCE 107 11 1667 - 1676 2016年11月 [査読有り]
     
    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
  • Satomi Watanabe; Hidetoshi Hayashi; Kunio Okamoto; Kimiko Fujiwara; Yoshikazu Hasegawa; Hiroyasu Kaneda; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 17 6 528 - 534 2016年11月 [査読有り]
     
    We identified 11 patients with ALK-rearranged non-small cell lung cancer treated with sequential crizotinib and alectinib. The median combined progression-free survival and overall survival in the present study was 18.2 and 48.6 months, respectively. These findings suggest that this regimen produces durable survival and therefore warrants further investigation. Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first-and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Materials and Methods: Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results: The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 020.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion: Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.
  • Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    LUNG CANCER 101 11 - 15 2016年11月 [査読有り]
     
    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Kiyohiro Sakai; Masayuki Takeda; Hidetoshi Hayashi; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Tetsuya Mitsudomi; Atsuko Koyama; Kazuhiko Nakagawa
    THORACIC CANCER 7 6 670 - 675 2016年11月 [査読有り]
     
    IntroductionThe concept of oligometastasis has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. Patients and methodsConsecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node-negative disease and a limited number of metastatic lesions (5) per organ site and a limited number of affected organ sites (1 or 2) were eligible. ResultsEighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median overall survival for all patients was 15.9months, with that for EGFR mutation-positive patients tending to be longer than that for EGFR mutation-negative patients. ConclusionCure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC, especially negative for driver mutations.
  • Takayuki Takahama; Kazuko Sakai; Masayuki Takeda; Koichi Azuma; Toyoaki Hida; Masataka Hirabayashi; Tetsuya Oguri; Hiroshi Tanaka; Noriyuki Ebi; Toshiyuki Sawa; Akihiro Bessho; Motoko Tachihara; Hiroaki Akamatsu; Shuji Bandoh; Daisuke Himeji; Tatsuo Ohira; Mototsugu Shimokawa; Yoichi Nakanishi; Kazuhiko Nakagawa; Kazuto Nishio
    ONCOTARGET 7 36 58492 - 58499 2016年09月 [査読有り]
     
    Introduction: Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. Methods: We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. Results: A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M. Conclusions: Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
  • Kiyotaka Yoh; Yukio Hosomi; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Toshiko Koue; Takashi Nakamura; Sotaro Enatsu; Pablo Lee; David Ferry; Tomohide Tamura; Kazuhiko Nakagawa
    LUNG CANCER 99 186 - 193 2016年09月 [査読有り]
     
    Objectives: Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methods: Patients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10 mg/kg or placebo, followed by docetaxel 60 mg/m(2) (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. Results: In the primary population (N = 160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52-6.97] months; n=76) than with placebodocetaxel (4.21 [2.83-5.62] months; n = 81); hazard ratio 0.83 (95% CI 0.59-1.16). Median (95% CI) overall survival was 15.15 (12.45-26.55) months with ramucirumab-docetaxel and 14.65 con (11.93-24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56-1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). Conclusion: Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Xin Wang; Sotaro Enatsu; Tarun Puri; Mauro Orlando; James Chih-Hsin Yang
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3258 - + 2016年09月 [査読有り]
     
    Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2: 1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-freesurvival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P =.014; two-sided P =.029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+ G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
  • Yoshiko Urata; Nobuyuki Katakami; Satoshi Morita; Reiko Kaji; Hiroshige Yoshioka; Takashi Seto; Miyako Satouchi; Yasuo Iwamoto; Masashi Kanehara; Daichi Fujimoto; Norihiko Ikeda; Haruyasu Murakami; Haruko Daga; Tetsuya Oguri; Isao Goto; Fumio Imamura; Shunichi Sugawara; Hideo Saka; Naoyuki Nogami; Shunichi Negoro; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3248 - + 2016年09月 [査読有り]
     
    Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinibwere 6.5 and 7.5months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P =.257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P =.768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFRmutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P =.424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.
  • Yoshiko Urata; Nobuyuki Katakami; Satoshi Morita; Reiko Kaji; Hiroshige Yoshioka; Takashi Seto; Miyako Satouchi; Yasuo Iwamoto; Masashi Kanehara; Daichi Fujimoto; Norihiko Ikeda; Haruyasu Murakami; Haruko Daga; Tetsuya Oguri; Isao Goto; Fumio Imamura; Shunichi Sugawara; Hideo Saka; Naoyuki Nogami; Shunichi Negoro; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3248 - + 2016年09月 [査読有り]
     
    Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinibwere 6.5 and 7.5months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P =.257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P =.768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFRmutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P =.424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.
  • Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Xin Wang; Sotaro Enatsu; Tarun Puri; Mauro Orlando; James Chih-Hsin Yang
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3258 - + 2016年09月 [査読有り]
     
    Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2: 1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-freesurvival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P =.014; two-sided P =.029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+ G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
  • Takayuki Takahama; Kazuko Sakai; Masayuki Takeda; Koichi Azuma; Toyoaki Hida; Masataka Hirabayashi; Tetsuya Oguri; Hiroshi Tanaka; Noriyuki Ebi; Toshiyuki Sawa; Akihiro Bessho; Motoko Tachihara; Hiroaki Akamatsu; Shuji Bandoh; Daisuke Himeji; Tatsuo Ohira; Mototsugu Shimokawa; Yoichi Nakanishi; Kazuhiko Nakagawa; Kazuto Nishio
    ONCOTARGET 7 36 58492 - 58499 2016年09月 [査読有り]
     
    Introduction: Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. Methods: We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. Results: A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M. Conclusions: Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
  • Kiyotaka Yoh; Yukio Hosomi; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Toshiko Koue; Takashi Nakamura; Sotaro Enatsu; Pablo Lee; David Ferry; Tomohide Tamura; Kazuhiko Nakagawa
    LUNG CANCER 99 186 - 193 2016年09月 [査読有り]
     
    Objectives: Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methods: Patients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10 mg/kg or placebo, followed by docetaxel 60 mg/m(2) (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. Results: In the primary population (N = 160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52-6.97] months; n=76) than with placebodocetaxel (4.21 [2.83-5.62] months; n = 81); hazard ratio 0.83 (95% CI 0.59-1.16). Median (95% CI) overall survival was 15.15 (12.45-26.55) months with ramucirumab-docetaxel and 14.65 con (11.93-24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56-1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). Conclusion: Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Kazuhiko Nakagawa
    TRANSLATIONAL CANCER RESEARCH 5 3 S554 - S556 2016年09月 [査読有り]
  • Koichi Goto; Yuichiro Ohe; Taro Shibata; Takashi Seto; Toshiaki Takahashi; Kazuhiko Nakagawa; Hiroshi Tanaka; Koji Takeda; Makoto Nishio; Kiyoshi Mori; Miyako Satouchi; Toyoaki Hida; Naruo Yoshimura; Toshiyuki Kozuki; Fumio Imamura; Katsuyuki Kiura; Hiroaki Okamoto; Toshiyuki Sawa; Tomohide Tamura
    LANCET ONCOLOGY 17 8 1147 - 1157 2016年08月 [査読有り]
     
    Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1: 1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1.0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided a of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22.7 months (IQR 20.0-35.3). Overall survival was significantly longer in the combination chemotherapy group (median 18.2 months, 95% CI 15.7-20.6) than in the topotecan group (12.5 months, 10.8-14.9; hazard ratio 0.67, 90% CI 0.51-0.88; p=0.0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.
  • Benjamin J. Solomon; Federico Cappuzzo; Enriqueta Felip; Fiona H. Blackhall; Daniel B. Costa; Dong-Wan Kim; Kazuhiko Nakagawa; Yi-Long Wu; Tarek Mekhail; Jolanda Paolini; Jennifer Tursi; Tiziana Usari; Keith D. Wilner; Paulina Selaru; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 34 24 2858 - + 2016年08月 [査読有り]
     
    Purpose Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer. Patients and Methods Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3weeks for <= six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. Results Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < . 001; median, 10.9v 7.0months, respectively). Conclusion Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
  • Benjamin J. Solomon; Federico Cappuzzo; Enriqueta Felip; Fiona H. Blackhall; Daniel B. Costa; Dong-Wan Kim; Kazuhiko Nakagawa; Yi-Long Wu; Tarek Mekhail; Jolanda Paolini; Jennifer Tursi; Tiziana Usari; Keith D. Wilner; Paulina Selaru; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 34 24 2858 - + 2016年08月 [査読有り]
     
    Purpose Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer. Patients and Methods Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3weeks for <= six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. Results Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < . 001; median, 10.9v 7.0months, respectively). Conclusion Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
  • Koichi Goto; Yuichiro Ohe; Taro Shibata; Takashi Seto; Toshiaki Takahashi; Kazuhiko Nakagawa; Hiroshi Tanaka; Koji Takeda; Makoto Nishio; Kiyoshi Mori; Miyako Satouchi; Toyoaki Hida; Naruo Yoshimura; Toshiyuki Kozuki; Fumio Imamura; Katsuyuki Kiura; Hiroaki Okamoto; Toshiyuki Sawa; Tomohide Tamura
    LANCET ONCOLOGY 17 8 1147 - 1157 2016年08月 [査読有り]
     
    Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1: 1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1.0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided a of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22.7 months (IQR 20.0-35.3). Overall survival was significantly longer in the combination chemotherapy group (median 18.2 months, 95% CI 15.7-20.6) than in the topotecan group (12.5 months, 10.8-14.9; hazard ratio 0.67, 90% CI 0.51-0.88; p=0.0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.
  • Kazuo Nakagawa; Hisao Asamura; Koji Tsuta; Kanji Nagai; Eiji Yamada; Genichiro Ishii; Tetsuya Mitsudomi; Akihiko Ito; Masahiko Higashiyama; Yasuhiko Tomita; Masayoshi Inoue; Eiichi Morii; Nariaki Matsuur; Meinoshin Okumura
    LUNG CANCER 97 1 - 7 2016年07月 [査読有り]
     
    Objectives: The precise and rapid diagnosis of the presence or absence of lymph node (LN) metastasis is essential for deciding upon an appropriate therapeutic strategy for patients with non-small cell lung cancer (NSCLC). We conducted a prospective multicenter clinical trial in Japan to evaluate a rapid, automated and objective assay system, the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp), which targets cytokeratin 19 mRNA, to detect LN metastasis of NSCLC. Materials and methods: A total of 410 Lymph nodes (LNs) from 111 patients with clinical stage IB to IIIA NSCLC who underwent lung resection with LN dissection were included in this study. The LNs were divided into 4 blocks and examined by either the OSNA assay or a 3-level histological examination. The results of each method were compared and further analyses were performed for discordant cases. The primary endpoint was a concordance rate of more than 85% between the two methods. Results: The concordance rate between the two methods was 92.7% (95% CI, 89.7-95.0%), with a sensitivity of 79.7% (95% CI, 67.2-89.0%). Discordant results were observed in 30 LNs (5.8%), and were mainly due to a tissue allocation bias and/or contamination by CK19-expressing alveolar cells in LNs. Conclusion: The OSNA assay gave a diagnosis that was as accurate as a 3-level histological examination, which is more detailed than a histological examination in routine clinical practice. The OSNA assay might be useful in intraoperative decision-making in personalized lung cancer surgery based on the LN status. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Takekazu Iwata; Ichiro Yoshino; Shigetoshi Yoshida; Norihiko Ikeda; Masahiro Tsuboi; Yuji Asato; Nobuyuki Katakami; Kazuhiro Sakamoto; Yoshinori Yamashita; Jiro Okami; Tetsuya Mitsudomi; Motohiro Yamashita; Hiroshi Yokouchi; Kenichi Okubo; Morihito Okada; Mitsuhiro Takenoyama; Masayuki Chida; Keisuke Tomii; Motoki Matsuura; Arata Azuma; Tae Iwasawa; Kazuyoshi Kuwano; Shuji Sakai; Kenzo Hiroshima; Junya Fukuoka; Kenichi Yoshimura; Hirohito Tada; Kazuhiko Nakagawa; Yoichi Nakanishi
    RESPIRATORY RESEARCH 17 1 90  2016年07月 [査読有り]
     
    Background: Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. Methods: Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non-AE-IPF rate during postoperative days 0-30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. Results: From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7-99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5-99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3-5 adverse events were observed. Conclusions: Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients.
  • Iwata T; Yoshino I; Yoshida S; Ikeda N; Tsuboi M; Asato Y; Katakami N; Sakamoto K; Yamashita Y; Okami J; Mitsudomi T; Yamashita M; Yokouchi H; Okubo K; Okada M; Takenoyama M; Chida M; Tomii K; Matsuura M; Azuma A; Iwasawa T; Kuwano K; Sakai S; Hiroshima K; Fukuoka J; Yoshimura K; Tada H; Nakagawa K; Nakanishi Y; West Japan; Oncology Group
    Respiratory research 17 1 90  2016年07月 [査読有り]
  • Shunta Nagashima; Junichi Maruyama; Shodai Kawano; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Hiroshi Nishina; Yutaka Hata
    CANCER SCIENCE 107 6 791 - 802 2016年06月 [査読有り]
     
    Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. It is phosphorylated by large tumor suppressor kinases, the core kinases of the tumor-suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and upregulates genes implicated in epithelial-mesenchymal transition. It also confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attention as a therapeutic target in cancer therapy. We applied 18 606 small chemical compounds to human osteosarcoma U2OS cells expressing GFP-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for compounds that inhibit TAZ and show anticancer properties. To develop anticancer drugs, we need additional assays to select the compounds.
  • 大学病院における早期からの緩和ケア・地域連携の実践 腫瘍内科と緩和ケアの融合の試み
    吉田 健史; 和泉 宏昌; 牧村 ちひろ; 松岡 弘道; 三瀬 博之; 尾崎 公俊; 前田 宗之; 新田 隆; 鶴谷 純司; 小山 敦子; 中川 和彦
    Palliative Care Research 11 Suppl. S502 - S502 (NPO)日本緩和医療学会 2016年06月
  • Toshio Shimizu; Takashi Seto; Fumihiko Hirai; Mitsuhiro Takenoyama; Kaname Nosaki; Junji Tsurutani; Hiroyasu Kaneda; Tsutomu Iwasa; Hisato Kawakami; Kazuo Noguchi; Takashi Shimamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 347 - 354 2016年06月 [査読有り]
     
    Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.
  • Satomi Watanabe; Masayuki Takeda; Takayuki Takahama; Tsutomu Iwasa; Junji Tsurutani; Junko Tanizaki; Toshio Shimizu; Kazuko Sakai; Yoshitaka Wada; Noritaka Isogai; Kazuto Nishio; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 394 - 396 2016年06月 [査読有り]
     
    Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.
  • Toshio Shimizu; Takashi Seto; Fumihiko Hirai; Mitsuhiro Takenoyama; Kaname Nosaki; Junji Tsurutani; Hiroyasu Kaneda; Tsutomu Iwasa; Hisato Kawakami; Kazuo Noguchi; Takashi Shimamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 347 - 354 2016年06月 [査読有り]
     
    Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.
  • Satomi Watanabe; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Annals of Translational Medicine 4 11 225  2016年06月 [査読有り]
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Satoshi Ikeo; Takashi Yokoi; Yoshitaro Torii; Kunio Okamoto; Yosuke Tamura; Kaoru Tanaka; Yasuhito Fujisaka; Isao Goto; Hiroyasu Kaneda; Takayasu Kurata; Hiroshige Yoshioka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Toshio Shimizu; Kazuto Nishio; Kazuko Sakai; Hidetoshi Hayashi; Kunio Okamoto; Masayuki Takeda; Tsutomu Iwasa; Kaoru Tanaka; Koji Aoyama; Maiko Morishita; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Toshio Shimizu; Kazuya Fukuoka; Masayuki Takeda; Tutomu Iwasa; Takeshi Yoshida; Joanna Horobin; Mitchell Keegan; Lou Vaickus; Ajit Chavan; Mahesh Padval; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 77 5 997 - 1003 2016年05月 [査読有り]
     
    Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. Methods VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Results Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.
  • Akira Inoue; Kazushi Yoshida; Satoshi Morita; Fumio Imamura; Takashi Seto; Isamu Okamoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Satoshi Muto; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 5 462 - 467 2016年05月 [査読有り]
     
    Background: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years x 100. Results: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with >= 2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.
  • Akira Inoue; Kazushi Yoshida; Satoshi Morita; Fumio Imamura; Takashi Seto; Isamu Okamoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Satoshi Muto; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 5 462 - 467 2016年05月 [査読有り]
     
    Background: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years x 100. Results: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with >= 2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.
  • Toshio Shimizu; Kazuya Fukuoka; Masayuki Takeda; Tutomu Iwasa; Takeshi Yoshida; Joanna Horobin; Mitchell Keegan; Lou Vaickus; Ajit Chavan; Mahesh Padval; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 77 5 997 - 1003 2016年05月 [査読有り]
     
    Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. Methods VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Results Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.
  • N. Takegawa; H. Hayashi; N. Iizuka; T. Takahama; H. Ueda; K. Tanaka; M. Takeda; K. Nakagawa
    ANNALS OF ONCOLOGY 27 5 953 - 955 2016年05月 [査読有り]
  • M. Takeda; K. Sakai; K. Okamoto; H. Hayashi; K. Tanaka; T. Shimizu; K. Nishio; K. Nakagawa
    ANNALS OF ONCOLOGY 27 4 748 - 750 2016年04月 [査読有り]
     
    RET fusion genes have recently been identified as new "druggable" drivers in 1% to 2% of lung adenocarcinomas, with several clinical trials now being under way to evaluate the therapeutic effects of RET tyrosine kinase inhibitors in patients with RET fusion-positive lung cancer. We here describe a case study of long-term efficacy of docetaxel plus nintedanib (BIBF 1120) that was manifest over 33 months in a female never-smoker with non-small cell lung cancer wild-type for EGFR and ALK. Multiplex genetic testing of lung biopsy specimens revealed a CCDC6-RET fusion gene but no other actionable mutations. Our findings suggest that RET rearrangement as identified by multiplex testing is a potential target for nintedanib therapy.
  • Masayuki Takeda; Takeharu Yamanaka; Takashi Seto; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Haruhiro Saito; Akihito Kubo; Toshiyuki Sawa; Eiji Miyahara; Naoyuki Nogami; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto
    CANCER 122 7 1050 - 1059 2016年04月 [査読有り]
     
    BACKGROUNDBevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODSWest Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTSOne hundred patients were randomly assigned to receive docetaxel (n=50) or docetaxel plus bevacizumab (n=50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P<.2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P=.11). No unexpected or severe adverse events were recorded. CONCLUSIONSFurther evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. Cancer 2016;122:1050-1059. (c) 2016 American Cancer Society There has been no evidence to support the use of bevacizumab beyond disease progression in patients with advanced nonsquamous non-small cell lung cancer whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. A randomized trial has now shown that the continuation of bevacizumab therapy beyond disease progression in such patients meets the predefined threshold of P<.2 for the primary endpoint of progression-free survival. See also pages 000-000.
  • Masayuki Takeda; Takeharu Yamanaka; Takashi Seto; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Haruhiro Saito; Akihito Kubo; Toshiyuki Sawa; Eiji Miyahara; Naoyuki Nogami; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto
    CANCER 122 7 1050 - 1059 2016年04月 [査読有り]
     
    BACKGROUNDBevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODSWest Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTSOne hundred patients were randomly assigned to receive docetaxel (n=50) or docetaxel plus bevacizumab (n=50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P<.2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P=.11). No unexpected or severe adverse events were recorded. CONCLUSIONSFurther evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. Cancer 2016;122:1050-1059. (c) 2016 American Cancer Society There has been no evidence to support the use of bevacizumab beyond disease progression in patients with advanced nonsquamous non-small cell lung cancer whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. A randomized trial has now shown that the continuation of bevacizumab therapy beyond disease progression in such patients meets the predefined threshold of P<.2 for the primary endpoint of progression-free survival. See also pages 000-000.
  • Yoshikane Nonagase; Kunio Okamoto; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Toshio Shimizu; Junji Tsurutani; Kazuhiko Nakagawa
    ANTI-CANCER DRUGS 27 3 251 - 253 2016年03月 [査読有り]
     
    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.
  • Yoshikane Nonagase; Kunio Okamoto; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Toshio Shimizu; Junji Tsurutani; Kazuhiko Nakagawa
    ANTI-CANCER DRUGS 27 3 251 - 253 2016年03月 [査読有り]
     
    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.
  • Kazuo Nakagawa; Kohei Yokoi; Jun Nakajima; Fumihiro Tanaka; Yoshimasa Maniwa; Makoto Suzuki; Takeshi Nagayasu; Hisao Asamura
    ANNALS OF THORACIC SURGERY 101 2 520 - 526 2016年02月 [査読有り]
     
    Background. The optimal mode of resection for thymoma in nonmyasthenic patients remains unclear. The aim of this study was to explore whether or not thymomectomy alone is a relevant option for patients with stage I (T1N0M0) thymoma in the proposed TNM classification. Methods. We investigated 2,835 patients with thymic epithelial tumors treated at 32 institutions participating in the Japanese Association for Research on the Thymus (JART). A total of 1286 patients with thymomectomy: resection of thymoma with partial thymectomy (n = 289) or thymothymomectomy: resection of thymoma with total thymectomy (n = 997) for stage I thymoma were included. Surgical and oncologic outcomes were compared between the 2 groups. Results. Patients who underwent thymomectomy were older (61.1 versus 57.0 years; p = 0.000) and had smaller tumors (4.77 versus 5.99 cm; p = 0.000) than those who underwent thymothymomectomy. There was a significant difference in the distribution of histologic subtype (p = 0.007). After propensity-score matching, the matched cohort consisted of 276 patients in each group. Postoperative complications were seen more frequently in the thymothymomectomy group than in the thymomectomy group (8.3% versus 4.3%; p = 0.0397). The 5-year overall survival rate was 97.3% in the thymomectomy group and 96.9% in the thymothymomectomy group (p = 0.487). Patients who underwent thymomectomy tended to have local recurrence more frequently than did those who underwent thymothymomectomy (2.2% versus 0.4%; p = 0.0613). Conclusions. Thymomectomy alone is acceptable for stage I thymoma in regard to postoperative complications and prognosis. Further studies are needed to evaluate long-term outcomes. (C) 2016 by The Society of Thoracic Surgeons
  • K. Yonesaka; K. Hirotani; H. Kawakami; M. Takeda; H. Kaneda; K. Sakai; I. Okamoto; K. Nishio; P. A. Jaenne; K. Nakagawa
    ONCOGENE 35 7 878 - 886 2016年02月 [査読有り]
     
    Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
  • Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Kenjiro Aogi; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Yasuhiro Udagawa; Yutaka Okawa; Yusuke Onozawa; Hidenori Sasaki; Yasuo Shima; Naohito Shimoyama; Masayuki Takeda; Toshihiko Nishidate; Akifumi Yamamoto; Tadashi Ikeda; Koichi Hirata
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 21 1 1 - 12 2016年02月 [査読有り]
     
    The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT(3)) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT(3) receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT(3) receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.
  • Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Kenjiro Aogi; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Yasuhiro Udagawa; Yutaka Okawa; Yusuke Onozawa; Hidenori Sasaki; Yasuo Shima; Naohito Shimoyama; Masayuki Takeda; Toshihiko Nishidate; Akifumi Yamamoto; Tadashi Ikeda; Koichi Hirata
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 21 1 1 - 12 2016年02月 [査読有り]
     
    The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT(3)) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT(3) receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT(3) receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.
  • K. Takeuchi; Y. Togashi; Y. Kamihara; T. Fukuyama; H. Yoshioka; A. Inoue; H. Katsuki; K. Kiura; K. Nakagawa; T. Seto; M. Maemondo; T. Hida; M. Harada; Y. Ohe; N. Nogami; N. Yamamoto; M. Nishio; T. Tamura
    ANNALS OF ONCOLOGY 27 1 185 - 192 2016年01月 [査読有り]
     
    Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
  • K. Haratani; H. Hayashi; S. Watanabe; H. Kaneda; T. Yoshida; M. Takeda; T. Shimizu; K. Nakagawa
    ANNALS OF ONCOLOGY 27 1 200 - 202 2016年01月 [査読有り]
  • Report of two cases of pseudoprogression in patients with non-small cell lung cancer treated with nivolumab-including histological analysis of one case after tumor regression.
    Tanizaki J; Hayashi H; Kimura M; Tanaka K; Takeda M; Shimizu S; Ito A; Nakagawa K
    Lung Cancer. 102 44 - 48 2016年 [査読有り]
  • Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer.
    Garon EB; Reck M; Paz-Ares L; Ponce S; Jaime JC; Juan O; Nadal E, Lee P; Dalal R; Liu J; He S; Treat J; Nakagawa K
    Clin Lung Cancer. 16 30 139 - 405 2016年 [査読有り]
  • Current evidence in support of the second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor alectinib for the treatment of non-small cell lung cancer positive for ALK translocation.
    Hayashi H; Nakagawa K
    J Thorac Dis. 8 10 E1311 - E1316 2016年 [査読有り]
  • Clinical outcome of node-negative oligometastatic non-small cell lung cancer.
    Sakai K; Takeda M; Hayashi H; Tanaka K; Okuda T; Kato A; Nishimura Y; Mitsudomi T; Koyama A; Nakagawa K
    Thorac Cancer. 7 6 670 - 675 2016年 [査読有り]
  • Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.
    Watanabe S; Hayashi H; Okamoto K; Fujiwara K; Hasegawa Y; Kaneda H; Tanaka K; Takeda M; Nakagawa K
    Clin Lung Cancer. 17 6 528 - 534 2016年 [査読有り]
  • Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer?
    Watanabe S; Hayashi H; Nakagawa K
    Ann Transl Med. 4 11 225  2016年 [査読有り]
  • Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget's disease.
    Watanabe S; Takeda M; Takahama T; Iwasa T; Tsurutani J; Tanizaki J; Shimizu T; Sakai K; Wada Y; Isogai N; Nishio K; Nakagawa K
    Invest New Drugs. 34 3 394 - 396 2016年 [査読有り]
  • Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Hiroto Ueda; Satomi Watanabe; Yoshikane Nonagase; Tatsuya Okuno; Masayuki Takeda; Osamu Maenishi; Junji Tsurutani; Taroh Satoh; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ONCOTARGET 7 3 3443 - 3450 2016年01月 [査読有り]
     
    Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
  • Motohiro Tamiya; Akihiro Tamiya; Hiroyasu Kaneda; Kazuhiko Nakagawa; Kiyotaka Yoh; Koichi Goto; Hiroaki Okamoto; Tsuneo Shimokawa; Tetsuya Abe; Hiroshi Tanaka; Haruko Daga; Koji Takeda; Tomonori Hirashima; Shinji Atagi
    MEDICAL ONCOLOGY 33 1 2  2016年01月 [査読有り]
     
    A phase I study recommended carboplatin (CBDCA, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m(2)) for elderly patients (>= 75-years old) with non-squamous non-small cell lung cancer (NSCLC). PEM maintenance therapy was well tolerated. We conducted a multicenter phase II trial to evaluate the efficacy and safety of this regimen in elderly patients with NSCLC. Four courses of CBDCA plus PEM, followed by PEM, were administered. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression-free survival (PFS), response rate (RR), and safety. Thirty-four patients (median age, 77 years) were enrolled between June 2012 and May 2013. The median observation time was 22.7 months. The primary endpoint of the 1-year OS rate was 58.0 % (95 % confidence interval (CI) 42.9-78.4 %), and RR and disease control rate were 41.2 and 85.3 %, respectively. Fourteen patients had partial responses, 15 had stable disease, 4 had disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8 %. The median PFS was 5.7 months (95 % CI 3.9-8.9 months), and median OS was 20.5 months (95 % CI 10.0-infinity months). Grade >= 3 hematological adverse events included leucopenia (23.5 % of patients), neutropenia (55.9 %), anemia (35.3 %), and thrombocytopenia (20.6 %). Grade >= 3 non-hematological adverse events included febrile neutropenia (8.8 %), elevated aminotransferases (5.9 %), infection (23.5 %), and anorexia/fatigue (5.9 %). Four patients had interstitial lung diseases (ILD) and one died due to ILD. CBDCA plus PEM, followed by PEM, was effective and reasonably tolerated in chemotherapy-naive elderly patients with non-squamous NSCLC.
  • Motohiro Tamiya; Akihiro Tamiya; Hiroyasu Kaneda; Kazuhiko Nakagawa; Kiyotaka Yoh; Koichi Goto; Hiroaki Okamoto; Tsuneo Shimokawa; Tetsuya Abe; Hiroshi Tanaka; Haruko Daga; Koji Takeda; Tomonori Hirashima; Shinji Atagi
    MEDICAL ONCOLOGY 33 1 2  2016年01月 [査読有り]
     
    A phase I study recommended carboplatin (CBDCA, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m(2)) for elderly patients (>= 75-years old) with non-squamous non-small cell lung cancer (NSCLC). PEM maintenance therapy was well tolerated. We conducted a multicenter phase II trial to evaluate the efficacy and safety of this regimen in elderly patients with NSCLC. Four courses of CBDCA plus PEM, followed by PEM, were administered. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression-free survival (PFS), response rate (RR), and safety. Thirty-four patients (median age, 77 years) were enrolled between June 2012 and May 2013. The median observation time was 22.7 months. The primary endpoint of the 1-year OS rate was 58.0 % (95 % confidence interval (CI) 42.9-78.4 %), and RR and disease control rate were 41.2 and 85.3 %, respectively. Fourteen patients had partial responses, 15 had stable disease, 4 had disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8 %. The median PFS was 5.7 months (95 % CI 3.9-8.9 months), and median OS was 20.5 months (95 % CI 10.0-infinity months). Grade >= 3 hematological adverse events included leucopenia (23.5 % of patients), neutropenia (55.9 %), anemia (35.3 %), and thrombocytopenia (20.6 %). Grade >= 3 non-hematological adverse events included febrile neutropenia (8.8 %), elevated aminotransferases (5.9 %), infection (23.5 %), and anorexia/fatigue (5.9 %). Four patients had interstitial lung diseases (ILD) and one died due to ILD. CBDCA plus PEM, followed by PEM, was effective and reasonably tolerated in chemotherapy-naive elderly patients with non-squamous NSCLC.
  • Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Hiroto Ueda; Satomi Watanabe; Yoshikane Nonagase; Tatsuya Okuno; Masayuki Takeda; Osamu Maenishi; Junji Tsurutani; Taroh Satoh; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ONCOTARGET 7 3 3443 - 3450 2016年01月 [査読有り]
     
    Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
  • Koichi Azuma; Tomonori Hirashima; Nobuyuki Yamamoto; Isamu Okamoto; Toshiaki Takahashi; Makoto Nishio; Taizo Hirata; Kaoru Kubota; Kazuo Kasahara; Toyoaki Hida; Hiroshige Yoshioka; Kaoru Nakanishi; Shiro Akinaga; Kazuto Nishio; Tetsuya Mitsudomi; Kazuhiko Nakagawa
    ESMO open 1 4 e000063  2016年 [査読有り]
     
    BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. METHODS: This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. RESULTS: The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. CONCLUSIONS: Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. TRIAL REGISTRATION NUMBER: NCT01580735.
  • Nishio M; Hida T; Atagi S; Sakai H; Nakagawa K; Takahashi T; Nogami N; Saka H; Takenoyama M; Maemondo M; Ohe Y; Nokihara H; Hirashima T; Tanaka H; Fujita S; Takeda K; Goto K; Satouchi M; Isobe H; Minato K; Sumiyoshi N; Tamura T
    ESMO open 1 4 e000108  2016年 [査読有り]
     
    OBJECTIVE: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC. METHODS: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety. RESULTS: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab. CONCLUSIONS: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-132073.
  • Shinichiro Ryuge; Noriyuki Masuda; Nobuyuki Yamamoto; Toshiaki Takahashi; Haruyasu Murakami; Koji Takeda; Haruko Daga; Kimio Yonesaka; Hiroshi Tsukuda; Kazuhiko Nakagawa; Kaoru Tanaka; Katsuyuki Kiura; Nagio Takigawa; Toyoaki Hida; Takashi Seto; Masanori Yokoba; Shinzoh Kudoh; Takeshi Takagaki; Kazushige Shono; Hideo Kitagawa; Takeshi Kurihara; Masahiro Fukuoka
    Cancer Treatment and Research Communications 9 81 - 87 2016年 [査読有り]
     
    Objective The pharmacokinetics of amrubicin in patients with impaired hepatic function have not been reported. The aim of this study was to compare the pharmacokinetics of amrubicin and its major metabolite, amrubicinol, and to assess the safety of amrubicin in lung cancer patients with impaired hepatic function and those with normal hepatic function. Materials and methods Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) with small or non-small cell lung carcinoma were enrolled. Liquid chromatography with tandem mass spectrometry was used to determine the amrubicin and amrubicinol concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. Results The terminal half-lives of amrubicin and amrubicinol in whole blood and plasma were slightly longer in arm I than in arm N. The area under the concentration–time curve (AUC0–24h) values of amrubicin in plasma and AUC0–120h of amrubicinol in whole blood in arm I were not larger than those in arm N because of dose adjustments based on prior treatment history and baseline values of total bilirubin, aspartate aminotransferase and alanine aminotransferase. The dose-normalized AUCs (dose 40 mg/m2) of amrubicin and amrubicinol in arm I were slightly larger than those in arm N. There were two deaths in arm I, one related to disease progression and one from an unknown cause. Conclusion If an adjusted dose of amrubicin is used in patients with impaired hepatic function, the exposure of amrubicin and amrubicinol would be within the range of variation observed in patients with normal hepatic function.
  • Succsessful osimertinib treatment for leptomeningeal carcinomatosis from lung adenocarcinoma with the T790M mutation of EGFR.
    Hitomi Sakai; Hidetoshi Hayashi; Tsutomu Iwasa; Yoshikazu Hasegawa; Masayuki Takeda; Kazuhiko Nakagawa
    ESMO Open. 1 - 4 2016年 [査読有り]
  • The Efficacy and Safety of Sterile Graded Talc in Pleurodesis for Malignant Pleural Effusion:Phase II study
    Hideo Saka; Masahide Oki; Chiyoe Kitagawa; Yoshihito Kogure; Yuki Kojima; Akiko M. Siato; Atsuko Ishida; Terunao Miyazawa; Koji Takeda; Kazuhiko Nakagawa; Shinji Sasada; Shunishi Negoro
    Journal of Clinical Trials 6 6 279 - 281 2016年 [査読有り]
  • Takayuki Takahama; Masayuki Takeda; Shinichi Nishina; Kazuhiko Nakagawa
    BMC Research Notes 8 1 100  2015年12月 [査読有り]
     
    Background: Trastuzumab∈+∈chemotherapy is considered the standard therapy for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer with mild manageable toxicity, on the basis of the results of a pivotal phase-III trial. Cerebrovascular events are not recognized as expected adverse effects of such therapy. Case presentation: We report the case of a 67-year-old, current-smoking male with stage-IV HER2-positive gastric cancer who suffered right middle cerebral artery (MCA) embolism after trastuzumab∈+∈chemotherapy. He received trastuzumab and cisplatin on Day 1, followed by a continuous 5-fluorouracil infusion for 5 days as a first-line treatment. Four days after chemotherapy initiation, he presented with left hemiplegia, and brain magnetic resonance imaging and magnetic resonance angiography revealed a right MCA occlusion. No further chemotherapy was administered because of worsening performance status. Conclusion: The present case, possibly the first such reported case, suggests the risk of development of embolism after trastuzumab∈+∈chemotherapy in HER2-positive advanced gastric cancer, although other factors should be considered.
  • M. Takeda; K. Sakai; M. Terashima; H. Kaneda; H. Hayashi; K. Tanaka; K. Okamoto; T. Takahama; T. Yoshida; T. Iwasa; T. Shimizu; Y. Nonagase; K. Kudo; S. Tomida; T. Mitsudomi; K. Saigo; A. Ito; K. Nakagawa; K. Nishio
    ANNALS OF ONCOLOGY 26 12 2477 - 2482 2015年12月 [査読有り]
     
    The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. Multiplex genomic testing can assist physicians in matching patients with approved or experimental targeted treatments. Background: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. Patients and methods: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS). Results: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). Conclusions: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of >= 95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. Clinical trial registration: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.
  • Haruko Daga; Koji Takeda; Hideaki Okada; Masaki Miyazaki; Shinya Ueda; Hiroyasu Kaneda; Isamu Okamoto; Kiyotaka Yoh; Koichi Goto; Koichi Konishi; Akiko Sarashina; Tetsuya Tanaka; Rolf Kaiser; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 6 1225 - 1233 2015年12月 [査読有り]
     
    This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After a parts per thousand yen4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was < 33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade a parts per thousand yen3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.
  • Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Haruko Daga; Koichi Goto; Hideo Saka; Shunichi Sugawara; Toshiaki Takahashi; Soichiro Yokota; Hiroyasu Kaneda; Tomoya Kawaguchi; Seisuke Nagase; Tetsuya Oguri; Yasuo Iwamoto; Takashi Nishimura; Yoshihiro Hattori; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto
    LANCET ONCOLOGY 16 16 1630 - 1638 2015年12月 [査読有り]
     
    Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1: 1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13.6 months, 95% CI 11.6-15.6) than in the cisplatin group (11.4 months, 10.2-12.2; hazard ratio 0.81, 95% CI 0.65-1.02; p=0.037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
  • Yasuo Iwamoto; Tetsuya Mitsudomi; Kazuko Sakai; Takeharu Yamanaka; Hiroshige Yoshioka; Makoto Takahama; Masahiro Yoshimura; Ichiro Yoshino; Masayuki Takeda; Shunichi Sugawara; Tomoya Kawaguchi; Toshiaki Takahashi; Mitsunori Ohta; Yukito Ichinose; Shinji Atagi; Morihito Okada; Hideo Saka; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    CLINICAL CANCER RESEARCH 21 23 5245 - 5252 2015年12月 [査読有り]
     
    Purpose: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. Experimental Design: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m2) on day 1 plus oral S-1 (40 mg/m2 twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. Results: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. Conclusions: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. (C) 2015 AACR.
  • Yasuo Iwamoto; Tetsuya Mitsudomi; Kazuko Sakai; Takeharu Yamanaka; Hiroshige Yoshioka; Makoto Takahama; Masahiro Yoshimura; Ichiro Yoshino; Masayuki Takeda; Shunichi Sugawara; Tomoya Kawaguchi; Toshiaki Takahashi; Mitsunori Ohta; Yukito Ichinose; Shinji Atagi; Morihito Okada; Hideo Saka; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    CLINICAL CANCER RESEARCH 21 23 5245 - 5252 2015年12月 [査読有り]
     
    Purpose: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. Experimental Design: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m2) on day 1 plus oral S-1 (40 mg/m2 twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. Results: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. Conclusions: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. (C) 2015 AACR.
  • Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Haruko Daga; Koichi Goto; Hideo Saka; Shunichi Sugawara; Toshiaki Takahashi; Soichiro Yokota; Hiroyasu Kaneda; Tomoya Kawaguchi; Seisuke Nagase; Tetsuya Oguri; Yasuo Iwamoto; Takashi Nishimura; Yoshihiro Hattori; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto
    LANCET ONCOLOGY 16 16 1630 - 1638 2015年12月 [査読有り]
     
    Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1: 1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13.6 months, 95% CI 11.6-15.6) than in the cisplatin group (11.4 months, 10.2-12.2; hazard ratio 0.81, 95% CI 0.65-1.02; p=0.037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
  • Haruko Daga; Koji Takeda; Hideaki Okada; Masaki Miyazaki; Shinya Ueda; Hiroyasu Kaneda; Isamu Okamoto; Kiyotaka Yoh; Koichi Goto; Koichi Konishi; Akiko Sarashina; Tetsuya Tanaka; Rolf Kaiser; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 6 1225 - 1233 2015年12月 [査読有り]
     
    This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After a parts per thousand yen4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was < 33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade a parts per thousand yen3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    Therapeutics and Clinical Risk Management 11 1701 - 1706 2015年11月 [査読有り]
     
    Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study.
  • Shodai Kawano; Junichi Maruyama; Shunta Nagashima; Kazutoshi Inami; Wenzhe Qiu; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Hiroshi Nishina; Yutaka Hata
    JOURNAL OF BIOCHEMISTRY 158 5 413 - 423 2015年11月 [査読有り]
     
    Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators.
  • 日本発の抗悪性腫瘍薬をいち早く患者へ届けるには アジアの中の日本 これからの"日亜主導的"グローバルがん早期新薬開発
    清水 俊雄; Lin Chia-Chi Josh; 中川 和彦
    臨床薬理 46 Suppl. S83 - S84 (一社)日本臨床薬理学会 2015年11月
  • Masayuki Takeda; Kazuhiko Nakagawa
    Current Cancer Drug Targets 15 9 792 - 802 2015年11月 [査読有り]
     
    Dysregulation of epidermal growth factor receptor (EGFR) signaling due to receptor overexpression or activating mutation is associated with cancer cell proliferation, metastasis, and survival. EGFR has become an important therapeutic target for non–small cell lung cancer (NSCLC), and several EGFR-targeted agents, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), have been developed. The EGFR-TKIs gefitinib, erlotinib, and afatinib have been approved for the treatment of advanced NSCLC, and sensitivity to these drugs has been shown to be associated with the presence of EGFR mutations. Various mAbs to EGFR have also been evaluated in preclinical and clinical studies. In particular, phase III trials have shown a clinically significant survival benefit for addition of the anti-EGFR mAbs cetuximab or necitumumab to a platinum doublet in chemotherapy-naïve patients with advanced NSCLC. We here summarize the results of completed and ongoing clinical trials of EGFR-targeted mAbs for the treatment of NSCLC.
  • Kimio Yonesaka; Naoki Takegawa; Taroh Satoh; Hiroto Ueda; Takeshi Yoshida; Masayuki Takeda; Toshio Shimizu; Yasutaka Chiba; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    PLOS ONE 10 11 e0143132  2015年11月 [査読有り]
     
    Background Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC. Methods Plasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis. Results Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort. Conclusion A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients.
  • 武田 晃司; 阿部 徹哉; 大江 裕一郎; 川口 知哉; 一瀬 幸人; 岡本 浩明; 山本 信之; 吉岡 弘鎮; 湊 浩一; 澤 祥幸; 岩本 康男; 坂 英雄; 水谷 友紀; 中村 慎一郎; 安藤 昌彦; 横山 晶; 中川 和彦; 西條 長宏; 田村 友秀
    肺癌 55 5 394 - 394 (NPO)日本肺癌学会 2015年10月
  • 安宅 信二; 西尾 誠人; 樋田 豊明; 中川 和彦; 酒井 洋; 野上 尚之; 高橋 利明; 軒原 浩; 坂 英雄; 竹之山 光広; 藤田 史郎; 田中 洋史; 武田 晃司; 里内 美弥子; 磯部 宏; 前門戸 任; 後藤 功一; 平島 智徳; 湊 浩一; 田村 友秀
    肺癌 55 5 392 - 392 (NPO)日本肺癌学会 2015年10月
  • 林 秀敏; 武田 真幸; 山中 竹春; 瀬戸 貴司; 岡田 守人; 東 公一; 菅原 俊一; 駄賀 晴子; 平島 智徳; 米阪 仁雄; 浦田 佳子; 村上 晴泰; 齋藤 春洋; 久保 昭仁; 澤 祥幸; 宮原 栄治; 野上 尚之; 中川 和彦; 中西 洋一; 岡本 勇
    肺癌 55 5 430 - 430 (NPO)日本肺癌学会 2015年10月
  • H. Yoshioka; K. Azuma; N. Yamamoto; T. Takahashi; M. Nishio; N. Katakami; M. J. Ahn; T. Hirashima; M. Maemondo; S. W. Kim; M. Kurosaki; S. Akinaga; K. Park; C. M. Tsai; T. Tamura; T. Mitsudomi; K. Nakagawa
    ANNALS OF ONCOLOGY 26 10 2066 - 2072 2015年10月 [査読有り]
     
    Background: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). Methods: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Results: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade >= 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). Conclusions: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR.
  • Akiyoshi Kasuga; Kazuhiko Nakagawa; Fumio Nagashima; Toshio Shimizu; Daisuke Naruge; Shinichi Nishina; Hiroshi Kitamura; Takayasu Kurata; Atsuko Takasu; Yasuhito Fujisaka; Wataru Okamoto; Yuichiro Nishimura; Akihira Mukaiyama; Hideki Matsushita; Junji Furuse
    INVESTIGATIONAL NEW DRUGS 33 5 1058 - 1067 2015年10月 [査読有り]
     
    Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single- agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)
  • Akiyoshi Kasuga; Kazuhiko Nakagawa; Fumio Nagashima; Toshio Shimizu; Daisuke Naruge; Shinichi Nishina; Hiroshi Kitamura; Takayasu Kurata; Atsuko Takasu; Yasuhito Fujisaka; Wataru Okamoto; Yuichiro Nishimura; Akihira Mukaiyama; Hideki Matsushita; Junji Furuse
    INVESTIGATIONAL NEW DRUGS 33 5 1058 - 1067 2015年10月 [査読有り]
     
    Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single- agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)
  • Kimio Yonesaka; Keita Kudo; Satomi Nishida; Takayuki Takahama; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Isamu Okamoto; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET 6 32 33602 - 33611 2015年10月 [査読有り]
     
    Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
  • Masayuki Takeda; Kazuko Sakai; Masato Terashima; Hiroyasu Kaneda; Hidetoshi Hayashi; Kaoru Tanaka; Tsutomu Iwasa; Takeshi Yoshida; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 10 9 S700 - S701 2015年09月 [査読有り]
  • Junichi Shimizu; Takeshi Kodaira; Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Naonobu Kunitake; Fumiyoshi Ohyanagi; Takuyo Kozuka; Masayuki Takeda; Kiyoshi Nakamatsu; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Kazuhiko Nakagawa; Yasumasa Nishimura; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 10 9 S286 - S286 2015年09月 [査読有り]
  • Manami Kodaka; Zeyu Yang; Kentaro Nakagawa; Junichi Maruyama; Xiaoyin Xu; Aradhan Sarkar; Ayana Ichimura; Yusuke Nasu; Takeaki Ozawa; Hiroaki Iwasa; Mari Ishigami-Yuasa; Shigeru Ito; Hiroyuki Kagechika; Yutaka Hata
    EXPERIMENTAL CELL RESEARCH 336 2 171 - 181 2015年08月 [査読有り]
     
    The development of the efficient screening system of detecting compounds that promote myogenesis and prevent muscle atrophy is important. Mouse C2C12 cells are widely used to evaluate myogenesis but the procedures of the assay are not simple and the quantification is not easy. We established C2C12 cells expressing the N-terminal green fluorescence protein (GFP) and the C-terminal GFP (GFP1-10 and GFP11 cells). GFP1-10 and GFP11 cells do not exhibit GFP signals until they are fused. The signal intensity correlates with the expression of myogenic markers and myofusion. Myogenesis-promoting reagents, such as insulin-like growth factor-1 (IGF1) and beta-guanidinopropionic acid (GPA), enhance the signals, whereas the poly-caspase inhibitor, z-VAD-FMK, suppresses it. GFP signals are observed when myotubes formed by GFP1-10 cells are fused with single nuclear GFP11 cells, and enhanced by IGF1, GPA, and 185008738, a recently-reported myogenesis-promoting reagent. Fusion between myotubes formed by GFP1-10 and GFP11 cells is associated with the appearance of GFP signals. IGF1 and CPA augment these signals, whereas NSC23766, Rac inhibitor, decreases them. The conditioned medium of cancer cells suppresses GFP signals during myogenesis and reduces the width of GFP-positive myotubes after differentiation. Thus the novel split GFP-based assay will provide the useful method for the study of myogenesis, myofusion, and atrophy. (C) 2015 Elsevier Inc. All rights reserved.
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Masatomo Otsuka; Kazuhiko Nakagawa
    PALLIATIVE & SUPPORTIVE CARE 13 4 859 - 864 2015年08月 [査読有り]
     
    Objective: Delirium is a frequently encountered psychiatric disease in terminal cancer patients. However, the mechanism of delirium is unclear. The aim of our study was to investigate the relationship between administration of chemotherapy drugs that penetrate the blood-brain barrier (BBB) and the development of delirium in cancer patients. Method: We retrospectively analyzed 166 cancer patients (97 males, 69 females) continuously who died between September of 2007 and January of 2010 using a review of medical charts. Multiple logistic regression analysis was employed to investigate the effects of antineoplastic drugs penetrating the BBB on development of delirium in cancer patients with control for other risk factors. Results: In multivariate analysis, antineoplastic drugs that penetrated the BBB were significantly associated with development of delirium (OR = 18.92, CI95 = 1.08-333.04, p < 0.001). Significance of results: The use of chemotherapy drugs that penetrate the BBB may be a risk factor for delirium. This information may allow palliative care doctors and medical oncologists to predict which patients are at increased risk for delirium.
  • Jean-Charles Soria; Yi-Long Wu; Kazuhiko Nakagawa; Sang-We Kim; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Dae Ho Lee; Yunpeng Liu; Kiyotaka Yoh; Jian-Ying Zhou; Xiaojin Shi; Alan Webster; Haiyi Jiang; Tony S. K. Mok
    LANCET ONCOLOGY 16 8 990 - 998 2015年08月 [査読有り]
     
    Background Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. Methods The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapynaive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1: 1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0 . 86, 95% CI 0 . 65-1 . 13; p=0 . 27; median progression-free survival 5 . 4 months in both groups [95% CI 4 . 5-5 . 7 in the gefitinib group and 4 . 6-5 . 5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Interpretation Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.
  • Shinya Ueda; Hisato Kawakami; Shinichi Nishina; Tsutomu Sakiyama; Yoshikane Nonagase; Takafumi Okabe; Takao Tamura; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 2 279 - 285 2015年08月 [査読有り]
     
    Purpose The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer. Methods Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results Overall, nine patients were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were diagnosed with squamous cell carcinoma. No dose-limiting toxicity was observed at any level, and planned dose escalation was completed without reaching the MTD. No grade 4 or higher toxicity was observed in this study. The observed grade 3 hematological toxicities included neutropenia in five patients (55.6 %) and leukopenia in three patients (33.3 %). None of the patients developed febrile neutropenia, and no grade 3 or 4 non-hematological toxicities were observed. The overall response rate was 77.8 %, including two complete responses, and the disease control rate was 100 %. Conclusion The RD of UDON was identified as level 3. The good tolerability and high antitumor efficacy of this regimen warrant further evaluation in this setting.
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Masatomo Otsuka; Kazuhiko Nakagawa
    PALLIATIVE & SUPPORTIVE CARE 13 4 859 - 864 2015年08月 [査読有り]
     
    Objective: Delirium is a frequently encountered psychiatric disease in terminal cancer patients. However, the mechanism of delirium is unclear. The aim of our study was to investigate the relationship between administration of chemotherapy drugs that penetrate the blood-brain barrier (BBB) and the development of delirium in cancer patients. Method: We retrospectively analyzed 166 cancer patients (97 males, 69 females) continuously who died between September of 2007 and January of 2010 using a review of medical charts. Multiple logistic regression analysis was employed to investigate the effects of antineoplastic drugs penetrating the BBB on development of delirium in cancer patients with control for other risk factors. Results: In multivariate analysis, antineoplastic drugs that penetrated the BBB were significantly associated with development of delirium (OR = 18.92, CI95 = 1.08-333.04, p < 0.001). Significance of results: The use of chemotherapy drugs that penetrate the BBB may be a risk factor for delirium. This information may allow palliative care doctors and medical oncologists to predict which patients are at increased risk for delirium.
  • Shinya Ueda; Hisato Kawakami; Shinichi Nishina; Tsutomu Sakiyama; Yoshikane Nonagase; Takafumi Okabe; Takao Tamura; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 2 279 - 285 2015年08月 [査読有り]
     
    Purpose The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer. Methods Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results Overall, nine patients were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were diagnosed with squamous cell carcinoma. No dose-limiting toxicity was observed at any level, and planned dose escalation was completed without reaching the MTD. No grade 4 or higher toxicity was observed in this study. The observed grade 3 hematological toxicities included neutropenia in five patients (55.6 %) and leukopenia in three patients (33.3 %). None of the patients developed febrile neutropenia, and no grade 3 or 4 non-hematological toxicities were observed. The overall response rate was 77.8 %, including two complete responses, and the disease control rate was 100 %. Conclusion The RD of UDON was identified as level 3. The good tolerability and high antitumor efficacy of this regimen warrant further evaluation in this setting.
  • Jean-Charles Soria; Yi-Long Wu; Kazuhiko Nakagawa; Sang-We Kim; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Dae Ho Lee; Yunpeng Liu; Kiyotaka Yoh; Jian-Ying Zhou; Xiaojin Shi; Alan Webster; Haiyi Jiang; Tony S. K. Mok
    LANCET ONCOLOGY 16 8 990 - 998 2015年08月 [査読有り]
     
    Background Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. Methods The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapynaive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1: 1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0 . 86, 95% CI 0 . 65-1 . 13; p=0 . 27; median progression-free survival 5 . 4 months in both groups [95% CI 4 . 5-5 . 7 in the gefitinib group and 4 . 6-5 . 5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Interpretation Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.
  • Shimizu T; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 73 8 1342 - 1348 2015年08月 [査読有り]
     
    Aberrant activation of the Wnt, Notch and Hedgehog pathways via mutations or ligand overexpression has been implicated in a large number of cancer types where they are involved in functions ranging from tumor initiation to cancer stem cell (CSC) maintenance and angiogenesis. Agents targeting each one of these three pathways have now reached clinical trials, and the first one of these, Vismodegib, a hedgehog pathway inhibitor, was approved in 2012 by US FDA for the treatment of advanced basal cell carcinoma. Development of agents that target critical steps in these pathways as novel signal transduction pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are being explored coupled with early phase I clinical studies.
  • 乳癌骨転移患者におけるゾレドロン酸治療に関する後ろ向きコホート研究
    田根 香織; 柳江 正嗣; 鶴谷 純司; 谷岡 真樹; 藤本 伸一郎; 藤原 季美子; 山添 譲; 千葉 康敬; 中川 和彦; 菰池 佳史; 高尾 信太郎
    日本乳癌学会総会プログラム抄録集 23回 358 - 358 (一社)日本乳癌学会 2015年07月
  • James Chin-Hsin Yang; Myung-Ju Ahn; Kazuhiko Nakagawa; Tomohide Tamura; Helen Barraclough; Sotaro Enatsu; Rebecca Cheng; Mauro Orlando
    CANCER RESEARCH AND TREATMENT 47 3 424 - 435 2015年07月 [査読有り]
     
    Purpose A recent phase III study (PARAMOUNT) demonstrated that pemetrexed continuation maintenance therapy is a new treatment paradigm for advanced nonsquamous non-small cell lung cancer (NSCLC). The majority of patients enrolled in PARAMOUNT were Caucasian (94%). We reviewed efficacy and safety data from two clinical trials, which enrolled East Asian (EA) patients, to supplement data from PARAMOUNT on pemetrexed continuation maintenance therapy in patients with nonsquamous NSCLC. Materials and Methods Study S110 was a phase II, multicenter, randomized, controlled, open-label trial in never-smoker, chemonaive, EA patients (n=31) with locally advanced or metastatic nonsquamous NSCLC (n=27). Study JMII was a multicenter, open-label, single-arm, post-marketing, clinical trial in Japanese patients (n=109) with advanced nonsquamous NSCLC. PARAMOUNT was a multicenter, randomized, double-blind, placebo-controlled trial in patients with advanced nonsquamous NSCLC. Results In EA patients with nonsquamous NSCLC, the median progression-free survival (PFS) for pemetrexed continuation maintenance therapy was 4.04 months (95% confidence interval [CI], 3.22 to 5.29 months) in study S110 and 3.9 months (95% CI, 3.2 to 5.2 months) in study JMII. The median PFS for pemetrexed continuation maintenance therapy in PARAMOUNT was 4.1 months (95% CI, 3.2 to 4.6 months). Pemetrexed continuation maintenance therapy in EA patients in studies S110 and JMII did not lead to any unexpected safety events, and was consistent with PARAMOUNT's safety profile. Conclusion The efficacy and safety data in the EA trials were similar to those in PARAMOUNT despite differences in patient populations and study designs. These data represent consistent evidence for pemetrexed continuation maintenance therapy in EA patients with advanced nonsquamous NSCLC.
  • James Chin-Hsin Yang; Myung-Ju Ahn; Kazuhiko Nakagawa; Tomohide Tamura; Helen Barraclough; Sotaro Enatsu; Rebecca Cheng; Mauro Orlando
    CANCER RESEARCH AND TREATMENT 47 3 424 - 435 2015年07月 [査読有り]
     
    Purpose A recent phase III study (PARAMOUNT) demonstrated that pemetrexed continuation maintenance therapy is a new treatment paradigm for advanced nonsquamous non-small cell lung cancer (NSCLC). The majority of patients enrolled in PARAMOUNT were Caucasian (94%). We reviewed efficacy and safety data from two clinical trials, which enrolled East Asian (EA) patients, to supplement data from PARAMOUNT on pemetrexed continuation maintenance therapy in patients with nonsquamous NSCLC. Materials and Methods Study S110 was a phase II, multicenter, randomized, controlled, open-label trial in never-smoker, chemonaive, EA patients (n=31) with locally advanced or metastatic nonsquamous NSCLC (n=27). Study JMII was a multicenter, open-label, single-arm, post-marketing, clinical trial in Japanese patients (n=109) with advanced nonsquamous NSCLC. PARAMOUNT was a multicenter, randomized, double-blind, placebo-controlled trial in patients with advanced nonsquamous NSCLC. Results In EA patients with nonsquamous NSCLC, the median progression-free survival (PFS) for pemetrexed continuation maintenance therapy was 4.04 months (95% confidence interval [CI], 3.22 to 5.29 months) in study S110 and 3.9 months (95% CI, 3.2 to 5.2 months) in study JMII. The median PFS for pemetrexed continuation maintenance therapy in PARAMOUNT was 4.1 months (95% CI, 3.2 to 4.6 months). Pemetrexed continuation maintenance therapy in EA patients in studies S110 and JMII did not lead to any unexpected safety events, and was consistent with PARAMOUNT's safety profile. Conclusion The efficacy and safety data in the EA trials were similar to those in PARAMOUNT despite differences in patient populations and study designs. These data represent consistent evidence for pemetrexed continuation maintenance therapy in EA patients with advanced nonsquamous NSCLC.
  • Junji Tsurutani; Katsumasa Kuroi; Tsutomu Iwasa; Masaki Miyazaki; Shinichi Nishina; Chihiro Makimura; Junko Tanizaki; Kunio Okamoto; Toshinari Yamashita; Tomoyuki Aruga; Takashi Shigekawa; Yoshifumi Komoike; Toshiaki Saeki; Kazuhiko Nakagawa
    CANCER SCIENCE 106 6 734 - 739 2015年06月 [査読有り]
     
    We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80mg/m(2)) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100mg/m(2)nab-paclitaxel on days 1, 8, and 15 with 80mg/m(2) S-1 daily for 14days, followed by 7days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.
  • Makoto Nishio; Atsushi Horiike; Haruyasu Murakami; Nobuyuki Yamamoto; Hiroyasu Kaneda; Kazuhiko Nakagawa; Hidehito Horinouchi; Masaki Nagashima; Masaru Sekiguchi; Tomohide Tamura
    LUNG CANCER 88 3 275 - 281 2015年06月 [査読有り]
     
    Objectives: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients and methods: This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0-1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. Results: Twenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0(22.0-133.0) days for the EGFR wild-type group (n = 9) and 107.0(74.0-224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. Conclusion: Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Junji Tsurutani; Katsumasa Kuroi; Tsutomu Iwasa; Masaki Miyazaki; Shinichi Nishina; Chihiro Makimura; Junko Tanizaki; Kunio Okamoto; Toshinari Yamashita; Tomoyuki Aruga; Takashi Shigekawa; Yoshifumi Komoike; Toshiaki Saeki; Kazuhiko Nakagawa
    CANCER SCIENCE 106 6 734 - 739 2015年06月 [査読有り]
     
    We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80mg/m(2)) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100mg/m(2)nab-paclitaxel on days 1, 8, and 15 with 80mg/m(2) S-1 daily for 14days, followed by 7days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.
  • Makoto Nishio; Atsushi Horiike; Haruyasu Murakami; Nobuyuki Yamamoto; Hiroyasu Kaneda; Kazuhiko Nakagawa; Hidehito Horinouchi; Masaki Nagashima; Masaru Sekiguchi; Tomohide Tamura
    LUNG CANCER 88 3 275 - 281 2015年06月 [査読有り]
     
    Objectives: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients and methods: This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0-1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. Results: Twenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0(22.0-133.0) days for the EGFR wild-type group (n = 9) and 107.0(74.0-224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. Conclusion: Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Hiroyuki Sakurai; Kazuo Nakagawa; Shun-ichi Watanabe; Hisao Asamura
    ANNALS OF THORACIC SURGERY 99 5 1731 - 1738 2015年05月 [査読有り]
     
    Background. Subcentimeter lung cancers are still rare, and their pathobiologic behavior and management have not yet been fully clarified. Methods. From 1993 through 2011, 291 patients with resected lung cancers 1.0 cm or less in diameter were studied regarding their clinicopathologic characteristics. According to appearance on high-resolution computed tomography (HRCT), the tumors were classified into four types: type 1 (n = 50), nonsolid ground-glass opacity (GGO) lesion; type 2 (n = 89), part-solid GGO lesion including 50% or more GGO within the lesion; type 3 (n = 62), part-solid GGO lesion including less than 50% GGO within the lesion, and type 4 (n = 90), solid lesion. Results. Although none of types 1 to 3 tumors had lymph node metastases, these were found in 10% of type 4 tumors. Recurrence was observed in 13 patients, almost all of whom had type 4 tumors. The lone exception was a patient with a type 3 tumor in whom local recurrence developed on a surgical staple line. The 5-year overall survival rates were 100% in type 1 and type 2, 98% in type 3, and 88% in type 4. Type 4 had a significantly worse prognosis than the other types. Conclusions. Subcentimeter lung cancers with a GGO component on HRCT (types 1 to 3) can be considered "early" lung cancers. In these cases, limited resection may be warranted to achieve a cure because they had no lymph node metastasis. By contrast, lobectomy should still be considered the standard operation of choice for type 4 tumors. (C) 2015 by The Society of Thoracic Surgeons
  • Yukio Hosomi; Kiyotaka Yoh; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Kaoru Tanaka; Toyoaki Hida; Hiroshige Yoshioka; Terufumi Kato; Koji Takeda; Makoto Nishio; Hiroshi Sakai; Makoto Maemondo; Mitsuhiro Takenoyama; Hiroshi Nokihara; Masumi Tatsumi; Takashi Nakamura; Sotaro Enatsu; Tomohide Tamura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 33 15 2015年05月 [査読有り]
  • Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Naonobu Kunitake; Junichi Shimizu; Takeshi Kodaira; Makoto Nishio; Takuyo Kozuka; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Kazuhiko Nakagawa; Yasumasa Nishimura; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 33 15 2015年05月 [査読有り]
  • Kazuko Sakai; Junji Tsurutani; Takeharu Yamanaka; Azusa Yoneshige; Akihiko Ito; Yosuke Togashi; Marco A. De Velasco; Masato Terashima; Yoshihiko Fujita; Shuta Tomida; Takao Tamura; Kazuhiko Nakagawa; Kazuto Nishio
    PLOS ONE 10 5 e0121891  2015年05月 [査読有り]
     
    Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (alpha = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.
  • ALK陽性完全切除不能進行肺癌に対し化学療法および分子標的治療後にサルベージ手術を行った1例
    阪口 全宏; 須田 健一; 岩崎 拓也; 武本 智樹; 富沢 健二; 佐藤 克明; 水内 寛; 下治 正樹; 小林 祥久; 岡部 崇記; 金田 裕靖; 中川 和彦; 光冨 徹哉
    日本呼吸器外科学会雑誌 29 3 O2 - 4 (一社)日本呼吸器外科学会 2015年04月
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    LUNG CANCER 88 1 74 - 79 2015年04月 [査読有り]
     
    Objectives: Three epidermal growth factor receptor (EGER) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade >= 3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >= 3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >= 3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Yasuhito Fujisaka; Takayasu Kurata; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 33 2 380 - 388 2015年04月 [査読有り]
     
    Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
  • Yasuhito Fujisaka; Takayasu Kurata; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 33 2 380 - 388 2015年04月 [査読有り]
     
    Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
  • Yosuke Togashi; Hidetoshi Hayashi; Kunio Okamoto; Soichi Fumita; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio
    LUNG CANCER 88 1 16 - 23 2015年04月 [査読有り]
     
    Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. Materials and methods: PC-9 and 11-18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1 mu M nicotine for 3 months and were designated as PC-9/N and 11-18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. Results: The PC-9/N and 11-18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    LUNG CANCER 88 1 74 - 79 2015年04月 [査読有り]
     
    Objectives: Three epidermal growth factor receptor (EGER) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade >= 3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >= 3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >= 3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Nanjo S; Nakagawa T; Takeuchi S; Kita K; Fukuda K; Nakada M; Uehara H; Nishihara H; Hara E; Uramoto H; Tanaka F; Yano S
    Cancer science 106 3 244 - 52 2015年03月 [査読有り]
     
    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
  • Toshiaki Saeki; Kazuo Tamura; Keisuke Aiba; Kenjiro Aogi; Keiko Lino; Chiyo Imamura; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Kazuo Matsuura; Makoto Wada; Tatsuo Akechi; Yuichi Kakudo; Yong-Il Kim; Hide-Nori Sasaki; Yasuo Shima; Masayuki Takeda; Eijiro Nagasaki; Toshihiko Nishidate; Mitsue Saito; Yukino Ashikaga; Yusuke Tanigawara; Koichi Hirata; Chikashi Ishioka; Masahiko Nishiyama
    Japanese Journal of Cancer and Chemotherapy 42 3 305 - 311 2015年03月 [査読有り]
     
    Background: Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. Material: Questionnaire analysis From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff f