HAYASHI Hidetoshi

Researcher Information

J-Global ID

• 201401024996540884

Research Interests

• Cancer of Unknown Primary   Lung Cancer   Gene analysis   medical oncology   immune checkpoint inhibitor   

Research Areas

• Life sciences / Tumor diagnostics and therapeutics

Academic & Professional Experience

• 2023/04 - Today  Kindai University, Faculty of MedicineDepartment of Medical OncologyProfessor
• 2022/04 - Today  Kindai University, Faculty of MedicineDepartment of Medical Oncology特命准教授
• 2020/04 - 2022/03  近畿大学医学部内科学腫瘍内科講師
• 2015/10 - 2020/03  Kindai university hospitalDepartment of Medical OncologyLecturer
• 2015/04 - 2015/09  Kindai university hospitalDepartment of Medical OncologyAssistant professor
• 2013/04 - 2015/03  Kishiwada City HospitalDepartment of Medical OncologyDirector
• 2009/04 - 2013/03  Kindai university hospitalDepartment of Medical Oncologyassistant professor
• 2006/04 - 2009/03  Kurashiki Central HospitalRespiratory MedicineMedical Staff
• 2003/04 - 2006/03  Sumitomo HospitalGeneral MedicineResident

Education

• 2009/04 - 2012/03  Kindai University  Faculty of Medicine  大学院
• 1997/04 - 2003/03  Osaka University  Faculty of Medicine  Medical School

Association Memberships

• American Society of Clinical Oncology   日本臨床腫瘍学会   THE JAPAN LUNG CANCER SOCIETY   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   International Association for the Study of Lung Cancer   

Published Papers

• Anti-integrin αvβ6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

  Masataka Yokode; Masahiro Shiokawa; Hisato Kawakami; Takeshi Kuwada; Yoshihiro Nishikawa; Yuya Muramoto; Hiroki Kitamoto; Makoto Okabe; Hajime Yamazaki; Norihiro Okamoto; Toshihiro Morita; Kazuya Ohno; Risa Nakanishi; Ikuhisa Takimoto; Muneji Yasuda; Koki Chikugo; Shimpei Matsumoto; Hiroyuki Yoshida; Sakiko Ota; Takeharu Nakamura; Hirokazu Okada; Tomonori Hirano; Nobuyuki Kakiuchi; Tomoaki Matsumori; Shuji Yamamoto; Norimitsu Uza; Makoto Ooi; Yuzo Kodama; Tsutomu Chiba; Hidetoshi Hayashi; Hiroshi Seno

  British journal of cancer 130 (9) 1552 - 1560 2024/05 

  BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvβ6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvβ6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvβ6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvβ6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvβ6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvβ6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvβ6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvβ6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvβ6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.
• Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade

  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 2024/04
• Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

  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 2024/03 

  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.
• Hemophagocytic lymphohistiocytosis induced by nivolumab/ipilimumab combination therapy: A case of lung adenocarcinoma that responded to early steroid pulse therapy.

  Satoru Hagiwara; Junko Tanizaki; Hidetoshi Hayashi; Yoriaki Komeda; Naoshi Nishida; Akihiro Yoshida; Tomoki Yamamoto; Takuya Matsubara; Masatoshi Kudo

  Cancer reports (Hoboken, N.J.) e1960  2024/01 

  BACKGROUND: Immune checkpoint inhibitors have been reported to have excellent therapeutic effects on various malignant tumors. However, immune-related adverse events can occur, targeting various organs. CASE PRESENTATION: A 49-year-old male with lung carcinoma was started on carboplatin + pemetrexed + nivolumab (every 3 weeks) + ipilimumab (every 6 weeks), and nivolumab/ipilimumab was administered in the 3rd course. Subsequently, fever and fatigue developed, and grade 3 liver damage was also noted, so he was admitted to Kindai University Hospital. A bone marrow aspirate examination was performed on the third day of illness, and a definitive diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. It was determined that immediate therapeutic intervention was necessary, and pulse therapy with methylprednisolone was started on the third day of illness. After 3 days of pulse treatment, a rapid recovery of platelet values, a decrease in ferritin levels, and a decrease in lactate dehydrogenase were observed. Subjective symptoms such as fever and fatigue also quickly improved. CONCLUSION: Early diagnosis and treatment for HLH resulted in a positive response. The number of HLH cases may increase in the future due to the expansion of immune checkpoint inhibitor indications.
• Unraveling Pseudo Kidney Injury: The Significance of Understanding Our “MATE” in Molecular-Targeted Therapies

  Junko Tanizaki; Hidetoshi Hayashi

  Journal of Thoracic Oncology 2024/01
• Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

  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 2023/12 

  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.
• Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study

  Yoshiaki Nakamura; Nobumasa Mizuno; Yu Sunakawa; Jean-Luc Canon; Matthew D. Galsky; Erika Hamilton; Hidetoshi Hayashi; Guy Jerusalem; Seung Tae Kim; Keun-Wook Lee; Lionel Aurelien Kankeu Fonkoua; Bradley J. Monk; Danny Nguyen; Do-Youn Oh; Alicia Okines; David M. O'Malley; Paula Pohlmann; Martin Reck; Sang Joon Shin; Kazuki Sudo; Shunji Takahashi; Cedric Van Marcke; Evan Y. Yu; Roman Groisberg; Jorge Ramos; Sherry Tan; Thomas E. Stinchcombe; Tanios Bekaii-Saab

  Journal of Clinical Oncology 2023/12
• HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy

  Helena A. Yu; Yasushi Goto; Hidetoshi Hayashi; Enriqueta Felip; James Chih-Hsin Yang; Martin Reck; Kiyotaka Yoh; Se-Hoon Lee; Luis Paz-Ares; Benjamin Besse; Paolo Bironzo; Dong-Wan Kim; Melissa L. Johnson; Yi-Long Wu; Thomas John; Steven Kao; Toshiyuki Kozuki; Erminia Massarelli; Jyoti Patel; Egbert Smit; Karen L. Reckamp; Qian Dong; Pomy Shrestha; Pang-Dian Fan; Parul Patel; Andrea Sporchia; David W. Sternberg; Dalila Sellami; Pasi A. Jänne

  Journal of Clinical Oncology 2023/12
• NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

  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 2023/10 

  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.
• Real-World Data About Treatment Outcomes for Patients with EGFR-Mutated NSCLC Resistance to Osimertinib and Platinum-Based Chemotherapy

  Hidetoshi Hayashi; Makoto Nishio; Michiko Takahashi; Hiroaki Tsuchiya; Mami Kasahara-Kiritani

  Advances in Therapy 2023/10
• Lack of Association of Plasma Levels of Soluble PD-1, PD-L1, and CTLA-4 with Survival for Stage II to IIIA Non–Small Cell Lung Cancer after Complete Resection and Adjuvant Chemotherapy

  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 Elsevier BV 100590 - 100590 2666-3643 2023/10
• First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1.

  Makoto Nishio; Yuichiro Ohe; Satoshi Ikeda; Toshihide Yokoyama; Hidetoshi Hayashi; Tatsuro Fukuhara; Yuki Sato; Hiroshi Tanaka; Katsuyuki Hotta; Shunichi Sugawara; Haruko Daga; Isamu Okamoto; Kazuo Kasahara; Tateaki Naito; Li Li; Ravi G Gupta; Judith Bushong; Hideaki Mizutani

  International journal of clinical oncology 28 (10) 1354 - 1368 2023/10 

  BACKGROUND: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. METHODS: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. RESULTS: At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%-75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. CONCLUSIONS: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.
• Correction to: First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1.

  Makoto Nishio; Yuichiro Ohe; Satoshi Ikeda; Toshihide Yokoyama; Hidetoshi Hayashi; Tatsuro Fukuhara; Yuki Sato; Hiroshi Tanaka; Katsuyuki Hotta; Shunichi Sugawara; Haruko Daga; Isamu Okamoto; Kazuo Kasahara; Tateaki Naito; Li Li; Ravi G Gupta; Judith Bushong; Hideaki Mizutani

  International journal of clinical oncology 28 (10) 1369 - 1370 2023/10
• Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain

  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 SPANDIDOS PUBL LTD 26 (2) 1792-1074 2023/08 

  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.
• Tumor microenvironment landscape of non-small cell lung cancer reveals resistance mechanisms for PD-L1 blockade following chemoradiotherapy: a multi-center prospective biomarker study (WJOG11518L/SUBMARINE).

  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 2023/06 

  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.
• Alternating Therapy With Osimertinib and Afatinib Blockades EGFR Secondary Mutation in EGFR-Mutant Lung Cancer: A Single-Arm Phase II Trial.

  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 2023/06 

  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.
• Efficacy of Crizotinib After Entrectinib Resistance Due to MET Polysomy in ROS1-Rearranged NSCLC: A Case Report.

  Toshiaki Takakura; Hiroaki Kanemura; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa; Hidetoshi Hayashi

  JTO clinical and research reports 4 (6) 100523 - 100523 2023/06 

  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.
• Predictive value of co-existing genetic alterations and tumor mutation burden for patients with completely resected non-small cell lung cancer harboring EGFR mutation: Biomarker analysis of phase III IMPACT study.

  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 American Society of Clinical Oncology ({ASCO}) 41 (16{\_}suppl) 8524 - 8524 0732-183X 2023/06 

  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 .
• A Retrospective, Multicenter, Observational Study to Evaluate Clinical Outcomes of Lorlatinib After Alectinib in Patients With ALK-Positive NSCLC in Japan

  Yasushi Goto; Hirotsugu Kenmotsu; Motohiro Tamiya; Shuji Murakami; Takayasu Kurata; Noriko Yanagitani; Hirokazu Taniguchi; Shoichi Kuyama; Junichi Shimizu; Toshihide Yokoyama; Naoko Shimada; Tadashi Maeda; Akihiro Tamiya; Ayumi Uchiyama; Kazuyoshi Imaizumi; Takayuki Takahama; Terufumi Kato; Hidetoshi Hayashi; Naoko Shiraiwa; Shigeyuki Toyoizumi; Hironori Kikkawa; Despina Thomaidou; Makoto Nishio

  JTO Clinical and Research Reports Elsevier BV 4 (5) 100508 - 100508 2666-3643 2023/05
• Soluble programmed cell death ligand 1 predicts prognosis for gastric cancer patients treated with nivolumab: Blood-based biomarker analysis for the DELIVER trial

  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 2023/05
• First-Line Lorlatinib Versus Crizotinib in ALK-Positive NSCLC: Japanese Subgroup Analysis of CROWN

  Hidetoshi Hayashi; Shunsuke Teraoka; Yasushi Goto; Toru Kumagai; Makoto Nishio; Shunichi Sugawara; Satoshi Oizumi; Masakazu Matsumura; Masayuki Okura; Gerson Peltz; Terufumi Kato

  JTO Clinical and Research Reports 2023/04
• Effectiveness and Safety of Atezolizumab Monotherapy in Previously Treated Japanese Patients With Unresectable Advanced or Recurrent NSCLC: A Multicenter, Prospective, Observational Study (J-TAIL).

  Satoru Miura; Makoto Nishio; Hiroaki Akamatsu; Yasushi Goto; Hidetoshi Hayashi; Akihiko Gemma; Ichiro Yoshino; Toshihiro Misumi; Akito Hata; Osamu Hataji; Kohei Fujita; Masahiro Seike; Noriko Yanagitani; Kazumi Nishino; Satoshi Hara; Ryota Saito; Masahide Mori; Takeshi Tsuda; Shunichiro Iwasawa; Shintaro Nakagawa; Tetsuya Mitsudomi

  JTO clinical and research reports 4 (3) 100484 - 100484 2023/03 [Refereed]
   

  INTRODUCTION: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. METHODS: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. RESULTS: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. CONCLUSIONS: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.
• A phase II study (WJOG12819L) 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.

  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 2023/01 

  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.
• Correction: Implication of changes in PD-L1 expression during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen in esophageal squamous cell carcinoma.

  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 2023/01
• The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study.

  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 

  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.
• Creation of an Integrated Clinical Trial Database and Data Sharing for Conducting New Research by the Japan Lung Cancer Society

  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 0386-9628 2023 

  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.
• Implication of changes in PD-L1 expression during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen in esophageal squamous cell carcinoma.

  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 2022/12 

  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.
• Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study)

  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 Oxford University Press (OUP) 1083-7159 2022/11 

  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.
• Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study.

  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 2022/11 

  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).
• Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non–Small-Cell Lung Cancer From the Phase III CROWN Study

  Benjamin J. Solomon; Todd M. Bauer; Sai-Hong Ignatius Ou; Geoffrey Liu; Hidetoshi Hayashi; Alessandra Bearz; Konstantin Penkov; Yi-Long Wu; Oscar Arrieta; Jacek Jassem; Anna M. Calella; Gerson Peltz; Anna Polli; Holger Thurm; Tony Mok

  Journal of Clinical Oncology 2022/11
• 第1・2世代EGFR-TKIおよびプラチナPD(T790M陰性)を示したEGFR陽性NSCLCに対するオシメルチニブの第2相試験

  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 (NPO)日本肺癌学会 62 (6) 660 - 660 0386-9628 2022/11
• 既治療進行非小細胞肺癌に対するアテゾリズマブとドセタキセル/ラムシルマブ併用療法の比較試験:WJOG10317L

  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 (NPO)日本肺癌学会 62 (6) 648 - 648 0386-9628 2022/11
• 切除不能な進行・再発NSCLC患者に対するアテゾリズマブの多施設共同前向き観察研究(J-TAIL) 最終解析

  畑地 治; 西尾 誠人; 赤松 弘朗; 後藤 悌; 林 秀敏; 三浦 理; 弦間 昭彦; 吉野 一郎; 三角 俊裕; 秦 明登; 藤田 浩平; 清家 正博; 柳谷 典子; 西野 和美; 原 聡志; 岩澤 俊一郎; 仲川 慎太郎; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 62 (6) 524 - 524 0386-9628 2022/11
• 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 (NPO)日本肺癌学会 62 (6) 594 - 594 0386-9628 2022/11
• 切除不能な進行・再発NSCLC患者に対するアテゾリズマブの多施設共同前向き観察研究(J-TAIL) 最終解析

  畑地 治; 西尾 誠人; 赤松 弘朗; 後藤 悌; 林 秀敏; 三浦 理; 弦間 昭彦; 吉野 一郎; 三角 俊裕; 秦 明登; 藤田 浩平; 清家 正博; 柳谷 典子; 西野 和美; 原 聡志; 岩澤 俊一郎; 仲川 慎太郎; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 62 (6) 524 - 524 0386-9628 2022/11
• Mechanisms of primary and acquired resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer: A multiplex immunohistochemistry-based single-cell analysis.

  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 2022/10 

  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.
• 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 (NPO)日本肺癌学会 62 (5) 442 - 442 0386-9628 2022/10
• Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study.

  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 2022/09 

  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.
• The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

  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 2022/08 

  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.
• Progression from early to advanced stage of immune-related cholangitis.

  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 2022/07 

  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.
• Nivolumab Retreatment in Non-Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L).

  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  2022/06 

  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.
• プラチナダブレット術後化学療法を受けた非小細胞肺癌患者におけるEGFR遺伝子変異による効果予測

  西尾 和人; 坂井 和子; 林 秀敏; 高橋 利明; 釼持 広知; 葉 清隆; 坪井 正博; 駄賀 晴子; 大平 達夫; 上野 剛; 青木 正; 山崎 宏司; 細見 幸生; 芳川 豊史; 奥村 典仁; 山本 信之

  肺癌 (NPO)日本肺癌学会 62 (3) 260 - 260 0386-9628 2022/06
• Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection

  Satoru Hagiwara; 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 Wiley 1386-6346 2022/05
• Nivolumab retreatment in non-small cell lung cancer patients who responded to prior immune-checkpoint inhibitors and had ICI-free intervals (WJOG9616L).

  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 2022/05 

  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.
• Creation of an Integrated Clinical Trial Database and Data Sharing for Conducting New Research by the Japan Lung Cancer Society.

  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

  JTO clinical and research reports 3 (5) 100317 - 100317 2022/05 

  Introduction: Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. Methods: The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results: A total of eight trials, JCOG9812, JCOG0301, 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; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, 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. Conclusions: 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.
• Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L).

  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 2022/04 

  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.
• Apixaban in Japanese patients with cancer-associated venous thromboembolism: a multi-center phase II trial.

  Yoshinori Imamura; Kazunori Otsui; Kenta Mori; Koichi Kitagawa; Hideaki Okada; Akito Hata; Hidetoshi Hayashi; Taku Nose; Shinya Ohata; Yoshiharu Miyata; Yohei Funakoshi; Masanori Toyoda; Kimikazu Yakushijin; Naomi Kiyota; Hiroshi Matsuoka; Hironobu Minami

  International journal of hematology 115 (4) 499 - 507 2022/04 

  BACKGROUND: Recent pivotal phase III trials involving direct oral anticoagulant (DOAC) versus low molecular weight heparin have demonstrated the utility of DOACs in Western patients with cancer-associated venous thromboembolism (VTE). However, these trials did not include Japanese patients. This phase II trial evaluated the safety and efficacy of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). METHOD AND RESULTS: Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. The primary endpoint was the incidence of major or clinically relevant non-major (CRNM) bleeding events during the treatment period. The study was terminated due to safety concerns after enrolling 27 patients. Median age was 71 years; median body weight was 51.3 kg; and major primary tumor sites were the gastrointestinal tract (26%) and lung (19%). During the median follow-up period of 5.4 months, major or CRNM bleeding occurred in in 26% of patients (major, n = 5; CRNM, n = 2; 95% confidence interval, 11-46%). No recurrent VTE or VTE-related death occurred. Estimated overall survival at 6 months was 68%. CONCLUSION: This study demonstrated the excessive bleeding risk of apixaban at the standard dose in Japanese patients with cancer-associated VTE.
• Nintedanib plus chemotherapy for non-small cell lung cancer with IPF: a randomized phase 3 trial.

  Kohei Otsubo; Junji Kishimoto; Masahiko Ando; Hirotsugu Kenmotsu; Yuji Minegishi; Hidehito Horinouchi; Terufumi Kato; Eiki Ichihara; Masashi Kondo; Shinji Atagi; Motohiro Tamiya; Satoshi Ikeda; Toshiyuki Harada; Shinnosuke Takemoto; Hidetoshi Hayashi; Keita Nakatomi; Yuichiro Kimura; Yasuhiro Kondoh; Masahiko Kusumoto; Kazuya Ichikado; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto

  The European respiratory journal 60 (6) 2022/03 

  BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced non-small cell lung cancer (NSCLC) with IPF. METHODS: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nab-paclitaxel (100 mg m-2 on days 1, 8, and 15) every 3 weeks with or without nintedanib (150 mg b.i.d., daily). The primary end point was exacerbation-free survival (EFS). RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (HR, 0.89; 90% CI, 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR, 0.68; 95% CI, 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR, 0.61; 95% CI, 0.40-0.93) and in those at GAP stage I (HR, 0.61; 95% CI, 0.38-0.98). Seven (2.9%) of 240 patients experienced acute exacerbation during study treatment. CONCLUSIONS: The primary end point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.
• A Randomized Phase II Study Comparing Nivolumab with Carboplatin-Pemetrexed for EGFR-Mutated NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors (WJOG8515L).

  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 2022/03 

  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.
• Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary.

  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 2022/02 

  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.
• MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer.

  Byoung Chul Cho; Enriqueta Felip; Hidetoshi Hayashi; Michael Thomas; Shun Lu; Benjamin Besse; Tao Sun; Melissa Martinez; Seema N Sethi; S Martin Shreeve; Alexander I Spira

  Future oncology (London, England) 18 (6) 639 - 647 2022/02 

  Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated efficacy in patients with EGFR-mutant non-small-cell lung cancer; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS study (NCT02609776), amivantamab in combination with lazertinib, a potent, brain-penetrant third-generation EGFR TKI, demonstrated antitumor activity in the treatment-naive and osimertinib-relapsed setting. Here the authors present the methodology for the MARIPOSA study (NCT04487080), a phase 3, multicenter, randomized study designed to compare the efficacy and safety of amivantamab and lazertinib combination therapy versus single-agent osimertinib as first-line treatment for EGFR-mutant non-small-cell lung cancer.
• Phase II study of atezolizumab with bevacizumab for non-squamous non-small cell lung cancer with high PD-L1 expression (@Be Study).

  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) 2022/02 

  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.
• Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT).

  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 2022/01 

  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.
• HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer.

  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 2022/01 

  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.
• Correction: KRAS Inhibitor Resistance in MET-Amplified KRAS G12C Non-Small Cell Lung Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms.

  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 2022/01
• Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer.

  Pasi A Jänne; Christina Baik; Wu-Chou Su; Melissa L Johnson; Hidetoshi Hayashi; Makoto Nishio; Dong-Wan Kim; Marianna Koczywas; Kathryn A Gold; Conor E Steuer; Haruyasu Murakami; James Chih-Hsin Yang; Sang-We Kim; Michele Vigliotti; Rong Shi; Zhenhao Qi; Yang Qiu; Lihui Zhao; David Sternberg; Channing Yu; Helena A Yu

  Cancer discovery 12 (1) 74 - 89 2022/01 

  Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.
• Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

  Toshiaki Takahashi; Kazuko Sakai; Hirotsugu Kenmotsu; Kiyotaka Yoh; Haruko Daga; Tatsuo Ohira; Tsuyoshi Ueno; Tadashi Aoki; Hidetoshi Hayashi; Koji Yamazaki; Yukio Hosomi; Toyofumi F Chen-Yoshikawa; Norihito Okumura; Yuichi Takiguchi; Akimasa Sekine; Tomohiro Haruki; Hiromasa Yamamoto; Yuki Sato; Hiroaki Akamatsu; Takashi Seto; Sho Saeki; Kenji Sugio; Makoto Nishio; Hidetoshi Inokawa; Nobuyuki Yamamoto; Kazuto Nishio; Masahiro Tsuboi

  Cancer science 113 (1) 287 - 296 2022/01 

  The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).
• Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations.

  Hidetoshi Hayashi; Ernest Nadal; Jhanelle E Gray; Andrea Ardizzoni; Nicola Caria; Tarun Puri; Christian Grohe

  Clinical lung cancer 23 (1) e69-e82  2022/01 

  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.
• Association of tumour burden with the efficacy of programmed cell death-1/programmed cell death ligand-1 inhibitors for treatment-naïve advanced non-small-cell lung cancer.

  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 2022/01 

  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.
• Clinical Characteristics and Outcomes in Advanced KRAS-Mutated NSCLC: A Multicenter Collaboration in Asia (ATORG-005).

  Jiyun Lee; Aaron C Tan; Siqin Zhou; Shinkyo Yoon; Siyang Liu; Ken Masuda; Hidetoshi Hayashi; Ullas Batra; Dong-Wan Kim; Yasushi Goto; Sze Huey Tan; Yi-Long Wu; Dae Ho Lee; Daniel S W Tan; Myung-Ju Ahn

  JTO clinical and research reports 3 (1) 100261 - 100261 2022/01 

  INTRODUCTION: Whereas interpatient heterogeneity in clinical characteristics and treatment outcomes of NSCLC harboring a KRAS mutation is recognized, the characterization of these patients in Asia has been limited. METHODS: A multicenter, retrospective cohort study was conducted in eight academic centers across Asia. Patients diagnosed with advanced NSCLC harboring a KRAS mutation and who had received at least one line of anticancer therapy between January 2014 and December 2018 were included. Modified time to next treatment (TTNT) was adopted as a proxy for progression-free survival. RESULTS: A total of 216 patients were analyzed. The median age at diagnosis of advanced NSCLC was 63.3 years, 70.8% were men and 89.8% had adenocarcinoma. KRAS G12D was the most common subtype (25.5%), followed by G12C (24.5%), and G12V (19.4%) The proportion of current or former smokers was 65.7% in the overall population, with 86.8% in G12C and 58.9% in non-G12C subgroups. For all treatments combined for the total population, the first-line duration of therapy, modified TTNT, and TTNT were 4.5 (95% confidence interval: 3.4-5.9), 6.2 (4.9-8.8), and 9.5 (7.1-11.4) months, respectively. The median overall survival for the total population was 10.3 (6.9-12.4) months and was prolonged in patients ever treated with immunotherapy (14.6 [8.6-19.1] versus 7.0 [5.9-10.6] mo, hazard ratio = 0.54, p < 0.001), with left truncation to account for the time of KRAS testing. CONCLUSIONS: Whereas treatment outcomes with conventional anticancer therapy are reasonable and immunotherapy looks promising, the unmet need remains high for patients with KRAS-mutated NSCLC in Asia, underscoring the need for novel therapeutic approaches.
• 原発不明癌に対するNivolumab(ONO-4538)の有効性を検討する第II相試験

  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 近畿大学医学会 46 (3-4) 20A - 20A 0385-8367 2021/12
• Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease

  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 Springer Science and Business Media LLC 11 (1) 2021/12 

  Immune 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.
• [Handling of Japanese Subgroup Data in Global Clinical Trials and Its Clinical Significance-In Terms of Systemic Therapies for Advanced Lung Cancer].

  Takashi Kurosaki; Hidetoshi Hayashi

  Gan to kagaku ryoho. Cancer & chemotherapy 48 (11) 1330 - 1334 0385-0684 2021/11 

  There has been remarkable progress in systemic therapy for advanced lung cancer in recent years. Novel molecular targeted agents directed against oncogenic driver mutations as well as combination strategies with immune checkpoint inhibitors have been continuously emerged in the clinical practice, which is driving the expansion of precision medicine. As most of these newly developed drugs and therapies were approved on the basis of global randomized studies, the robust data for the efficacy and safety focused on the Japanese patients are limited. Given that the genetic, environmental, and social backgrounds of the Japanese are different from those of Caucasians, it is questionable whether the available global data for the efficacy and safety of newly developed drugs can passively be extrapolated to the Japanese patients. In this article, we discuss the regional and racial differences of the responses or toxicity profiles of anti-cancer agents, and review the characteristics of the Japanese subgroup data in global clinical studies focusing on the following 3 different types of drugs: epidermal growth factor receptor-tyrosine kinase inhibitors, cytotoxic chemotherapeutic agents, and immune checkpoint inhibitors.
• Docetaxel plus cisplatin in recurrent and/or metastatic non-squamous-cell head and neck cancer: a multicenter phase II trial

  Yoshinori Imamura; Kaoru Tanaka; Naomi Kiyota; Hidetoshi Hayashi; Ichiro Ota; Akihito Arai; Shigemichi Iwae; Shujiro Minami; Katsunari Yane; Tomoko Yamazaki; Yoshiaki Nagatani; Masanori Toyoda; Takayuki Takahama; Kazuko Sakai; Kazuto Nishio; Naoki Otsuki; Ken-ichi Nibu; Hironobu Minami

  Medical Oncology Springer Science and Business Media LLC 38 (11) 128 - 128 1357-0560 2021/11 

  The clinical utility of systemic therapy and genomic profiling in non-squamous-cell head and neck cancer (NSCHNC) has not been fully elucidated. This phase II trial evaluated the efficacy and safety of docetaxel and cisplatin combination in the first-line setting. Eligibility criteria were recurrent and/or metastatic NSCHNC; progressive disease within the last 6 months; no prior systemic therapy; and ECOG performance status of 0-1. Patients received docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1), repeated every 21 days for 6 cycles. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Next-generation sequencing (NGS) was performed using the Ion AmpliSeq Cancer Hotspot Panel v2. Twenty-three patients were enrolled from November 2012 to October 2016, of whom 8 were male. Median age was 57 years. Ninety-six percent of cases were metastatic. Among 22 evaluable patients, confirmed ORR was 45% (95% confidential interval 24-68%). With a median follow-up period of 18.8 months, median PFS and OS were 6.7 and 20.1 months, respectively. Grade 3/4 adverse events included febrile neutropenia (39%) and anemia (22%). No treatment-related deaths were observed. NGS analysis revealed potential treatment targets, including ERBB2, KIT, and ALK. The docetaxel and cisplatin combination regimen can be considered a new treatment option in recurrent and/or metastatic NSCHNC, although primary prophylaxis for febrile neutropenia should be considered. Diverse genomic alterations may lead novel treatment options.This trial was registered with the UMIN Clinical Trials Registry as UMIN000008333 on [September 1st, 2012].
• Phase III Clinical Trial for the Combination of Erlotinib Plus Ramucirumab Compared With Osimertinib in Previously Untreated Advanced or Recurrent Non-Small Cell Lung Cancer Positive for the L858R Mutation of EGFR: REVOL858R (WJOG14420L).

  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  2021/10 

  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.
• 実臨床における肺癌クリニカルシーケンスの現状と展望～最良効率での利用を目指して～ 肺癌学会としてのオンコマインデータ収集事業について

  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 (NPO)日本肺癌学会 61 (6) 517 - 517 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 649 - 649 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 594 - 594 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 498 - 498 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 627 - 627 0386-9628 2021/10
• EGFR-TKIはHER3の発現を促し、HER3阻害剤パトリツマブデルクステカンの有効性を高める(EGFR-TKI augments HER3 expression and enhances the efficacy of HER3 targeting patritumab deruxtecan)

  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 (NPO)日本肺癌学会 61 (6) 623 - 623 0386-9628 2021/10
• MET-amplifiedによるKRASG12C阻害薬の獲得耐性とメカニズム

  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 (NPO)日本肺癌学会 61 (6) 629 - 629 0386-9628 2021/10
• 耐性化したEGFR遺伝子変異陽性非小細胞肺癌に対するNivolumabとCBDCA+PEMの第2相比較臨床試験(WJOG8515L)

  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 (NPO)日本肺癌学会 61 (6) 677 - 677 0386-9628 2021/10
• 切除不能な進行・再発NSCLC患者に対するアテゾリズマブの多施設共同前向き観察研究(J-TAIL) 中間解析

  中谷 光一; 西尾 誠人; 赤松 弘朗; 後藤 悌; 林 秀敏; 三浦 理; 弦間 昭彦; 吉野 一郎; 三角 俊裕; 秦 明登; 畑地 治; 清家 正博; 柳谷 典子; 熊谷 融; 原 聡志; 森岡 麻未; 仲川 慎太郎; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 606 - 606 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 499 - 499 0386-9628 2021/10
• 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 (一社)日本癌治療学会 59回 O13 - 5 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 498 - 498 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 627 - 627 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 499 - 499 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 649 - 649 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 594 - 594 0386-9628 2021/10
• 切除不能な進行・再発NSCLC患者に対するアテゾリズマブの多施設共同前向き観察研究(J-TAIL) 中間解析

  中谷 光一; 西尾 誠人; 赤松 弘朗; 後藤 悌; 林 秀敏; 三浦 理; 弦間 昭彦; 吉野 一郎; 三角 俊裕; 秦 明登; 畑地 治; 清家 正博; 柳谷 典子; 熊谷 融; 原 聡志; 森岡 麻未; 仲川 慎太郎; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 606 - 606 0386-9628 2021/10
• 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 (NPO)日本肺癌学会 61 (6) 662 - 662 0386-9628 2021/10
• Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L.

  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 2021/10 

  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.
• KRAS inhibitor-resistance in MET-amplified KRAS G12C non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms.

  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 2021/08 

  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.
• Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study.

  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 2021/07 

  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.
• CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M–positive lung cancer after osimertinib

  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 Springer Science and Business Media LLC 26 (9) 1628 - 1639 1341-9625 2021/06 

  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.
• Clinical implications of bronchoscopy for immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer.

  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 2021/05 

  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.
• First-line durvalumab plus platinum-etoposide in extensive-stage small-cell lung cancer: CASPIAN Japan subgroup analysis.

  Katsuyuki Hotta; Makoto Nishio; Haruhiro Saito; Isamu Okamoto; Yasuharu Nakahara; Hidetoshi Hayashi; Manabu Hayama; Peter Laud; Haiyi Jiang; Luis Paz-Ares; Koichi Azuma

  International journal of clinical oncology 26 (6) 1073 - 1082 2021/04 

  BACKGROUND: In the phase 3 CASPIAN study (NCT03043872), first-line durvalumab plus etoposide and cisplatin or carboplatin (EP) significantly improved OS versus EP alone in patients with extensive-stage (ES)-SCLC (HR 0.73 [95% CI 0.59-0.91; p = 0.0047]). Here we report results for a preplanned subgroup analysis of patients recruited in Japan. METHODS: Treatment-naïve patients with ES-SCLC received either 4 cycles of durvalumab 1500 mg plus EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression or up to 6 cycles of EP q3w. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability. RESULTS: In the Japan subgroup, 18 patients were randomized to durvalumab plus EP and 16 patients to EP. At the interim analysis with a median follow-up of 12.5 months in the subgroup, OS numerically favored durvalumab plus EP versus EP (HR 0.77 [95% CI 0.26‒2.26]; median not reached vs 15.2 months). PFS was similar for durvalumab plus EP versus EP (HR 0.90 [95% CI 0.43‒1.89]). Confirmed ORR was 89% with durvalumab plus EP versus 69% with EP. Adverse events (AEs) of CTCAE grade 3 or 4 were reported in 78% versus 94% of patients in the durvalumab plus EP versus EP arms. There were no AEs leading to treatment discontinuation or death in the Japan subgroup. CONCLUSION: First-line durvalumab plus EP was effective and well tolerated in Japanese patients with ES-SCLC. Despite the small size of the Japan subgroup, results were generally consistent with the global study population.
• Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

  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  2021/04 

  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.
• Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts

  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 Springer Science and Business Media {LLC} 124 (5) 914 - 924 2021/03 

  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.
• 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; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之

  和歌山医学 和歌山医学会 72 (1) 41 - 41 0043-0013 2021/03
• Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.

  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 2021/03 

  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.
• Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

  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) Elsevier {BV} 145 183 - 193 2021/03 

  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.
• Intestinal Microbiota and Gene Expression Reveal Similarity and Dissimilarity Between Immune-Mediated Colitis and Ulcerative Colitis.

  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 

  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.
• Rationale and Design for a Multicenter, Phase II Study of Durvalumab Plus Concurrent Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer: The DOLPHIN Study (WJOG11619L).

  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 

  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.
• Phase I/II Study of Cisplatin plus Nab-Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer.

  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  2021/01 

  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.
• Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study.

  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 2021/01 

  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.
• Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

  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 2020/10 

  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.
• 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 (NPO)日本肺癌学会 60 (6) 578 - 578 0386-9628 2020/10
• 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 (NPO)日本肺癌学会 60 (6) 578 - 578 0386-9628 2020/10
• 未治療進行非小細胞肺癌における化学療法の治療効果と総腫瘍量の関連性

  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 (NPO)日本肺癌学会 60 (6) 635 - 635 0386-9628 2020/10
• Lorlatinib in previously treated anaplastic lymphoma kinase-rearranged non-small cell lung cancer: Japanese subgroup analysis of a global study.

  Takashi Seto; Hidetoshi Hayashi; Miyako Satouchi; Yasushi Goto; Seiji Niho; Naoyuki Nogami; Toyoaki Hida; Toshiaki Takahashi; Jun Sakakibara-Konishi; Masahiro Morise; Takashi Nagasawa; Mie Suzuki; Masayuki Ohkura; Kei Fukuhara; Holger Thurm; Gerson Peltz; Makoto Nishio

  Cancer science 111 (10) 3726 - 3738 2020/10 

  Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
• A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer.

  Nobuyuki Yamamoto; Hidetoshi Hayashi; David Planchard; Teresa Morán; Vanesa Gregorc; Jonathan Dowell; Hiroshi Sakai; Kiyotaka Yoh; Makoto Nishio; Alexis B Cortot; Karim A Benhadji; Nital Soni; Jinhong Huang; Lukas Makris; Susana Cedres

  Investigational new drugs 38 (5) 1588 - 1597 2020/10 [Refereed]
   

  Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
• Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

  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 2020/09 [Refereed]
   

  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.
• Bleeding Events Associated with Anticoagulant Therapy; Apixaban in Japanese Patients with Cancer-associated Venous Thromboembolism: A Multicenter Phase II Trial(J-CAV)(和訳中)

  Mori Kenta; Otsui Kazunori; Imamura Yoshinori; Kitagawa Koichi; Okada Hideaki; Hata Akito; Hayashi Hidetoshi; Nose Taku; Ohata Shinya; Miyata Yoshiharu; Funakoshi Yohei; Toyoda Masanori; Kiyota Naomi; Yakushijin Kimikazu; Matsuoka Hiroshi; Minami Hironobu

  日本循環器学会学術集会抄録集 (一社)日本循環器学会 84回 PE52 - 6 2020/07
• 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 (一社)日本頭頸部癌学会 46 (2) 151 - 151 1349-5747 2020/07
• 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 (一社)日本頭頸部癌学会 46 (2) 218 - 218 1349-5747 2020/07
• Combination therapy with PD-1 or PD-L1 inhibitors for cancer

  Hidetoshi Hayashi; Kazuhiko Nakagawa

  International Journal of Clinical Oncology Springer Science and Business Media {LLC} 25 (5) 818 - 830 2020/05 [Refereed]
   

  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.
• Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

  Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa

  BMC medicine 18 (1) 111 - 111 2020/04
• Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation–Positive Non–Small Cell Lung Cancer

  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 American Association for Cancer Research ({AACR}) 26 (8) 2037 - 2046 2020/04 [Refereed]
   

  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.
• アテゾリズマブによる重症肝炎に対して血漿交換を使用した1例

  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 (NPO)日本肺癌学会 60 (2) 149 - 150 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 155 - 155 0386-9628 2020/04
• PD-L1高発現未治療進行非小細胞肺癌におけるPembrolizumabの治療効果と総腫瘍量の関連性

  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 (NPO)日本肺癌学会 60 (2) 155 - 156 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 148 - 148 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 149 - 149 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 153 - 153 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 148 - 148 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 149 - 149 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 153 - 153 0386-9628 2020/04
• 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 (NPO)日本肺癌学会 60 (2) 155 - 155 0386-9628 2020/04
• Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L).

  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 2020/03 [Refereed]
   

  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.
• Severe Immune-Related Hepatitis Treated With Plasma Exchange.

  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  2020/03 [Refereed]
  
• Propensity score–weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non–small cell lung cancer (WJOG10217L)

  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 {BMJ} 8 (1) 2020/02 [Refereed]
   

  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.
• A Case of Pulmonary Tumor Thrombotic Microangiopathy Suggested by the Presence of Tumor Cells in Peripheral Blood

  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 

  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.
• Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.

  Alexander Drilon; Jeffrey W Clark; Jared Weiss; Sai-Hong Ignatius Ou; D Ross Camidge; Benjamin J Solomon; Gregory A Otterson; Liza C Villaruz; Gregory J Riely; Rebecca S Heist; Mark M Awad; Geoffrey I Shapiro; Miyako Satouchi; Toyoaki Hida; Hidetoshi Hayashi; Danielle A Murphy; Sherry C Wang; Sherry Li; Tiziana Usari; Keith D Wilner; Paul K Paik

  Nature medicine 26 (1) 47 - 51 2020/01 [Refereed]
   

  MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
• Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.

  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 0169-5002 2020/01 [Refereed]
   

  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.
• Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors.

  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 2019/12 [Refereed]
   

  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.
• [fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification

  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 Wiley 145 (12) 3414 - 3424 2019/12 [Refereed]
   

  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.
• U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

  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

  Journal of Clinical Investigation American Society for Clinical Investigation 130 (1) 374 - 388 0021-9738 2019/12 [Refereed]
   

  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.
• Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations.

  Makoto Nishio; Haruyasu Murakami; Yuichiro Ohe; Toyoaki Hida; Hiroshi Sakai; Kazuo Kasahara; Fumio Imamura; Tomohisa Baba; Kaoru Kubota; Yukio Hosomi; Tsuneo Shimokawa; Hidetoshi Hayashi; Kazutaka Miyadera; Tomohide Tamura

  Investigational new drugs 37 (6) 1207 - 1217 0167-6997 2019/12 [Refereed]
   

  Purpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.
• 辺縁系脳炎によるPS4のSCLC Stage3Bに対し化学療法が著効し逐次的放射線療法後予防的全脳照射を施行した一例

  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 (NPO)日本肺癌学会 59 (6) 785 - 785 0386-9628 2019/11
• 免疫治療の有害事象対策 間質性肺炎発症のリスク評価とその対策

  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 (NPO)日本肺癌学会 59 (6) 547 - 547 0386-9628 2019/11
• 局所進行非小細胞肺癌に対するシスプラチン/nab-パクリタキセル+放射線化学療法の第I/II相試験

  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 (NPO)日本肺癌学会 59 (6) 672 - 672 0386-9628 2019/11
• ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討

  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 (NPO)日本肺癌学会 59 (6) 694 - 694 0386-9628 2019/11
• PD-L1高発現の進行NSCLCにおける総腫瘍径とICIによる治療効果の関係性を検討する観察研究

  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 (NPO)日本肺癌学会 59 (6) 800 - 800 0386-9628 2019/11
• 実臨床におけるリキッドバイオプシーの役割 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; 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 (NPO)日本肺癌学会 59 (6) 575 - 575 0386-9628 2019/11
• EGFR変異陽性肺癌におけるHER3リガンド・ヘレグリン発現とEGFR-TKIの治療効果との関係

  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 (NPO)日本肺癌学会 59 (6) 723 - 723 0386-9628 2019/11
• EGFR-TKI治療前のEGFR遺伝子変異陽性NSCLCにおける別の遺伝子変異の存在が治療後のT790M遺伝子変異状態に及ぼす影響(Impact of Co-Mutations in EGFR-Mutated NSCLC Before EGFR-TKIs on T790M Mutation Status After TKIs)

  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 (NPO)日本肺癌学会 59 (6) 723 - 723 0386-9628 2019/11
• 腫瘍免疫と微小環境 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; 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 (NPO)日本肺癌学会 59 (6) 567 - 567 0386-9628 2019/11
• EGFR変異陽性非小細胞肺癌における組織、血漿中AXL・GAS6発現レベルに関する研究

  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 (NPO)日本肺癌学会 59 (6) 765 - 765 0386-9628 2019/11
• 免疫療法の新規バイオマーカー 進行NSCLCにおける可溶性免疫チェックポイント因子の役割(Novel biomarkers for immunotherapies The role of soluble immune-checkpoint factors in advanced NSCLC)

  Hayashi Hidetoshi; 茶本 健司; 冨樫 庸介; 中川 和彦; 本庶 佑

  肺癌 (NPO)日本肺癌学会 59 (6) 558 - 558 0386-9628 2019/11
• Subgroup Analysis of Japanese Patients in a Phase III Study of Atezolizumab in Extensive-stage Small-cell Lung Cancer (IMpower133).

  Makoto Nishio; Shunichi Sugawara; Shinji Atagi; Hiroaki Akamatsu; Hiroshi Sakai; Isamu Okamoto; Koichi Takayama; Hidetoshi Hayashi; Yuki Nakagawa; Tomohisa Kawakami

  Clinical lung cancer 20 (6) 469 - 476 2019/11 [Refereed]
   

  BACKGROUND: Atezolizumab is effective and well-tolerated in patients with extensive-stage small-cell lung cancer (ES-SCLC), but differences in response to systemic therapy exist between Asian and Caucasian patients. Here, we assess the efficacy and tolerability of atezolizumab in Japanese patients from the IMpower133 trial (NCT02763579). PATIENTS AND METHODS: Key eligibility criteria for this multicenter, double-blind, placebo-controlled, randomized study included age ≥ 18 years; histologically or cytologically confirmed ES-SCLC, measurable per Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status of 0/1; and no prior systemic treatment for ES-SCLC. Patients were treated with either atezolizumab 1200 mg or placebo with carboplatin (area under the curve of 5 mg/mL/min) and etoposide (100 mg/m2). Primary endpoints were overall survival and investigator-assessed progression-free survival in the intention-to-treat population. Of the 403 patients randomized in the IMpower133 trial, 42 were enrolled at Japanese centers. RESULTS: In Japanese patients in the intention-to-treat population, the median overall survival in the atezolizumab group (n = 20) was longer than that in the placebo group (n = 22; 14.6 months; 95% confidence interval [CI], 11.8-17.8 months vs. 11.9 months; 95% CI, 8.4-15.8, respectively; hazard ratio, 0.72; 95% CI, 0.31-1.67). The median progression-free survival was 4.5 months (95% CI, 4.2-8.1 months) versus 4.0 months (95% CI, 2.9-5.6 months; hazard ratio, 0.47; 95% CI, 0.23-0.96), respectively. Atezolizumab was generally well-tolerated, with no treatment-related deaths. CONCLUSION: The addition of atezolizumab to carboplatin and etoposide was effective and well-tolerated in Japanese patients with ES-SCLC. Results are consistent with the primary analysis of the IMpower133 trial.
• Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L).

  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 0368-2811 2019/10 [Refereed]
   

  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.
• Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR-mutated non-small cell lung cancer.

  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 1759-7706 2019/10 [Refereed]
   

  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.
• Aberrant HER3 ligand heregulin-expressing head and neck squamous cell carcinoma is resistant to anti-EGFR antibody cetuximab, but not second-generation EGFR-TKI.

  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 2019/09 [Refereed]
   

  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.
• Clinical and immune profiling for cancer of unknown primary site.

  Haratani K; Hayashi H; Takahama T; Nakamura Y; Tomida S; Yoshida T; Chiba Y; Sawada T; Sakai K; Fujita Y; Togashi Y; Tanizaki J; Kawakami H; Ito A; Nishio K; Nakagawa K

  Journal for immunotherapy of cancer BMJ 7 (1) 251  2019/09 [Refereed]
  
• Reply to A.-M. Conway et al.

  Hidetoshi Hayashi; Kazuto Nishio; Kazuhiko Nakagawa

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 (23) 2090 - 2090 0732-183X 2019/08 [Refereed]
  
• A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing.

  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 2019/08 [Refereed]
   

  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 (NPO)日本肺癌学会 59 (4) 413 - 414 0386-9628 2019/08
• 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 (NPO)日本肺癌学会 59 (4) 419 - 419 0386-9628 2019/08
• Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

  Satomi Watanabe; Kimio Yonesaka; Junko Tanizaki; Yoshikane Nonagase; Naoki Takegawa; Koji Haratani; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Junji Tsurutani; Kazuhiko Nakagawa

  Cancer Medicine Wiley 8 (3) 1258 - 1268 2019/03 [Refereed]
   

  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.
• Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site.

  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 : official journal of the American Society of Clinical Oncology American Society of Clinical Oncology (ASCO) 37 (7) 570 - 579 0732-183X 2019/03 [Refereed]
   

  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. 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. 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. 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.
• Safety and Efficacy of Alectinib in a Patient With Advanced NSCLC Undergoing Hemodialysis.

  Suzuki S; Haratani K; Takahama T; Watanabe S; Takegawa N; Hayashi H; Takeda M; Yonesaka K; Nakagawa K

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 (3) e50 - e52 1556-0864 2019/03 [Refereed]
  
• Dual blockade of EGFR tyrosine kinase using osimertinib and afatinib eradicates EGFR‑mutant Ba/F3 cells.

  Yonesaka K; Kobayashi Y; Hayashi H; Chiba Y; Mitsudomi T; Nakagawa K

  Oncology reports 41 (2) 1059 - 1066 1021-335X 2019/02 [Refereed]
   

  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.
• Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer

  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 Wiley 110 (1) 52 - 60 1347-9032 2019/01 [Refereed]
   

  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. .
• 非小細胞肺癌において上皮成長因子受容体が変異活性化すると細胞外シグナル調節キナーゼを介して主要組織適合遺伝子複合体クラスIの発現が下方制御される(Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer)

  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 John Wiley & Sons Australia, Ltd 110 (1) 52 - 60 1347-9032 2019/01 

  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。
• Impact of cytotoxic chemotherapy on PD-L1 expression in patients with non-small cell lung cancer negative for EGFR mutation and ALK fusion.

  Sakai H; Takeda M; Sakai K; Nakamura Y; Ito A; Hayashi H; Tanaka K; Nishio K; Nakagawa K

  Lung cancer (Amsterdam, Netherlands) 127 59 - 65 0169-5002 2019/01 [Refereed]
   

  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.
• ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討

  田中 薫; 谷崎 潤子; 野長瀬 祥兼; 原谷 浩司; 酒井 瞳; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦

  肺癌 (NPO)日本肺癌学会 58 (6) 691 - 691 0386-9628 2018/10
• Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations.

  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 1347-9032 2018/09 [Refereed]
   

  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.
• ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor-naïve Japanese patients with EGFR mutation-positive non-small-cell lung cancer.

  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 1347-9032 2018/08 [Refereed]
   

  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.
• Immune-Related Adverse Events-A Novel Prediction of Nivolumab Efficacy?-Reply.

  Haratani K; Hayashi H; Nakagawa K

  JAMA oncology 4 (7) 1017 - 1018 2374-2437 2018/07 [Refereed]
  
• Nivolumab-Induced Hemophilia A Presenting as Gastric Ulcer Bleeding in a Patient With NSCLC.

  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 13 (12) e239 - e241 1556-0864 2018/07 [Refereed]
  
• B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

  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 American Association for Cancer Research (AACR) 24 (11) 2653 - 2664 1078-0432 2018/06 [Refereed]
  
• 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 2018/06 [Refereed]
   

  © 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.
• In Reply

  Junko Tanizaki; Yasutaka Chiba; Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa

  Journal of Thoracic Oncology Elsevier Inc 13 (5) e86 - e87 1556-1380 2018/05 [Refereed]
  
• A case of ALK-rearranged non-small cell lung cancer that responded to ceritinib after development of resistance to alectinib

  Yosuke Makuuchi; Hidetoshi Hayashi; Koji Haratani; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Shigeki Shimizu; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa

  Oncotarget Impact Journals LLC 9 (33) 23315 - 23319 1949-2553 2018/05 [Refereed]
   

  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.
• Clinical characteristics of non-small cell lung cancer harboring mutations in exon 20 of EGFR or HER2

  Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Junko Tanizaki; Takayuki Takahama; Koji Haratani; Kazuto Nishio; Kazuhiko Nakagawa

  Oncotarget Impact Journals LLC 9 (30) 21132 - 21140 1949-2553 2018/04 [Refereed]
   

  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.
• 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 (一財)日本消化器病学会 115 (臨増総会) A328 - A328 0446-6586 2018/03
• Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer

  Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Keita Kudo; Kimio Yonesaka; Ryoji Kato; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa

  JAMA Oncology American Medical Association 4 (3) 374 - 378 2374-2445 2018/03 [Refereed]
   

  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.
• Peripheral Blood Biomarkers Associated with Clinical Outcome in Non–Small Cell Lung Cancer Patients Treated with Nivolumab

  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 Elsevier Inc 13 (1) 97 - 105 1556-1380 2018/01 [Refereed]
   

  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.
• Prognostic Impact of Minimal Pericardial Effusion in Patients With Advanced Non-small-cell Lung Cancer

  Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 18 (6) E449 - E455 1525-7304 2017/11 [Refereed]
   

  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.
• A Randomized Phase II Study Comparing Nivolumab With Carboplatin-Pemetrexed for Patients With EGFR MutationePositive Nonsquamous Non-Small-Cell Lung Cancer Who Acquire Resistance to Tyrosine Kinase Inhibitors Not Due to a Secondary T790M Mutation: Rationale and Protocol Design for the WJOG8515L Study

  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 CIG MEDIA GROUP, LP 18 (6) 719 - 723 1525-7304 2017/11 [Refereed]
   

  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.
• T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer

  Satomi Watanabe; Takeshi Yoshida; Hisato Kawakami; Naoki Takegawa; Junko Tanizaki; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Junji Tsurutani; Kazuhiko Nakagawa

  MOLECULAR CANCER THERAPEUTICS AMER ASSOC CANCER RESEARCH 16 (11) 2563 - 2571 1535-7163 2017/11 [Refereed]
   

  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.
• Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer

  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 AMER SOC CLINICAL ONCOLOGY 35 (32) 3662 - + 0732-183X 2017/11 [Refereed]
   

  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
• Immune-checkpoint inhibitors for lung cancer with EGFR mutation

  Hidetoshi Hayashi; Tetsuya Mitsudomi

  Japanese Journal of Cancer and Chemotherapy Japanese Journal of Cancer and Chemotherapy Publishers Inc. 44 (9) 722 - 726 0385-0684 2017/09 [Refereed]
   

  Recent clinical evidence that anti-PD-1/PD-L1 antibody therapy is superior to cytotoxic chemotherapy for patients with non-small cell lung cancer (NSCLC) that expresses PD-L1 has lead to a paradigm shift in treatment strategies for those patients. However, efficacy of anti-PD-1/PD-L1 antibodies for patients with NSCLC harboring EGFR mutation is generally poor. This lack of response is at least partially attributed to suppression of tumor infiltrating lymphocytes caused by EGFR pathway activation or to low non-synonymous mutation load in NSCLC with EGFR mutation. However, anti-PD-1/PD-L1 antibodies may play some roles in patients who acquired resistance against EGFR tyrosine kinase inhibitors. In this review, relationship between patients with EGFR mutation and treatment using immune-checkpoint inhibitors is summarized.
• Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer

  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 SPRINGER 35 (4) 529 - 536 0167-6997 2017/08 [Refereed]
   

  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.
• Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

  K. Haratani; H. Hayashi; T. Tanaka; H. Kaneda; Y. Togashi; K. Sakai; K. Hayashi; S. Tomida; Y. Chiba; K. Yonesaka; Y. Nonagase; T. Takahama; J. Tanizaki; K. Tanaka; T. Yoshida; K. Tanimura; M. Takeda; H. Yoshioka; T. Ishida; T. Mitsudomi; K. Nishio; K. Nakagawa

  ANNALS OF ONCOLOGY OXFORD UNIV PRESS 28 (7) 1532 - 1539 0923-7534 2017/07 [Refereed]
   

  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.
• 組織型転化を来したEGFR陽性肺癌症例の臨床的検討

  田中 薫; 加藤 了資; 原谷 浩司; 武川 直樹; 高濱 隆幸; 岩朝 勤; 林 秀敏; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦

  肺癌 (NPO)日本肺癌学会 57 (3) 243 - 244 0386-9628 2017/06 [Refereed]
  
• Retrospective study of unplanned hospital admission for metastatic cancer patients visiting the emergency department

  Tae Tanaka; Masataka Taguri; Soichi Fumita; Kunio Okamoto; Yoshio Matsuo; Hidetoshi Hayashi

  SUPPORTIVE CARE IN CANCER SPRINGER 25 (5) 1409 - 1415 0941-4355 2017/05 [Refereed]
   

  Purpose The purpose of the study was to identify factors that predict unplanned admission for metastatic cancer patients visiting the emergency department (ED). Methods Patients visiting the ED of a general hospital from April 2012 to March 2013 were investigated retrospectively. Data including demographics, vital signs, and laboratory measurements were collected from a chart review for each patient. Factors related to emergency admission were identified by univariate and multivariate analyses. Results A total of 15,716 individuals visiting the ED during the study period included 1244 (7.9%) patients with cancer. Among the 491 cancer patients with metastasis, univariate analysis revealed that emergency admission was significantly associatedwith an age of >= 76 years; an alteredmental status; fever (>= 38 degrees C); a blood oxygen saturation of <90%; a white blood cell (WBC) count of <= 2000 or >= 10,000/mu L; hypoalbuminemia (<= 2.5 g/dL); and elevated levels of aspartate aminotransferase (>= 100 IU/L), blood urea nitrogen (>= 25 mg/dL), and C-reactive protein (CRP, >= 10 mg/dL). Multivariate analysis identified age, an altered mental status, hypoxemia, an abnormalWBC count, and elevated CRP as putative independent predictive factors for emergency admission. The number of these five factors present was also correlated with 30-day mortality (c-statistic = 0.72). Conclusions Age, unconsciousness, hypoxemia, an abnormal WBC count, and elevated CRP were found to be associated with emergency admission and 30-day mortality for metastatic cancer patients. Prospective validation of a predictive scoring system based on these findings is warranted.
• Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A

  Masato Chiba; Yosuke Togashi; Eri Bannno; Yoshihisa Kobayashi; Yu Nakamura; Hidetoshi Hayashi; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  BMC CANCER BIOMED CENTRAL LTD 17 (1) 281  1471-2407 2017/04 [Refereed]
   

  Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second-or third-generation EGFR-TKIs. Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated. Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second-and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone. Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.
• Phase 1 study of new formulation of patritumab (U3-1287) Process 2, a fully human anti-HER3 monoclonal antibody in combination with erlotinib in Japanese patients with advanced non-small cell lung cancer

  Toshio Shimizu; Kimio Yonesaka; Hidetoshi Hayashi; Tsutomu Iwasa; Koji Haratani; Hironori Yamada; Shoichi Ohwada; Emi Kamiyama; Kazuhiko Nakagawa

  CANCER CHEMOTHERAPY AND PHARMACOLOGY SPRINGER 79 (3) 489 - 495 0344-5704 2017/03 [Refereed]
   

  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.
• Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies

  Mizukami T; Togashi Y; Naruki S; Banno E; Terashima M; de Velasco MA; Sakai K; Yoneshige A; Hayashi H; Fujita Y; Tomida S; Nakajima TE; Fujino T; Boku N; Ito A; Nakagawa K; Nishio K

  Mol Carcinog Wiley 56 (1) 106 - 117 1098-2744 2017/01 [Refereed]
  
• Clinical evaluation of palliative chemoradiotherapy for metastatic esophageal cancer

  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 Impact Journals LLC 8 (46) 80286 - 80294 1949-2553 2017 [Refereed]
   

  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. Copyright: Ueda et al.
• Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies

  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 WILEY-BLACKWELL 56 (1) 106 - 117 0899-1987 2017/01 [Refereed]
   

  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.
• Peritumoural ground-glass opacity associated with tumour 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 [Refereed]
  
• Successful osimertinib treatment for leptomeningeal carcinomatosis from lung adenocarcinoma with the T790M mutation of EGFR.

  Sakai H; Hayashi H; Iwasa T; Hasegawa Y; Takeda M; Nakagawa K

  ESMO open 2 (Suppl 1) e000104  2017 [Refereed]
  
• 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 (NPO)日本肺癌学会 56 (7) 1064 - 1064 0386-9628 2016/12
• Successful treatment with afatinib after gefitinib- and erlotinib-induced hepatotoxicity

  Hiroto Ueda; Hidetoshi Hayashi; Keita Kudo; Masayuki Takeda; Kazuhiko Nakagawa

  Investigational New Drugs Springer New York LLC 34 (6) 797 - 799 1573-0646 2016/12 [Refereed]
   

  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.
• Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1

  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 IMPACT JOURNALS LLC 7 (51) 84860 - 84871 1949-2553 2016/12 [Refereed]
   

  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.
• MEK inhibitors against MET-amplified non-small cell lung cancer

  Masato Chiba; Yosuke Togashi; Shuta Tomida; Hiroshi Mizuuchi; Yu Nakamura; Eri Banno; Hidetoshi Hayashi; Masato Terashima; Marco A. De Velasc; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY SPANDIDOS PUBL LTD 49 (6) 2236 - 2244 1019-6439 2016/12 [Refereed]
   

  Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFRmutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
• 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

  Junko Tanizaki; Hidetoshi Hayashi; Masatomo Kimura; Kaoru Tanaka; Masayuki Takeda; Shigeki Shimizu; Akihiko Ito; Kazuhiko Nakagawa

  LUNG CANCER ELSEVIER IRELAND LTD 102 44 - 48 0169-5002 2016/12 [Refereed]
   

  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.
• ニボルマブ治療によりpseudoprogressionを認めた肺腺癌の2例

  谷崎 潤子; 林 秀敏; 加藤 了資; 原谷 浩司; 高濱 隆幸; 田中 薫; 岩朝 勤; 武田 真幸; 中川 和彦

  肺癌 (NPO)日本肺癌学会 56 (6) 569 - 569 0386-9628 2016/11 [Refereed]
  
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 西尾 和人; 中川 和彦

  肺癌 (NPO)日本肺癌学会 56 (6) 637 - 637 0386-9628 2016/11 [Refereed]
  
• Clinical outcome of node-negative oligometastatic non–small cell lung cancer

  Kiyohiro Sakai; Masayuki Takeda; Hidetoshi Hayashi; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Tetsuya Mitsudomi; Atsuko Koyama; Kazuhiko Nakagawa

  Thoracic Cancer John Wiley and Sons Inc. 7 (6) 670 - 675 1759-7714 2016/11 [Refereed]
   

  Introduction: The 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 methods: Consecutive 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. Results: Eighteen 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 15.9 months, with that for EGFR mutation–positive patients tending to be longer than that for EGFR mutation–negative patients. Conclusion: Cure 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.
• Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib

  Satomi Watanabe; Hidetoshi Hayashi; Kunio Okamoto; Kimiko Fujiwara; Yoshikazu Hasegawa; Hiroyasu Kaneda; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 17 (6) 528 - 534 1525-7304 2016/11 [Refereed]
   

  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.
• Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation

  Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa

  LUNG CANCER ELSEVIER IRELAND LTD 101 11 - 15 0169-5002 2016/11 [Refereed]
   

  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.
• 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

  Hidetoshi Hayashi; Kazuhiko Nakagawa

  JOURNAL OF THORACIC DISEASE PIONEER BIOSCIENCE PUBL CO 8 (10) E1311 - E1316 2072-1439 2016/10 [Refereed]
  
• Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?

  Eri Banno; Yosuke Togashi; Yu Nakamura; Masato Chiba; Yoshihisa Kobayashi; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Tetsuya Mitsudomi; Kazuto Nishio

  Cancer Science Blackwell Publishing Ltd 107 (8) 1134 - 1140 1349-7006 2016/08 [Refereed]
   

  Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKI), and their sensitivities to various EGFR-TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKI were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.
• Afatinib against esophageal or head-and-neck squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in HNSCC

  Yu Nakamura; Yosuke Togashi; Hirokazu Nakahara; Shuta Tomida; Eri Banno; Masato Terashima; Hidetoshi Hayashi; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Takatsugu Okegawa; Kikuo Nutahara; Suguru Hamada; Kazuto Nishio

  Molecular Cancer Therapeutics American Association for Cancer Research Inc. 15 (8) 1988 - 1997 1538-8514 2016/08 [Refereed]
   

  The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cellline, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.
• Functional analyses of mutations in receptor tyrosine kinase genes in Non-Small cell lung cancer: Double-Edged Sword of DDR2

  Masato Terashima; Yosuke Togashi; Katsuaki Sato; Hiroshi Mizuuchi; Kazuko Sakai; Kenichi Suda; Yu Nakamura; Eri Banno; Hidetoshi Hayashi; Marco A. De Velasco; Yoshihiko Fujita; Shuta Tomida; Tetsuya Mitsudomi; Kazuto Nishio

  Clinical Cancer Research American Association for Cancer Research Inc. 22 (14) 3663 - 3671 1557-3265 2016/07 [Refereed]
   

  Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15 ERBB4, 1 ALK, 1 DDR2, 2 FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7 NRAS, 1 BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1 PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G DDR2 H246R and E655K FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growthsuppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen.
• Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer?

  Satomi Watanabe; Hidetoshi Hayashi; Kazuhiko Nakagawa

  Annals of Translational Medicine AME Publishing Company 4 (11) 225  2305-5847 2016/06 [Refereed]
  
• Phase I study of YM155, selective survivin suppressant in combination with elrotnib in patients with EGFR-mutant advanced non-small cell lung cancer.

  Shimizu Toshio; Nishio Kazuto; Sakai Kazuko; Hayashi Hidetoshi; Okamoto Kunio; Takeda Masayuki; Iwasa Tsutomu; Tanaka Kaoru; Aoyama Koji; Morishita Maiko; Nakagawa Kazuhiko

  JOURNAL OF CLINICAL ONCOLOGY 34 (15) 0732-183X 2016/05 [Refereed]
  
• 下咽頭癌頸部リンパ節転移に対して先行頸部郭清術を施行した症例の検討

  北野 睦三; 木村 隆幸; 西原 美沙子; 白石 功; 森川 大樹; 小林 孝光; 速水 康介; 藤原 良平; 石川 一樹; 横川 正樹; 高濱 隆幸; 吉田 健史; 林 秀敏; 田中 薫; 土井 勝美

  頭頸部癌 (一社)日本頭頸部癌学会 42 (2) 170 - 170 1349-5747 2016/05 [Refereed]
  
• Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib

  N. Takegawa; H. Hayashi; N. Iizuka; T. Takahama; H. Ueda; K. Tanaka; M. Takeda; K. Nakagawa

  Annals of Oncology Oxford University Press 27 (5) 953 - 955 1569-8041 2016/05 [Refereed]
  
• Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial

  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 WILEY-BLACKWELL 122 (7) 1050 - 1059 0008-543X 2016/04 [Refereed]
   

  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.
• Genome sequencing for nonsmall-cell lung cancer identifies a basis for nintedanib sensitivity

  M. Takeda; K. Sakai; K. Okamoto; H. Hayashi; K. Tanaka; T. Shimizu; K. Nishio; K. Nakagawa

  ANNALS OF ONCOLOGY OXFORD UNIV PRESS 27 (4) 748 - 750 0923-7534 2016/04 [Refereed]
   

  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.
• Two cases of EGFR mutation-positive lung adenocarcinoma that transformed into squamous cell carcinoma: successful treatment of one case with rociletinib

  K. Haratani; H. Hayashi; S. Watanabe; H. Kaneda; T. Yoshida; M. Takeda; T. Shimizu; K. Nakagawa

  ANNALS OF ONCOLOGY OXFORD UNIV PRESS 27 (1) 200 - 202 0923-7534 2016/01 [Refereed]
  
• Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinomas

  Yasumasa Yoshioka; Yosuke Togashi; Takaaki Chikugo; Akihiro Kogita; Masataka Taguri; Masato Terashima; Takuro Mizukami; Hidetoshi Hayashi; Kazuko Sakai; Marco A. De Velasco; Shuta Tomida; Yoshihiko Fujita; Tadao Tokoro; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio

  Cancer John Wiley and Sons Inc. 121 (24) 4359 - 4368 1097-0142 2015/12 [Refereed]
   

  BACKGROUND Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC). METHODS Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. RESULTS A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. CONCLUSIONS High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings. Cancer 2015 121:4359-68.
• MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor

  Yosuke Togashi; Hiroshi Mizuuchi; Shuta Tomida; Masato Terashima; Hidetoshi Hayashi; Kazuto Nishio; Tetsuya Mitsudomi

  Lung Cancer Elsevier Ireland Ltd 90 (3) 590 - 597 1872-8332 2015/12 [Refereed]
   

  Background: MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions. Materials and methods: We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset. Results: An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created this cell line had a higher MET protein expression level, enhanced MET phosphorylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion. Conclusions: These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion.
• Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer

  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 OXFORD UNIV PRESS 26 (12) 2477 - 2482 0923-7534 2015/12 [Refereed]
   

  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.
• 肺癌患者意思決定支援としての患者向けガイドブック「よくわかる肺がんQ&A」

  澤 祥幸; 坂 英雄; 岩本 康男; 倉田 宝保; 里内 美弥子; 関 順彦; 瀬戸 貴司; 千場 博; 武田 晃司; 中山 優子; 光冨 徹哉; 山本 信之; 山本 英彦; 金田 裕靖; 林 秀敏; 赤松 弘朗; 北口 聡一; 立原 素子; 吉岡 弘鎮; 西日本がん研究機構「よくわかる肺がん」編集委員会

  肺癌 (NPO)日本肺癌学会 55 (5) 477 - 477 0386-9628 2015/10
• BEV/プラチナ療法増悪後のnon-Sq NSCLCに対する、DOC+BEVとDOCの無作為化第II相試験 WJOG5910L

  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 (NPO)日本肺癌学会 55 (5) 430 - 430 0386-9628 2015/10
• 当院における非小細胞肺癌に対するre-biopsyの検討

  田中 薫; 西田 諭美; 原谷 浩司; 野長瀬 祥兼; 高濱 隆幸; 吉田 健史; 岩朝 勤; 林 秀敏; 武田 真幸; 金田 裕靖; 中川 和彦

  肺癌 (NPO)日本肺癌学会 55 (5) 547 - 547 0386-9628 2015/10 [Refereed]
  
• ALK阻害剤による治療後に小細胞肺癌・扁平上皮癌への形質転換を認めたALK融合遺伝子陽性肺癌の1例

  武川 直樹; 中川 和彦; 鶴谷 純司; 清水 俊雄; 武田 真幸; 田中 薫; 岩朝 勤; 吉田 健史; 林 秀敏; 谷崎 潤子; 高濱 隆幸; 原谷 浩司; 西田 諭美

  肺癌 (NPO)日本肺癌学会 55 (5) 661 - 661 0386-9628 2015/10 [Refereed]
  
• Clinical Applications of Next Generation Sequencing on Therapeutic Decision-Making in Lung Cancer

  Takeda Masayuki; Sakai Kazuko; Terashima Masato; Kaneda Hiroyasu; Hayashi Hidetoshi; Tanaka Kaoru; Iwasa Tsutomu; Yoshida Takeshi; Takahama Takayuki; Nishio Kazuto; Nakagawa Kazuhiko

  JOURNAL OF THORACIC ONCOLOGY 10 (9) S700 - S701 1556-0864 2015/09 [Refereed]
  
• 当院における非小細胞肺癌に対するre-biopsyの検討

  田中 薫; 西田 諭美; 原谷 浩司; 野長瀬 祥兼; 高濱 隆幸; 吉田 健史; 岩朝 勤; 林 秀敏; 武田 真幸; 中川 和彦; 金田 裕靖

  肺癌 (NPO)日本肺癌学会 55 (4) 306 - 307 0386-9628 2015/08 [Refereed]
  
• Afatinib is especially effective against non-small cell lung cancer carrying an EGFR exon 19 deletion

  Eri Banno; Yosuke Togashi; Yoshihisa Kobayashi; Hidetoshi Hayashi; Tetsuya Mitsudomi; Kazuto Nishio

  Anticancer Research International Institute of Anticancer Research 35 (4) 2005 - 2008 0250-7005 2015/04 [Refereed]
   

  Background: A recent pooled analysis of the LUX-LUNG3 and LUX-LUNG6 trials suggested that afatinib (an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) is especially effective against non-small cell lung cancer (NSCLC) carrying an EGFR exon 19 deletion. Materials and Methods: Stable viral transfectant HEK293 cell lines carrying an exon 19 deletion (HEK293/19 del) or exon 21 L858R mutation (HEK293/ L858R)) were created and their drug sensitivities to AG1478 (a reversible EGFR-TKI) and afatinib were examined using an MTT assay. Western blot analyses were performed to estimate the phosphorylation of EGFR. Results: In the HEK293/19 del, the 50% inhibitory concentration (IC< inf> 50< /inf> ) of afatinib was significantly lower than that in the HEK293/ L858R. In addition, afatinib inhibited the phosphorylation of EGFR to a greater degree in the HEK293/19 del than in the HEK293/L858R. Conclusion: Our experimental findings suggest that afatinib is especially effective against NSCLC carrying an EGFR exon 19 deletion.
• Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal

  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 ELSEVIER IRELAND LTD 88 (1) 16 - 23 0169-5002 2015/04 [Refereed]
   

  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.
• Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

  Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Eri Banno; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY SPANDIDOS PUBL LTD 46 (3) 1025 - 1030 1019-6439 2015/03 [Refereed]
   

  Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.
• Tolerability of Nintedanib (BIBF 1120) in Combination with Docetaxel: A Phase 1 Study in Japanese Patients with Previously Treated Non-Small-Cell Lung Cancer

  Isamu Okamoto; Masaki Miyazaki; Masayuki Takeda; Masaaki Terashima; Koichi Azuma; Hidetoshi Hayashi; Hiroyasu Kaneda; Takayasu Kurata; Junji Tsurutani; Takashi Seto; Fumihiko Hirai; Koichi Konishi; Akiko Sarashina; Nobutaka Yagi; Rolf Kaiser; Kazuhiko Nakagawa

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 10 (2) 346 - 352 1556-0864 2015/02 [Refereed]
   

  Background: This phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer. Methods: Eligible patients received docetaxel 60 or 75 mg/m(2) (day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; days 2-21) in 21-day cycles. Standard 3 + 3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of less than 1.5 m(2) (BSA < 1.5) and BSA greater than or equal to 1.5, respectively. Results: Forty-two patients (17 BSA < 1.5, 25 BSA >= 1.5) were treated. The maximum tolerated dose of nintedanib was 150 and 200 mg bid in patients with BSA less than 1.5 and BSA greater than or equal to 1.5 (BSA >= 1.5), respectively, in combination with 75 mg/m(2) of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease. Conclusion: Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced non-small-cell lung cancer.
• Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

  Yosuke Togashi; Akihiro Kogita; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Masayuki Kitano; Kiyotaka Okuno; Masatoshi Kudo; Kazuto Nishio

  Cancer Letters Elsevier Ireland Ltd 356 (2) 819 - 827 1872-7980 2015/01 [Refereed]
   

  We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Contrary to our expectations, however, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P=0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA (beta subunit of inhibin)-overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia. The activin signal might be a novel target for the treatment of PC.
• An activating ALK gene mutation in ALK IHC-positive/FISHnegative nonsmall-cell lung cancer

  Y. Togashi; H. Mizuuchi; Y. Kobayashi; H. Hayashi; M. Terashima; K. Sakai; E. Banno; T. Mizukami; Y. Nakamura; M. A. de Velasco; Y. Fujita; S. Tomida; T. Mitsudomi; K. Nishio

  Annals of Oncology Oxford University Press 26 (8) 1800 - 1801 1569-8041 2015 [Refereed]
  
• The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer

  H. Hayashi; T. Arao; Y. Togashi; H. Kato; Y. Fujita; M. A. De Velasco; H. Kimura; K. Matsumoto; K. Tanaka; I. Okamoto; A. Ito; Y. Yamada; K. Nakagawa; K. Nishio

  ONCOGENE NATURE PUBLISHING GROUP 34 (2) 199 - 208 0950-9232 2015/01 [Refereed]
   

  POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
• Inhibition of beta-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non-small-cell Lung Cancer with a T790M Mutation

  Yosuke Togashi; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 10 (1) 93 - 101 1556-0864 2015/01 [Refereed]
   

  Introduction: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). beta-Catenin is a key component of the Wnt/beta-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. Methods and Results: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of beta-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a beta-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the beta-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the beta-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that beta-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. Conclusion: Our findings indicate that beta-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.
• MEK inhibitor for gastric cancer with MEK1 gene mutations

  Shunsuke Sogabe; Yosuke Togashi; Hiroaki Kato; Akihiro Kogita; Takuro Mizukami; Yoichi Sakamoto; Eri Banno; Masato Terashima; Hidetoshi Hayashi; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takushi Yasuda; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuto Nishio

  Molecular Cancer Therapeutics American Association for Cancer Research Inc. 13 (12) 3098 - 3106 1538-8514 2014/12 [Refereed]
   

  The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors.
• Cystic Brain Metastasis in Non-Small-Cell Lung Cancer With ALK Rearrangement

  Hidetoshi Hayashi; Isamu Okamoto; Junko Tanizaki; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Kazuhiko Nakagawa

  JOURNAL OF CLINICAL ONCOLOGY AMER SOC CLINICAL ONCOLOGY 32 (36) E122 - E124 0732-183X 2014/12 [Refereed]
  
• 扁平上皮癌に転化を来たしたT790M変異陽性肺癌に第3世代EGFR-TKI(CO-1686)が奏効した症例

  林 秀敏; 金田 裕靖; 吉田 健史; 清水 俊雄; 古下 義彦; 飯塚 徳重; Rolfe Lindsey; 加藤 元一; 中川 和彦

  肺癌 (NPO)日本肺癌学会 54 (5) 398 - 398 0386-9628 2014/10
• 肺がん情報easy accessを目指して 患者向けガイドブック(よくわかる肺がん)の改訂と市販化事業

  澤 祥幸; 岩本 康男; 坂 英雄; 関 順彦; 瀬戸 貴司; 千場 博; 山本 英彦; 武田 晃司; 中山 優子; 西村 恭昌; 光冨 徹哉; 山本 信之; 吉野 一郎; 金田 裕靖; 林 秀敏; 赤松 弘朗; 北口 聡一; 立原 素子; 吉岡 弘鎮; 中西 洋一

  肺癌 (NPO)日本肺癌学会 54 (5) 495 - 495 0386-9628 2014/10
• Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: Phase I study in Japanese patients with advanced solid malignancies and advanced breast cancer

  Takayasu Kurata; Junji Tsurutani; Yasuhito Fujisaka; Wataru Okamoto; Hidetoshi Hayashi; Hisato Kawakami; Eisei Shin; Nobuya Hayashi; Kazuhiko Nakagawa

  INVESTIGATIONAL NEW DRUGS SPRINGER 32 (5) 946 - 954 0167-6997 2014/10 [Refereed]
   

  Background AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. Methods Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle). Results Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade a parts per thousand yen3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. Conclusion Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.
• Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition

  Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Shunsuke Sogabe; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio

  INTERNATIONAL JOURNAL OF ONCOLOGY SPANDIDOS PUBL LTD 45 (4) 1430 - 1436 1019-6439 2014/10 [Refereed]
   

  Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
• Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

  Yosuke Togashi; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Yoshihiko Fujita; Yasuo Kodera; Kazuko Sakai; Shuta Tomida; Masayuki Kitano; Akihiko Ito; Masatoshi Kudo; Kazuto Nishio

  Molecular Cancer BioMed Central Ltd. 13 (1) 126  1476-4598 2014/05 [Refereed]
   

  Background: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC) however the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. Methods and results: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. Conclusion: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC. © 2014 Togashi et al. licensee BioMed Central Ltd.
• Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma

  Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Hideharu Kimura; Yosuke Togashi; Yoshinori Hirashima; Yosuke Horita; Satoru Iwasa; Natsuko Tsuda Okita; Yoshitaka Honma; Atsuo Takashima; Ken Kato; Tetsuya Hamaguchi; Yasuhiro Shimada; Kazuhiko Nakagawa; Kazuto Nishio; Yasuhide Yamada

  ONCOTARGET IMPACT JOURNALS LLC 5 (9) 2588 - 2595 1949-2553 2014/05 [Refereed]
   

  Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.
• Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: A novel expression site of cytoglobin

  Yoshihiko Fujita; Satoshi Koinuma; Marco A. De Velasco; Jan Bolz; Yosuke Togashi; Masato Terashima; Hidetoshi Hayashi; Takuya Matsuo; Kazuto Nishio

  PLoS ONE Public Library of Science 9 (4) e97772  1932-6203 2014/04 [Refereed]
   

  The tissue distribution and function of hemoglobin or myoglobin are well known however, a newly found cytoglobin (CYGB), which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2′-, 7′-dichlorofluorescein diacetate (DCFH-DA), an indicator of reactive oxygen species (ROS), revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition. © 2014 Fujita et al.
• Risk Factors of Lung Cancer and Malignant Pleural Methothelioma

  Hayashi H.

  The Journal of the Japan Broncho-esophagological Society The Japan Broncho-esophagological Society 65 (2) 119 - 120 0029-0645 2014
• A case of pancreatic mixed acinar-endocrine carcinoma suggested by preoperative ultrasound-guided fine needle aspiration

  Takao Iemoto; Hidehiro Sawa; Hideki Sakai; Hiroki Hayashi; Katsuhide Tanaka; Junko Hori; Daisuke Kuroda; Ryosuke Matsuoka; Takashi Yamasaki; Tsuyoshi Sanuki

  Journal of Japanese Society of Gastroenterology Japanese Society of Gastroenterology 111 (8) 1609 - 1617 0446-6586 2014 [Refereed]
   

  A 73-year-old man visited our hospital for consultation regarding a pancreatic tumor. Abdominal computed tomography, magnetic resonance imaging, and endoscopic ultrasound scan (EUS) revealed tumor 2cm in diameter located in the pancreatic tail. EUS-guided fine needle aspiration (EUS-FNA) suggested pancreatic mixed acinar-endocrine carcinoma, and he underwent distal pancreatectomy. Few reports exist where preoperative EUS-FNA suggested pancreatic mixed acinar-endocrine carcinoma thus, we report this case.
• Administration of gefitinib via nasogastric tube effectively improved the performance status of a patient with lung adenocarcinoma-derived meningeal carcinomatosis

  Takeshi Okuda; Hidetoshi Hayashi; Mitsugu Fujita; Hiromasa Yoshioka; Takayuki Tasaki; Kazuhiko Nakagawa; Amami Kato

  Metallography, Microstructure, and Analysis Springer New York LLC 3 (4) 211 - 214 2192-9270 2014 [Refereed]
   

  Meningeal carcinomatosis (MC) is a refractory disease with a dismal prognosis, and no therapeutic strategy has been established to date. Herein we report a case of lung adenocarcinoma-derived MC in which the patient’s performance status was dramatically improved by administration of gefitinib suspension via a nasogastric tube. The patient was a 71-year-old woman who was originally admitted to our hospital for a progressive headache and subsequently presented with severe consciousness disturbance. Cerebrospinal fluid examination and systemic imaging studies revealed MC that was derived from lung adenocarcinoma. Moreover, epidermal growth factor receptor (EGFR) mutations were detected in the tumor cells. Since the patient suffered from hydrocephalus, a ventriculoperitoneal shunt was placed. Nevertheless, her consciousness disturbance persisted. Subsequently, gefitinib suspension was prepared and administered via nasogastric tube, which dramatically improved her consciousness level and enabled her to tolerate oral intake. She died 14 months after the disease onset. The observations in this case report suggest that gefitinib might be a therapeutic option for patients with MC derived from cancers harboring EGFR mutations even though the patient exhibited severe consciousness disturbance.
• Frequent amplification of oraov1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ros production

  Yosuke Togashi; Tokuzo Arao; Hiroaki Kato; Kazuko Matsumoto; Masato Terashima; Hidetoshi Hayashi; Marco A. de Velasco; Yoshihiko Fujita; Hideharu Kimura; Takushi Yasuda; Hitoshi Shiozaki; Kazuto Nishio

  Oncotarget Impact Journals LLC 5 (10) 2962 - 2973 1949-2553 2014 [Refereed]
   

  Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC). The oral cancer overexpressed 1 (ORAOV1) gene has been identified within this region, but its detailed biological function in human ESCC remains largely unclear. In our clinical samples of stage III ESCC, ORAOV1 amplification was observed in 49 of 94 cases (53%). ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus. Patients with ORAOV1 amplification tended to have a shorter survival period, although the difference was not significant. To investigate the function of ORAOV1, we created ORAOV1- overexpressed ESCC cell lines that exhibited increased cellular proliferation and colony formation, compared with in vitro controls. In vivo, ORAOV1-overexpressed cells exhibited a significantly increased tumorigenicity and a significantly larger tumor volume and poorer differentiation than controls. The peptide mass fingerprinting technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism and reactive oxygen species (ROS) production. Then, ORAOV1-overexpressed cell lines were resistant to stress treatment, which was cancelled by PYCR-knockdown. In addition, the ORAOV1-overexpressed cell line had a higher intracellular proline concentration and a lower ROS level. Our findings indicate that the ORAOV1 gene is frequently amplified in ESCC, enhances tumorigenicity and tumor growth, and is associated with a poorly differentiated tumor histology via proline metabolism and ROS production. ORAOV1 could be a novel target for the treatment of ESCC. © 2008-2014 Impact Journals, LLC.
• Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines

  Masato Terashima; Kazuko Sakai; Yosuke Togashi; Hidetoshi Hayashi; Marco A. De Velasco; Junji Tsurutani; Kazuto Nishio

  SpringerPlus 3 (1) 1 - 11 2193-1801 2014 [Refereed]
   

  Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC. © 2014 Terashima et al. licensee Springer.
• Clinical utility of erlotinib for the treatment of non-small-cell lung cancer in Japanese patients: current evidence

  Yosuke Togashi; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuto Nishio

  DRUG DESIGN DEVELOPMENT AND THERAPY DOVE MEDICAL PRESS LTD 8 1037 - 1046 1177-8881 2014 [Refereed]
   

  Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood-brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted.
• Phase I pharmacokinetic study of S-1 granules and nedaplatin for advanced head and neck cancer.

  Hidetoshi Hayashi; Isamu Okamoto; Shinya Ueda; Kaoru Tanaka; Kunio Okamoto; Hisato Kawakami; Shinichi Nishina; Masayuki Takeda; Yasuhito Fujisaka; Taroh Satoh; Kyoichi Terao; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa

  Anticancer research 33 (12) 5699 - 705 2013/12 [Refereed]
   

  AIM: We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%. CONCLUSION: This combination was well-tolerated and manifested a promising activity against HNSCC.
• CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib, in advanced/metastatic non-small cell lung cancer

  N. Yamamoto; H. Murakami; H. Hayashi; Y. Fujisaka; T. Hirashima; K. Takeda; M. Satouchi; K. Miyoshi; S. Akinaga; T. Takahashi; K. Nakagawa

  BRITISH JOURNAL OF CANCER NATURE PUBLISHING GROUP 109 (11) 2803 - 2809 0007-0920 2013/11 [Refereed]
   

  Background: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. Methods: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. Results: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (420%, any grade) were rash, diarrhoea, dry skin and nausea. Grade >= 3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (>= 24 weeks) were reported. Conclusion: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.
• Overexpression of heparan sulfate 6-O-sulfotransferase-2 in colorectal cancer.

  Shigeru Hatabe; Hideharu Kimura; Tokuzo Arao; Hiroaki Kato; Hidetoshi Hayashi; Tomoyuki Nagai; Kazuko Matsumoto; Marco DE Velasco; Yoshihiko Fujita; Go Yamanouchi; Masao Fukushima; Yasuhide Yamada; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio

  Molecular and clinical oncology 1 (5) 845 - 850 2049-9450 2013/09 [Refereed]
   

  The heparan sulfate sulfotransferase gene family catalyzes the transfer of sulfate groups to heparan sulfate and regulates various growth factor-receptor signaling pathways. However, the involvement of this gene family in cancer biology has not been elucidated. It was demonstrated that the heparan sulfate D-glucosaminyl 6-O-sulfotransferase-2 (HS6ST2) gene is overexpressed in colorectal cancer (CRC) and its clinical significance in patients with CRC was investigated. The mRNA levels of HS6ST2 in clinical CRC samples and various cancer cell lines were assessed using a microarray analysis and quantitative RT-PCR, respectively. An immunohistochemical (IHC) analysis of the HS6ST2 protein was performed using 102 surgical specimens of CRC. The correlations between the HS6ST2 expression status and clinicopathological characteristics were then evaluated. HS6ST2 mRNA was significantly overexpressed by 37-fold in CRC samples compared to paired colonic mucosa. High levels of HS6ST2 mRNA expression were also observed in colorectal, esophageal and lung cancer cell lines. The IHC analysis demonstrated that HS6ST2 was expressed in the cytoplasmic region of CRC cells, but not in normal colonic mucosal cells. Positive staining for HS6ST2 was detected in 40 patients (39.2%). There was no significant association between the clinicopathological characteristics and HS6ST2 expression. However, positive staining for HS6ST2 was associated with a poor survival (P=0.074, log-rank test). In conclusion, HS6ST2 was found to be overexpressed in CRC and its expression tended to be a poor prognostic factor, although the correlation was not significant. These findings indicate that HS6ST2 may be a novel cancer-related marker that may provide insight into the glycobiology of CRC.
• Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer

  Hisato Kawakami; Isamu Okamoto; Hidetoshi Hayashi; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa

  European Journal of Cancer 49 (14) 3003 - 3009 0959-8049 2013/09 [Refereed]
   

  Background With the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer. Patients and methods A literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated. Results The average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365). Conclusion An increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer. © 2013 Elsevier Ltd. All rights reserved.
• Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.

  Fujisaka Yasuhito; Kurata Takayasu; Tsurutani Junji; Okamoto Wataru; Hayashi Hidetoshi; Kawakami Hisato; Shin Eisei; Hayashi Nobuya; Nakagawa Kazuhiko

  JOURNAL OF CLINICAL ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 31 (15) 0732-183X 2013/05 [Refereed]
  
• Postprogression Survival in Patients With Advanced Non-Small-Cell Lung Cancer Who Receive Second-Line or Third-Line Chemotherapy

  Hidetoshi Hayashi; Isamu Okamoto; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 14 (3) 261 - 266 1525-7304 2013/05 [Refereed]
   

  The effect of subsequent chemotherapy on overall survival (OS) has the potential to result in underestimation of the efficacy of an experimental treatment in clinical trials for advanced non-small-cell lung cancer (NSCLC). In this study, we investigated postprogression survival (PPS), defined as overall survival (OS) minus progression-free survival (PFS), in the second-line setting. PPS was highly associated with OS, and the induction rate for subsequent chemotherapy was associated with the duration of PPS. Our findings indicate that a beneficial effect of treatment on OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Background: The increased availability of active agents has improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). We previously showed that postprogression survival (PPS) is highly associated with OS in the first-line setting, but little is known about PPS in the salvage setting. In this study, we analyzed PPS in phase III trials in the second-line or third-line setting. Patients and Methods: A literature search identified 18 trials for previously treated patients with advanced NSCLC. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the association between OS and either PFS or PPS. Correlation analysis to examine whether a treatment benefit for PFS carried over to OS was performed by calculation of incremental gains in OS and PFS at the trial level. Results: The average median PPS was longer than the average median PFS (5.4 and 2.6 months, respectively). The induction rate for subsequent chemotherapy after second-line or third-line treatment was related to the duration of PPS in linear regression analysis (r(2) = 0.4813). Median OS was highly associated with median PPS but not with PFS (r = 0.94 and 0.51, respectively), and only a weak association between the treatment benefits for PFS and OS was detected (r = 0.29). Conclusions: Treatment benefit for OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Whether PFS or OS is the more appropriate endpoint for trials in the salvage setting should be considered. Clinical Lung Cancer, Vol. 14, No. 3, 261-6 (C) 2013 Elsevier Inc. All rights reserved.
• Activation of HER Family signaling as a mechanism of acquired resistance to ALK Inhibitors in EML4-ALK-positive Non-Small Cell Lung Cancer.

  Tanizaki Junko; Okamoto Isamu; Okabe Takafumi; Sakai Kazuko; Tanaka Kaoru; Hayashi Hidetoshi; Kaneda Hiroyasu; Takezawa Ken; Nishio Kazuto; Nakagawa Kazuhiko

  CANCER RESEARCH AMER ASSOC CANCER RESEARCH 73 (8) 0008-5472 2013/04 [Refereed]
  
• Slug increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.

  Tamura D; Arao T; Nagai T; Kaneda H; Aomatsu K; Fujita Y; Matsumoto K; De Velasco MA; Kato H; Hayashi H; Yoshida S; Kimura H; Maniwa Y; Nishio W; Sakai Y; Ohbayashi C; Kotani Y; Nishimura Y; Nishio K

  Cancer Med 2 (2) 144 - 154 2013/04 [Refereed]
   

  Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of βIII and βIVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of βIVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of βIII and βIV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of βIII and βIVa-tubulin in lung cancer cells.
• Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

  Hiroaki Kato; Tokuzo Arao; Kazuko Matsumoto; Yoshihiko Fujita; Hideharu Kimura; Hidetoshi Hayashi; Kouhei Nishiki; Mitsuru Iwama; Osamu Shiraishi; Atsushi Yasuda; Masayuki Shinkai; Motohiro Imano; Haruhiko Imamoto; Takushi Yasuda; Kiyotaka Okuno; Hitoshi Shiozaki; Kazuto Nishio

  International Journal of Oncology 42 (4) 1151 - 1158 1019-6439 2013/04 [Refereed]
   

  Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC) however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one del745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.
• Phase II study of bi-weekly irinotecan for patients with previously treated HER2-negative metastatic breast cancer: KMBOG0610B

  Hidetoshi Hayashi; Junji Tsurutani; Taro Satoh; Norikazu Masuda; Wataru Okamoto; Ryotaro Morinaga; Masaaki Terashima; Masaki Miyazaki; Isamu Okamoto; Yukihiro Nishida; Shusei Tominaga; Yukihiko Tokunaga; Masahide Yamaguchi; Junichi Sakamoto; Takahiro Nakayama; Kazuhiko Nakagawa

  BREAST CANCER SPRINGER JAPAN KK 20 (2) 131 - 136 1340-6868 2013/04 [Refereed]
   

  A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy. Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m(2) on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol. Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred. This study demonstrated that biweekly administration of 150 mg/m(2) irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.
• Phase I and pharmacokinetic study of gefitinib and S-1 combination therapy for advanced adenocarcinoma of the lung

  Hidemi Kiyota; Isamu Okamoto; Masayuki Takeda; Haruko Daga; Tateaki Naito; Masaki Miyazaki; Hideaki Okada; Hidetoshi Hayashi; Kaoru Tanaka; Masaaki Terashima; Koichi Azuma; Haruyasu Murakami; Koji Takeda; Nobuyuki Yamamoto; Kazuhiko Nakagawa

  CANCER CHEMOTHERAPY AND PHARMACOLOGY SPRINGER 71 (4) 859 - 865 0344-5704 2013/04 [Refereed]
   

  A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
• Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor

  Hidetoshi Hayashi; Takayasu Kurata; Yasuhito Fujisaka; Hisato Kawakami; Kaoru Tanaka; Takafumi Okabe; Masayuki Takeda; Taroh Satoh; Koji Yoshida; Takuya Tsunoda; Tokuzo Arao; Kazuto Nishio; Kazuhiko Nakagawa

  CANCER SCIENCE WILEY 104 (1) 98 - 104 1349-7006 2013/01 [Refereed]
   

  OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 similar to mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 similar to mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 similar to mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active. (Cancer Sci 2013; 104: 98104)
• Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor.

  Hidetoshi Hayashi; Takayasu Kurata; Yasuhito Fujisaka; Hisato Kawakami; Kaoru Tanaka; Takafumi Okabe; Masayuki Takeda; Taroh Satoh; Koji Yoshida; Takuya Tsunoda; Tokuzo Arao; Kazuto Nishio; Kazuhiko Nakagawa

  Cancer science 104 (1) 98 - 104 1347-9032 2013/01 [Refereed]
   

  OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active.
• [Progress of molecular targeted therapies].

  Hayashi H; Nishio K

  Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 7 - 11 0047-1852 2012/11 [Refereed]
  
• Activation of HER Family Signaling as a Mechanism of Acquired Resistance to ALK Inhibitors in EML4-ALK-Positive Non-Small Cell Lung Cancer

  Junko Tanizaki; Isamu Okamoto; Takafumi Okabe; Kazuko Sakai; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyasu Kaneda; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Erina Hatashita; Kazuto Nishio; Kazuhiko Nakagawa

  CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH 18 (22) 6219 - 6226 1078-0432 2012/11 [Refereed]
   

  Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Clin Cancer Res; 18(22); 6219-26. (C)2012 AACR.
• Clinical Outcomes of Thoracic Radiotherapy for Locally Advanced NSCLC with EGFR Mutations or EML4-ALK Rearrangement

  Hidetoshi Hayashi; Isamu Okamoto; Hideharu Kimura; Kazuko Sakai; Yasumasa Nishimura; Kazuto Nishio; Kazuhiko Nakagawa

  ANTICANCER RESEARCH INT INST ANTICANCER RESEARCH 32 (10) 4533 - 4537 0250-7005 2012/10 [Refereed]
   

  Background: Little is known about the occurrence and consequences of epidermal growth factor receptor gene (EGFR) mutations and the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes in locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively examined 37 patients with locally advanced NSCLC treated with definitive thoracic radiotherapy (TRT). Characteristics were compared among patients classified positive for EGFR mutations, EML4-ALK rearrangement, or patients who were double-negative for these changes. Results: We identified 11 (29.7%) patients with EGFR mutations and 3 (8.1%) with an EML4-ALK rearrangement. Progression-free survival of patients with EGFR mutation-positive NSCLC was similar to the one of those with double-negative disease (13.1 and 18.6 months). The incidence of local recurrence was higher in EGFR mutation positive patients with NSCLC than in double-negative NSCLC. Conclusion: EGFR mutations and the EML4-ALK rearrangements were detected in substantial proportions of patients with locally advanced NSCLC. The efficacy of TRT was limited in patients with EGFR mutations.
• 血管破壊剤(VDA)、オンブラブリンの進行固形がん患者に対する第I相臨床試験(Phase I study of ombrabulin, a vascular disrupting agent (VDA) in Japanese patients with advanced solid tumors)

  村上 晴泰; 倉田 宝保; 藤阪 保仁; 林 秀敏; 田中 薫; 金田 裕靖; 中川 和彦; 横田 知哉; 朴 成和; 山本 信之

  日本癌学会総会記事 日本癌学会 71回 55 - 55 0546-0476 2012/08 [Refereed]
  
• Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer

  H. Hayashi; I. Okamoto; S. Morita; M. Taguri; K. Nakagawa

  ANNALS OF ONCOLOGY OXFORD UNIV PRESS 23 (6) 1537 - 1541 0923-7534 2012/06 [Refereed]
   

  Background: Given the growing number of drugs available for non-small-cell lung cancer (NSCLC), an effect of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. We examined the relation between postprogression survival (PPS) and OS in phase III trials of first-line chemotherapy for advanced NSCLC. Patients and methods: A literature search identified 69 trials that were published during the past decade. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. Results: The average PPS was longer in recent trials than in older trials (6.5 versus 4.4 months, P < 0.0001). For all trials, PPS was strongly associated with OS (r = 0.82), whereas PFS was moderately associated with OS (r = 0.43). The correlation between OS and PPS in recent trials was stronger than that in older trials (r = 0.89 and 0.66). Conclusions: Our findings indicate that, especially for recent trials, PPS is highly associated with OS in first-line chemotherapy for advanced NSCLC, whereas PFS is only moderately associated with OS.
• Oral S-1 and carboplatin plus bevacizumab with maintenance S-1 and bevacizumab for chemo-naive patients (Pts) with advanced non-squamous non-small cell lung cancer (NSCLC).

  Kaneda Hiroyasu; Urata Yoshiko; Okamoto Isamu; Hattori Yoshihiro; Okuno Keiko; Shimada Temiko; Takeda Masayuki; Kurata Takayasu; Miyazaki Masaki; Terashima Masaaki; Tanaka Kaoru; Kiyota Hidemi; Hayashi Hidetoshi; Kudo Toshihiro; Okabe Takafumi; Azuma Koichi; Morita Satoshi; Nakagawa Kazuhiko; Negoro Shunichi; Satouchi Miyako

  JOURNAL OF CLINICAL ONCOLOGY 30 (15) 0732-183X 2012/05 [Refereed]
  
• Perirenal hematoma associated with bevacizumab treatment

  Hidetoshi Hayashi; Isamu Okamoto; Kazuhiko Nakagawa

  INVESTIGATIONAL NEW DRUGS SPRINGER 30 (2) 808 - 809 0167-6997 2012/04 [Refereed]
   

  We now describe the first example of a patient who developed perirenal hematoma during the course of bevacizumab-containing chemotherapy. A 59-years-old woman with metastatic rectal cancer treated with bevacizumab, who developed low back pain after 11 cycles of chemotherapy. CT-scan was consistent with perirenal hematoma and discontinuation of bevacizumab resulted in symptomatic improvement. Nontraumatic perirenal hematoma is a rare condition that can cause shock in severe cases. Given that several types of bleeding complication are known to be associated with bevacizumab treatment, we concluded that bevacizumab likely contributed to the perirenal hematoma in this case. Although the appropriate modification of bevacizumab treatment in the setting of perirenal hematoma is still unclear, physicians should be aware of this potential bevacizumab-associated bleeding complication.
• Slug Is Upregulated during Wound Healing and Regulates Cellular Phenotypes in Corneal Epithelial Cells

  Keiichi Aomatsu; Tokuzo Arao; Kosuke Abe; Aya Kodama; Koji Sugioka; Kazuko Matsumoto; Kanae Kudo; Hideharu Kimura; Yoshihiko Fujita; Hidetoshi Hayashi; Tomoyuki Nagai; Yoshikazu Shimomura; Kazuto Nishio

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE ASSOC RESEARCH VISION OPHTHALMOLOGY INC 53 (2) 751 - 756 0146-0404 2012/02 

  PURPOSE. The involvement of the epithelial mesenchymal transition (EMT) in the process of corneal wound healing remains largely unclear. The purpose of the present study was to gain insight into Slug expression and corneal wound healing. METHODS. Slug expression during wound healing in the murine cornea was evaluated using fluorescence staining in vivo. Slug or Snail was stably introduced into human corneal epithelial cells (HCECs). These stable transfectants were evaluated for the induction of the EMT, cellular growth, migration activity, and expression changes in differentiation-related molecules. RESULTS. Slug, but not Snail, was clearly expressed in the nuclei of corneal epithelial cells in basal lesion of the corneal epithelium during wound healing in vivo. The overexpression of Slug or Snail induced an EMT-like cellular morphology and cadherin switching in HCECs, indicating that these transcription factors were able to mediate the typical EMT in HCECs. The overexpression of Slug or Snail suppressed cellular proliferation but enhanced the migration activity. Furthermore, ABCG2, TP63, and keratin 19, which are known as stemness-related molecules, were downregulated in these transfectants. CONCLUSIONS. It was found that Slug is upregulated during corneal wound healing in vivo. The overexpression of Slug mediated a change in the cellular phenotype affecting proliferation, migration, and expression levels of differentiation-related molecules. This is the first evidence that Slug is regulated during the process of corneal wound healing in the corneal epithelium in vivo, providing a novel insight into the EMT and Slug expression in corneal wound healing. (Invest Ophthalmol Vis Sci. 2012; 53: 751-756) DOI: 10.1167/iovs.11-8222
• Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer

  Taroh Satoh; Yasuhide Yamada; Kei Muro; Hidetoshi Hayashi; Yasuhiro Shimada; Daisuke Takahari; Keisei Taku; Takako Eguchi Nakajima; Xiaojin Shi; Kathryn H. Brown; Narikazu Boku

  CANCER CHEMOTHERAPY AND PHARMACOLOGY SPRINGER 69 (2) 439 - 446 0344-5704 2012/02 [Refereed]
   

  The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer.Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m(2) iv day 1) plus S-1 (40-60 mg bid, days 1-21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m(2) iv, day 1) plus capecitabine (1,000 mg/m(2) bid, days 1-14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1.Fourteen patients (Arm A, n = 6; Arm B, n = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n = 1; Arm B, n = 2) partial responses that were ongoing at data cut-off.Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.
• Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: Clinical benefit with optimal patient selection

  Akito Hata; Nobuyuki Katakami; Hiroshige Yoshioka; Shiro Fujita; Kei Kunimasa; Shigeki Nanjo; Kyoko Otsuka; Reiko Kaji; Keisuke Tomii; Masahiro Iwasaku; Akihiro Nishiyama; Hidetoshi Hayashi; Satoshi Morita; Tadashi Ishida

  LUNG CANCER ELSEVIER IRELAND LTD 74 (2) 268 - 273 0169-5002 2011/11 [Refereed]
   

  Background: Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy. Methods: One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009. Results: The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months). Conclusions: Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
• High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin

  Yasuhiro Kidera; Taroh Satoh; Shinya Ueda; Wataru Okamoto; Isamu Okamoto; Soichi Fumita; Kimio Yonesaka; Hidetoshi Hayashi; Chihiro Makimura; Kunio Okamoto; Hidemi Kiyota; Junji Tsurutani; Masaki Miyazaki; Masahiro Yoshinaga; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Masanobu Tsubaki; Yasutaka Chiba; Shozo Nishida; Kazuhiko Nakagawa

  INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY SPRINGER TOKYO 16 (3) 244 - 249 1341-9625 2011/06 [Refereed]
   

  Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.
• A case report:Ewing sarcoma originating in the upper jaw

  正垣 直樹; 吉川 構; 森 一功; 土井 勝美; 林 秀敏

  57 (1) 13 - 17 2011/01
• Gemcitabine: Efficacy in the treatment of advanced stage nonsquamous non-small cell lung cancer

  Hidetoshi Hayashi; Takayasu Kurata; Kazuhiko Nakagawa

  Clinical Medicine Insights: Oncology Libertas Academica Ltd. 5 177 - 184 1179-5549 2011 [Refereed]
   

  Lung cancer is the leading cause of cancer-related death in many countries. Approximately half of the patients with non-small cell lung cancer have advanced disease and systemic chemotherapy, especially platinum-based doublets, is currently the standard treatment. Several trials have recently indicated the importance of histological subtype for treatment with molecular target chemotherapy and pemetrexed. Over the last decade, gemcitabine, a pyrimidine nucleoside antimetabolite, has been one of the most effective agents for patients with advanced non-small cell lung cancer. It is unknown whether histological type is a predictor of the outcome of treatment with this agent. This is a review of the past trials and reviews of first-line treatment for advanced NSCLC, focusing on efficacy and safety of treatment with gemcitabine according to histological subtype. © the author(s), publisher and licensee Libertas Academica Ltd.
• ZOLEDRONIC ACID-INDUCED REGRESSION OF MULTIPLE METASTASES AT NONSKELETAL SITES

  Tsurutani Junji; Okamoto Kunio; Makimura Chihior; Azuma Koichi; Takeda Masayuki; Takezawa Ken; Okamoto Wataru; Kiyota Hidemi; Hayashi Hidetoshi; Tanaka Kaoru; Tanizaki Junko; Okamoto Isamu; Saijoh Nagahiro; Fukuoka Masahiro; Nakagawa Kazuhiko

  ANNALS OF ONCOLOGY 21 38 - 39 0923-7534 2010/11 [Refereed]
  
• SORAFENIB INHIBITS NSCLC CELL GROWTH BY TARGETING BRAF IN KRAS WILD TYPE CELLS AND CRAF IN KRAS MUTANT CELLS

  Takezawa Ken; Okamoto Isamu; Tanaka Kaoru; Hayashi Hidetoshi; Okamoto Kunio; Yonesaka Kimio; Fukuoka Masahiro; Nakagawa Kazuhiko

  ANNALS OF ONCOLOGY 21 20  0923-7534 2010/11 [Refereed]
  
• EARLY CONCURRENT CHEMORADIOTHERAPY FOR LIMITED-DISEASE SMALL CELL LUNG CANCER IN ELDERLY PATIENTS

  Okamoto Kunio; Okamoto Isamu; Takezawa Ken; Tanaka Kaoru; Tanizaki Junko; Makimura Chihiro; Hayashi Hidetoshi; Tachibana Izumi; Nishimura Yasumasa; Fukuoka Masahiro; Nakagawa Kazuhiko

  ANNALS OF ONCOLOGY 21 27  0923-7534 2010/11 [Refereed]
  
• RETREATMENT OF RECURRENT MALIGNANT PLEURAL MESOTHELIOMA WITH CISPLATIN AND PEMETREXED

  Hayashi Hidetoshi; Okamoto Isamu; Miyazaki Masaki; Ichikawa Yasuko; Yoshioka Hiroshige; Kunimasa Kei; Tanaka Kaoru; Okamoto Kunio; Makimura Chihiro; Iwasaku Masahiro; Nisiyama Akihiro; Korogi Yohhei; Nakagawa Kazuhiko

  ANNALS OF ONCOLOGY 21 26  0923-7534 2010/11 [Refereed]
  
• Desire for Information and Involvement in Treatment Decisions Lung Cancer Patients' Preferences and Their Physicians' Perceptions: Results from Okayama Lung Cancer Study Group Trial 0705

  Katsuyuki Hotta; Katsuyuki Kiura; Nagio Takigawa; Hiroshige Yoshioka; Hidetoshi Hayashi; Hajime Fukuyama; Akihiro Nishiyama; Toshihide Yokoyama; Shoichi Kuyama; Shigeki Umemura; Yuka Kato; Naoyuki Nogami; Yoshihiko Segawa; Masayuki Yasugi; Masahiro Tabata; Mitsune Tanimoto

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 5 (10) 1668 - 1672 1556-0864 2010/10 [Refereed]
   

  Introduction: This study explores patient preferences for involvement in lung cancer treatment decisions and the extent of concordance between the views of patients and physicians on decisional roles. The impact of demographic and psychosocial characteristics on the decisional role of patients is also examined. Methods: Patients with relapsed non-small cell lung cancer who were candidates for a phase II trial of erlotinib monotherapy were recruited. Patients were interviewed after they had learned of their relapse and the treatment decision had been made but before pharmacologic intervention. Results: Most of the 28 participants were married, had a smoking history, and were well educated. They reported moderate levels of depression and anxiety. Initially, 14% of the patients reported a preference for active decision making; later, 29% believed that the primary responsibility for the treatment decision had been theirs. Only 54% of the patients agreed with the physician's assessment of how the treatment decision was made (kappa = 0.31; test of symmetry, p = 0.23). The depression score was significantly associated with a patient's preferred level of control (p < 0.01). Conclusions: The limited concordance between patient preference and perception and between patient and physician perceptions regarding how the treatment decision was made suggests that physicians should more accurately identify patient preferences by directly asking patients at the beginning of each clinical encounter.
• Retreatment of recurrent malignant pleural mesothelioma with cisplatin and pemetrexed

  Hidetoshi Hayashi; Isamu Okamoto; Yasuko Ichikawa; Masaki Miyazaki; Hiroshige Yoshioka; Kei Kunimasa; Kazuhiko Nakagawa

  International Journal of Clinical Oncology 15 (5) 497 - 499 1341-9625 2010/10 [Refereed]
   

  Combination chemotherapy with cisplatin and pemetrexed is the most active first-line regimen for malignant pleural mesothelioma (MPM). However, no drugs have been approved for second-line treatment of MPM, with effective regimens remaining to be identified for patients in relapse. We have now evaluated the combination of cisplatin and pemetrexed for retreatment of patients with recurrent MPM. Four men with MPM, all of whom received initial treatment with cisplatin and pemetrexed, underwent retreatment with this drug combination. Two of the patients achieved an objective response to the first-line chemotherapy with no evidence of disease progression for 6.4 or 11.4 months, respectively. The other two patients had stable disease with a duration of 7.8 or 5.0 months, respectively. The two patients who showed an objective response to first-line chemotherapy showed a partial response to retreatment, with a time to progression of 5.0 or 8.2 months, whereas the other two patients had progressive disease with a time to progression of 1.0 or 1.4 months, respectively. Retreatment with cisplatin plus pemetrexed was generally well tolerated. Retreatment with cisplatin and pemetrexed is a potential therapeutic option for certain patients with recurrent epithelioid MPM, possibly including those who show tumor regression with a time to progression of 6 months or more after the initial chemotherapy. Further studies are warranted to evaluate the efficacy of such retreatment and to clarify the criteria for patient selection. © 2010 Japan Society of Clinical Oncology.
• A Randomized Phase II Study of a Combination of Docetaxel and S-1 versus Docetaxel Monotherapy in Patients with Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy Results of Okayama Lung Cancer Study Group (OLCSG) Trial 0503

  Yoshihiko Segawa; Katsuyuki Kiura; Katsuyuki Hotta; Nagio Takigawa; Masahiro Tabata; Keitaro Matsuo; Hiroshige Yoshioka; Hidetoshi Hayashi; Haruyuki Kawai; Keisuke Aoe; Tadashi Maeda; Hiroshi Ueoka; Mitsune Tanimoto

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 5 (9) 1430 - 1434 1556-0864 2010/09 [Refereed]
   

  Background: The survival impact of single-agent treatment with docetaxel, the standard regimen for relapsed patients with non-small cell lung cancer (NSCLC), remains modest We conducted a randomized phase II study to evaluate the efficacy and safety of the combination of docetaxel and S-I in the second-line setting Methods: Patients with relapse of NSCLC after first-line platinum-based chemotherapy were randomly assigned to docetaxel alone (60 mg/m(2), day I. q3 weeks, arm A) or a combination of docetaxel (40 mg/m(2). day 1. q3 weeks) and S-I (80 mg/m(2), days 1-15, arm B) The primary end point was response rate, whereas secondary endpoints included overall survival, progression-free survival, and toxicity Results: Between 2005 and 2008, a total of 60 patients were enrolled in the study The objective response rates were 20 7% and 16 1% in arms A and B. respectively (p = 0 81) Progression-free survival was comparable in the two arms (median 3 7 versus 3 4 months. p = 0 27), whereas overall survival time was longer in arm A (22 9 versus 8 7 months, p = 0 02) The major toxicity was myelosuppression with grade neutropenia in 89 7% of patients versus 64 5% in arms A and B. respectively Conclusions: This study suggests that docetaxel monotherapy should continue to be considered the standard for second-line chemotherapy against NSCLC
• 再発肺非小細胞癌に対するドセタキセルとドセタキセル+S-1併用の無作為化第2相試験

  川井 治之; 渡辺 一彦; 六車 満; 吉岡 弘鎮; 林 秀敏; 畝川 芳彦; 野上 尚之; 加藤 有加; 新海 哲; 前田 忠士; 青江 啓介; 細川 忍; 松尾 恵太郎; 堀田 勝幸; 瀧川 奈義夫; 田端 雅弘; 木浦 勝行; 谷本 光音

  肺癌 (NPO)日本肺癌学会 50 (2) 227 - 227 0386-9628 2010/04
• 腫瘍 EGFR遺伝子変異を認めない再発肺非小細胞癌患者に対するエルロチニブ療法の第2相試験

  加藤 有加; 野上 尚之; 畝川 芳彦; 新海 哲; 吉岡 弘鎮; 林 秀敏; 岩破 将博; 木浦 勝行; 瀧川 奈義夫; 田端 雅弘; 市川 英基; 八杉 昌幸; 久山 彰一; 張田 信吾; 岡田 俊明; 梅村 茂樹; 亀井 治人; 別所 昭宏; 谷本 光音

  日本呼吸器学会雑誌 (一社)日本呼吸器学会 48 (増刊) 112 - 112 1343-3490 2010/03
• プラチナ化学療法後に増悪した非小細胞肺癌に対するDocetaxel単剤療法とDocetaxel+S-1併用療法の無作為化第2相試験

  細川 忍; 渡辺 洋一; 別所 昭宏; 松尾 圭祐; 畝川 芳彦; 野上 尚之; 吉岡 弘鎮; 林 秀敏; 木浦 勝行; 瀧川 奈義夫; 田端 雅弘; 松尾 恵太郎; 堀田 勝幸; 市原 英基; 川井 治之; 渡辺 一彦; 青江 啓介; 前田 忠士; 上岡 博; 新海 哲; 谷本 光音

  日本呼吸器学会雑誌 (一社)日本呼吸器学会 48 (増刊) 317 - 317 1343-3490 2010/03
• A Phase II Trial of Erlotinib Monotherapy in Pretreated Patients with Advanced Non-small Cell Lung Cancer Who Do Not Possess Active EGFR Mutations Okayama Lung Cancer Study Group Trial 0705

  Hiroshige Yoshioka; Katsuyuki Hotta; Katsuyuki Kiura; Nagio Takigawa; Hidetoshi Hayashi; Shingo Harita; Shoichi Kuyama; Yoshihiko Segawa; Haruhito Kamei; Shigeki Umemura; Akihiro Bessho; Masahiro Tabata; Mitsune Tanimoto

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 5 (1) 99 - 104 1556-0864 2010/01 [Refereed]
   

  Backgrounds: Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR)-mutation status in Asian patients with non-small cell lung cancer. Recently, the survival advantage of erlotinib, another tyrosine kinase inhibitor, was not affected by EGFR mutation status in a phase III trial, indicating that patients with EGFR-wild-type (EGFR-wt) tumors might also benefit from this tyrosine kinase inhibitor. The aim of this trial was to evaluate the efficacy and toxicity of erlotinib in Japanese patients with EGFR-wt tumors. Methods: The primary end point was an objective response. Patients with EGFR-wt tumors previously receiving one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Erlotinib was administered (150 mg/d) until disease progression or unacceptable toxicities occurred. Results: Thirty patients were enrolled between January and December 2008. Objective response was observed in one patient (3.3%), and the disease became stable in 18 patients (60.0%). Skin rash was the most common side effect. Grades 3-4 adverse events included pulmonary embolism, keratitis, and anemia. Two other patients developed interstitial lung disease (grades 1 and 2). Nevertheless, all these events were reversible, resulting in no treatment-related deaths. With a median follow-Lip time of 10.7 months, the median survival time and median progression-free survival times were 9.2 and 2.1 months, respectively. Conclusion: This is the first prospective biomarker study showing that erlotinib therapy for pretreated patients with EGFR-wt tumors seems to have a modest activity with no irreversible toxicity.
• Localized Malignant Pleural Mesothelioma Showing a Thoracic Mass and Metastasizing to the Stomach

  Hidetoshi Hayashi; Kenji Notohara; Hiroshige Yoshioka; Tomoaki Matsuoka; Hiroyoshi Ikeda; Koichi Kagawa; Toshio Fukuoka; Tadashi Ishida

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 49 (7) 671 - 675 0918-2918 2010 [Refereed]
   

  Malignant mesothelioma typically shows either diffuse tumors or multiple pleura-based nodules. Localized malignant mesothelioma is rare. In this case report, a 70-year-old man with left chest wall tumor underwent tumor resection, and the lesion was pathologically diagnosed as biphasic malignant mesothelioma. Tumor recurrence was detected in the stomach due to vomiting of blood, and also spread to the mediastinal lymph node, and bone 3 months postoperatively. Total gastrectomy was performed and the histopathological diagnosis of metastasis of mesothelioma was made. In the previously reported cases, all of the localized malignant mesothelioma arose in the pleural space and there was no metastasis of localized malignant mesothelioma to the stomach. In the present case, gross and histological examinations were performed for both the primary lesion and gastric metastatic tumor. Though it was very difficult to distinguish mesothelioma from sarcoma and other chest wall tumors, immunochemical staining was able to facilitate making the diagnosis. This case suggests that localized malignant mesothelioma is capable of showing multiple forms and a variety of clinical courses. Localized malignant mesothelioma can arise primarily from the chest wall.
• Phase II trial of amrubicin for second-line treatment of advanced non-small cell lung cancer: Results of the west japan thoracic oncology group trial (WJTOG0401)

  Hiroyasu Kaneda; Isamu Okamoto; Hidetoshi Hayashi; Hiroshige Yoshioka; Masaki Miyazaki; Shinzoh Kudoh; Tatsuo Kimura; Takamune Sugiura; Toshiyuki Sawa; Koji Takeda; Yasuo Iwamoto; Miyako Satouchi; Kenji Akita; Hiroshi Saito; Isao Goto; Kazuhiko Shibata; Masahiro Fukuoka; Kazuhiko Nakagawa

  Journal of Thoracic Oncology Lippincott Williams and Wilkins 5 (1) 105 - 109 1556-1380 2010 [Refereed]
   

  BACKGROUND: Amrubicin is a synthetic anthracycline drug that is a potent inhibitor of topoisomerase II. We have performed a multicenter phase II trial to evaluate the efficacy and safety of amrubicin for patients with previously treated non-small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC who experienced disease recurrence after one platinum-based chemotherapy regimen were eligible for enrollment in the study. Amrubicin was administered by intravenous injection at a dose of 40 mg/m2 on 3 consecutive days every 3 weeks. RESULTS: Sixty-one enrolled patients received a total of 192 treatment cycles (median, 2 range, 1-15). Response was as follows: complete response, 0 partial response, seven (11.5%) stable disease, 20 (32.8%) and progressive disease, 34 (55.7%). Median progression-free survival was 1.8 months, whereas median overall survival was 8.5 months, and the 1-year survival rate was 32%. Hematologic toxicities of grade 3 or 4 included neutropenia (82.0%), leukopenia (73.8%), thrombocytopenia (24.6%), and anemia (27.9%). Febrile neutropenia occurred in 18 patients (29.5%). One treatment-related death due to infection was observed. Nonhematologic toxicities were mild. CONCLUSIONS: Amrubicin is a possible alternative for second-line treatment of advanced NSCLC, although a relevant hematological toxicity is significant, especially with a febrile neutropenia. Copyright © 2009 by the International Association for the Study of Lung Cancer.
• 糖尿病患者に発症した多発膿瘍とSeptic Pulmonary Emboliの1例

  岩破 将博; 野山 麻紀; 伊賀 知也; 國政 啓; 西山 明宏; 三枝 美香; 仲川 宏昭; 福山 一; 林 秀敏; 山本 正樹; 横山 俊秀; 吉岡 弘鎮; 橘 洋正; 有田 真知子; 橋本 徹; 石田 直

  倉敷中央病院年報 (公財)大原記念倉敷中央医療機構倉敷中央病院 71 59 - 64 0368-4954 2009/03 

  症例は62歳女性.3月末より発熱・関節痛を認め,4月上旬に近医で精査したところ,肺に多発小結節影を認めた.精査目的で当院に紹介入院となった.CTにて肝膿瘍を認め,肝膿瘍ドレナージ術を施行し,内容物からKlebsiella pneumoniaeが培養された.また,気管支鏡検査にて気管支洗浄液からKlebsiella sppが培養され,多発小結節影をseptic pulmonary emboli(SPE)と診断,抗菌薬にて加療を行った.SPEのほか全身精査にて左腎膿瘍,左腎静脈血栓を認めたが,いずれも抗菌薬治療が奏効し治癒した.なお,入院時HbA1c13.5%とコントロール不良の未治療糖尿病を認め,あわせて血糖コントロールを行った.全身状態改善に伴い,6月中旬に当院を退院し,外来にて経過観察を行った.抗菌薬投与終了後も全身状態良好であり,現在は近医にて糖尿病内服加療を継続している.SPEは比較的まれな疾患であり,本症例では全身に多発膿瘍を認めたものの抗菌薬加療にて治癒に至った.(著者抄録)
• Two cases of small bowel metastases from lung cancer diagnosed by double-balloon enteroscopy

  Hiroshige Yoshioka; Tadashi Ishida; Hidetoshi Hayashi; Masaki Yamamoto; Tomoya Ishii; Toru Hashimoto

  Japanese Journal of Lung Cancer 48 (2) 135 - 140 0386-9628 2008/04 [Refereed]
   

  Background. Small bowel metastases from lung cancer are uncommon. Early diagnosis of small bowel metastases is said to be difficult, and the prognosis has been reported to be poor. The recently developed double-balloon enteroscopy (DBE) allows diagnosis and therapeutic interventions in all segments of the small bowel. Cases. We treated 2 cases who were found to have small bowel metastases secondary to lung cancer, using DBE. Case 1 was a 49-year-old man who complained of right chest pain and was given a diagnosis of large cell carcinoma of the lung. He frequently passed black, tarry stools. DBE was done, and histological examination revealed multiple small bowel metastases. The patient died despite aggressive treatment, which included palliative surgical resection (i.e. partial resection) of the small bowel. Case 2 was a 75-year-old man whose chief complaints were general malaise and melena. DBE was done, and histological examination showed multiple small bowel metastases from lung adenocarcinoma. The metastases bled so easily that even temporary hemostasis could not be achieved. Despite repeated red blood cell transfusions, the patient died. Conclusion. DBE is a useful tool for assessing small bowel lesions, because it allows direct observation of the state of small bowel, and it permits a histological diagnosis to be made in a relatively early phase of the disease. However, since DBE can be associated with pain and discomfort, and does not lead to a cure in all patients, candidates for DBE should be assessed for their suitability for the procedure on an individual basis. © 2008 The Japan Lung Cancer Society.
• 32. CTで同定不能な肺癌を気管支鏡検査で診断し,定位放射線治療を施行した1例(第16回日本呼吸器内視鏡学会中国四国支部会)

  福山 一; 橋本 徹; 岩破 将博; 三枝 美香; 山本 正樹; 横山 俊秀; 林 秀敏; 時岡 史明; 永井 宏樹; 野山 麻紀; 吉岡 弘鎮; 橘 洋正; 有田 真知子; 石田 直

  気管支学 特定非営利活動法人 日本呼吸器内視鏡学会 30 (3) 163 - 163 2008

Conference Activities & Talks

• Prognostic impact of EMT-related genes on post-operative prognosis in hepatocellular carcinoma.  [Not invited]

  永井 知行; 荒尾 徳三; 松本 和子; 藤田 至彦; 林 秀敏; 木村 英晴; 萩原 智; 櫻井 俊治; 上嶋 一臣; 土師 誠二; 工藤 正俊; 西尾 和人

  AACR 103rd Annual Meeting 2011  2012/03  Chicago, USA  AACR 103rd Annual Meeting 2011
  
• 進行肺腺癌を対象としたゲフィチニブ／S-1併用療法第１層臨床試験  [Not invited]

  清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋応顕; 東 公一; 武田真幸; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦

  第51回日本肺癌学会総会  2010/11  広島  第51回日本肺癌学会総会
  
• 進行肺腺癌を対象としたゲフェチニブ／S-1 併用療法第１相臨床試験  [Not invited]

  清田 秀美; 岡本 勇; 谷﨑 潤子; 文田 壮一; 岡本 邦男; 牧村 ちひろ; 竹澤 健; 田中 薫; 林 秀敏; 岡本 渉; 寺嶋応顕; 東 公一; 金田裕靖; 武田真幸; 上田 眞也; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦

  第92回日本肺癌学会関西支部会  2010/07  大阪  第92回日本肺癌学会関西支部会
  
• ソラフェニブは肺癌細胞においてＫＲＡＳ野生型に対しては  [Not invited]

  竹澤 健; 岡本 勇; 田中 薫; 林 秀敏; 岡本 邦男; 米阪 仁雄; 福岡正博; 中川 和彦

  第8回日本臨床腫瘍学会総会  2010/03  東京  第8回日本臨床腫瘍学会総会
  

MISC

• PTPRRを介したEGFR活性化に起因するKRASG12C阻害薬耐性の克服(Combating acquired resistance to KRAS inhibitors in NSCLC by targeting PTPRR-mediated activation of EGFR signaling)

  金村 宙昌; 竹原 俊幸; 小野寺 勇太; 寺村 岳士; 鈴木 慎一郎; 坂井 和子; 西尾 和人; 中川 和彦; 林 秀敏; 米阪 仁雄  日本癌学会総会記事  82回-  422  -422  2023/09
• Providing Anti-Lung Cancer Drug Therapy Based on Genetic Information by Comprehensive Genomic Profiling

  米阪仁雄; 稲垣千昌; 稲垣千昌; 高濱隆幸; 高濱隆幸; 白石直樹; 磯本晃佑; 金村宙昌; 鈴木慎一郎; 谷崎潤子; 田中薫; 林秀敏; 中川和彦  日本癌学会学術総会抄録集(Web)  82nd-  2023
• ニボルマブ+イピリムマブ併用療法中に敗血症との鑑別を要する免疫関連下垂体炎を発症した肺腺癌の1例

  村田修一; 谷崎潤子; 岩朝勤; 黒崎隆; 田中薫; 林秀敏; 中川和彦; 濱有一郎  肺癌(Web)  63-  (3)  2023
• 腫瘍微小環境における免疫細胞の局在と免疫チェックポイント阻害薬の効果との関連

  磯本晃佑; 原谷浩司; 田中薫; 谷崎潤子; 高濱隆幸; 金村宙昌; 鈴木慎一郎; 林秀敏  日本肺癌学会学術集会号  64th (CD-ROM)-  2023
• 原発不明癌に対するニボルマブ治療中に肺サルコイド様肉芽腫変化をきたした一例

  川中雄介; 田中薫; 須田健一; 高濱隆幸; 林秀敏  日本肺癌学会学術集会号  64th (CD-ROM)-  2023
• 超音波気管支鏡下針生検後に発症した細菌性心膜炎の一例

  村田修一; 谷崎潤子; 黒崎隆; 鈴木慎一郎; 高濱隆幸; 田中薫; 林秀敏  日本肺癌学会学術集会号  64th (CD-ROM)-  2023
• 肺癌に対する遺伝子パネル検査の実際と出口戦略の検討

  高濱隆幸; 高濱隆幸; 米阪仁雄; 米阪仁雄; 谷崎潤子; 田中薫; 鈴木慎一郎; 金村宙昌; 磯本晃佑; 白石直樹; 坂井和子; 福岡和也; 福岡和也; 福岡和也; 西尾和人; 中川和彦; 中川和彦; 林秀敏  日本肺癌学会学術集会号  64th (CD-ROM)-  2023
• EGFR inhibitor upregulates HER3 expression and enhances the efficacy of anti-HER3 antibody drug conjugate U3-1402

  Kimio Yonesaka; Junko Tanizaki; Osamu Maenishi; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Kazuko Sakai; Maki Kobayashi; Ryoto Yoshimoto; Hiroki Goto; Masanori Funabashi; Yuuri Hashimoto; Kenji Hirotani; Takashi Kagari; Kazuto Nishio; Kazuhiko Nakagawa  ANNALS OF ONCOLOGY  32-  S296  -S296  2021/07
• 肺癌学会としてのオンコマインデータ収集事業について

  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  日本肺癌学会学術集会号  62nd (CD-ROM)-  2021
• 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; 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(Web)  59th-  2021
• 気管支鏡検査時の迅速細胞診(ROSE)の成功に関連する因子の検討

  金村宙昌; 田中薫; 鈴木慎一郎; 黒崎隆; 磯本晃佑; 岩朝勤; 白石直樹; 林秀敏; 武田真幸; 中川和彦  気管支学  43-  2021
• 【がんゲノム医療update】NGSを用いたマルチコンパニオン診断

  加藤 了資; 林 秀敏  呼吸器内科  38-  (4)  301  -305  2020/10
• 免疫療法時代における局所療法の意義 免疫チェックポイント阻害薬時代に期待される集学的治療、最新の話題と課題

  林 秀敏  日本癌治療学会学術集会抄録集  58回-  SY9  -4  2020/10
• 肺小細胞癌を含む神経内分泌腫瘍の実臨床での経験とエビデンスの融合 実臨床下における進展型小細胞肺癌に対するカルボプラチン+エトポシド+アテゾリズマブの治療成績

  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  2020/10
• ドライバー変異を有する肺癌をICIでいかに治療するか ドライバー変異陽性非小細胞肺がんに対する新規治療戦略

  林 秀敏  肺癌  60-  (6)  479  -479  2020/10
• 肺がんのバイオマーカー:現在地と未来図 実臨床で使用可能となった希少遺伝子変異陽性NSCLC Current knowledge and what's next step?

  林 秀敏  肺癌  60-  (6)  505  -505  2020/10
• 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  2020/10
• 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  2020/10
• 未治療進行非小細胞肺癌における化学療法の治療効果と総腫瘍量の関連性

  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  2020/10
• 【ゲノム医療時代のがん 分子標的薬と診断薬研究「治療」の選択肢を広げる新しい標的、併用療法、横断的・マルチコンパニオン診断薬、リキッドバイオプシー】(第4章)より精密ながんゲノム医療を目指して 免疫チェックポイント阻害薬と分子標的治療薬の併用

  林 秀敏  実験医学  38-  (15)  2582  -2586  2020/09
• 頭頸部癌に対する免疫療法の現状と展望 免疫チェックポイント阻害薬の有害事象 管理の実際と最近の話題

  林 秀敏  頭頸部癌  46-  (2)  123  -123  2020/07
• 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  2020/07
• 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  2020/07
• 遺伝子パネル導入において当院での気管支鏡検査における対応策

  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  2020/06
• 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  気管支学  42-  (Suppl.)  S391  -S391  2020/06
• NivoCUP: An open-label phase II study on the efficacy of nivolumab in cancer of unknown primary.

  Junko Tanizaki; Kan Yonemori; Kohei Akiyoshi; Hironobu Minami; Hiroki Ueda; Yuichi Takiguchi; Chihiro Nakayama Kondoh; Yoshihiko Segawa; Shin Takahashi; Yasuo Iwamoto; Yasuhiro Kidera; Kazuya Fukuoka; Yasushi Nakamura; Yasutaka Chiba; Kazuto Nishio; Kazuhiko Nakagawa; Hidetoshi Hayashi  JOURNAL OF CLINICAL ONCOLOGY  38-  (15)  2020/05
• HER3リガンド・ヘレグリン陽性肺癌のEGFRチロシンキナーゼ(EGFR-TKI)への治療抵抗性について

  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  2020/04
• 非小細胞肺癌患者における免疫チェックポイント阻害薬による消化管irAEにおけるヒト・腸内細菌叢の病態と炎症性腸疾患の類似性に関する検討

  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  2020/04
• 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(Web)  60-  (2)  2020
• 非小細胞肺癌患者における免疫チェックポイント阻害薬による消化管irAEにおけるヒト・腸内細菌叢の病態と炎症性腸疾患の類似性に関する検討

  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(Web)  60-  (2)  2020
• HER3リガンド・ヘレグリン陽性肺癌のEGFRチロシンキナーゼ(EGFR-TKI)への治療抵抗性について

  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(Web)  60-  (2)  2020
• 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; 高濱隆幸; 谷崎潤子; 野長瀬祥兼; 金田裕靖  肺癌(Web)  60-  (2)  2020
• PD-L1高発現未治療進行非小細胞肺癌におけるPembrolizumabの治療効果と総腫瘍量の関連性

  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(Web)  60-  (2)  2020
• 免疫治療の有害事象対策 間質性肺炎発症のリスク評価とその対策

  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  2019/11
• Novel biomarkers for immunotherapies The role of soluble immune-checkpoint factors in advanced NSCLC(和訳中)

  Hayashi Hidetoshi; 茶本 健司; 冨樫 庸介; 中川 和彦; 本庶 佑  肺癌  59-  (6)  558  -558  2019/11
• 腫瘍免疫と微小環境 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; 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  2019/11
• 進行非小細胞肺癌に対するPD-1阻害薬投与後の化学療法の有効性を検討する大規模比較研究(WJOG10217L)

  清水 淳市; 加藤 了資; 林 秀敏; 千葉 康敬; 宮脇 英里子; 尾崎 智博; 藤本 大智; 豊澤 亮; 坂本 信二郎; 新屋 智之; 知花 賢治; 横井 崇; 岡田 秀明; 秦 明登; 福山 誠一; 田幡 江利子; 長島 聖二; 濱元 陽一郎; 山本 信之; 中川 和彦  肺癌  59-  (6)  595  -595  2019/11
• Preliminary results of brigatinib in Japanese who previously received alectinib(和訳中)

  里内 美弥子; 村上 修司; 瀬戸 貴司; 西尾 誠人; 林 秀敏; 中川 和彦; 朝戸 臣敬; 橋上 美香; Zhang Pingkuan; 大江 裕一郎  肺癌  59-  (6)  668  -668  2019/11
• Pem maintenance with Bev prolonged the survival, with adv EGFR-wild nSQ-NSCLC treated Car+Pem+Bev(和訳中)

  中村 敦; 瀬戸 貴司; 山中 竹春; 東 公一; 吉岡 弘鎮; 小野 哲; 安宅 信二; 岩本 康男; 林 秀敏; 岡本 勇; 坂 英雄; 光岡 茂樹; 藤本 大智; 西野 和美; 堀池 篤; 駄賀 晴子; 曽根 崇; 山本 信之; 中川 和彦; 中西 洋一  肺癌  59-  (6)  671  -671  2019/11
• 局所進行非小細胞肺癌に対するシスプラチン/nab-パクリタキセル+放射線化学療法の第I/II相試験

  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  2019/11
• EGFR変異陽性肺癌におけるHER3リガンド・ヘレグリン発現とEGFR-TKIの治療効果との関係

  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  2019/11
• EGFR変異陽性非小細胞肺癌における組織、血漿中AXL・GAS6発現レベルに関する研究

  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  2019/11
• アテゾリズマブによる多臓器障害に対して血漿交換を使用した一例

  金村 宙昌; 林 秀敏; 萩原 智; 酒井 瞳; 米阪 仁雄; 中川 和彦  肺癌  59-  (6)  779  -779  2019/11
• 辺縁系脳炎によるPS4のSCLC Stage3Bに対し化学療法が著効し逐次的放射線療法後予防的全脳照射を施行した一例

  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  2019/11
• 実臨床におけるリキッドバイオプシーの役割 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; 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  2019/11
• ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討

  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  2019/11
• Impact of Co-Mutations in EGFR-Mutated NSCLC Before EGFR-TKIs on T790M Mutation Status After TKIs(和訳中)

  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  2019/11
• PD-L1高発現の進行NSCLCにおける総腫瘍径とICIによる治療効果の関係性を検討する観察研究

  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  2019/11
• 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  2019/08
• 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  2019/08
• 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; 武川 直樹; 野長瀬 祥兼; 川上 尚人; 林 秀敏; 中川 和彦  日本食道学会学術集会プログラム・抄録集  73回-  258  -258  2019/06
• 当院におけるオシメルチニブの使用成績と血漿中cfDNAの有用性に関する検討

  加藤 了資; 林 秀敏; 米阪 仁雄; 原谷 浩司; 酒井 瞳; 高濱 隆幸; 谷崎 潤子; 岩朝 勤; 田中 薫; 吉田 健史; 武田 真幸; 金田 裕靖; 中川 和彦; 清水 重喜; 伊藤 彰彦; 坂井 和子; 西尾 和人  肺癌  59-  (2)  194  -194  2019/04
• 【肺癌 免疫・ゲノム医療で急展開する肺癌治療】最新の実地診療のポイントと整理 次世代シークエンサーを用いた遺伝子検査(組織)

  高濱 隆幸; 林 秀敏  Medical Practice  36-  (2)  241  -245  2019/02
• 出血性NSAIDs潰瘍を契機にニボルマブによる後天性血友病Aを診断した肺扁平上皮癌の1例

  加藤 了資; 林 秀敏; 佐野 圭吾; 半田 康平; 中川 和彦  日本内科学会雑誌  108-  (Suppl.)  212  -212  2019/02
• 免疫チェックポイント阻害剤投与による下垂体機能低下症を来した4例

  広川 恵寿輝; 吉田 健史; 鈴木 慎一郎; 奥野 達哉; 田中 薫; 林 秀敏; 武友 保憲; 能宗 伸輔; 池上 博司; 中川 和彦  日本内科学会雑誌  108-  (Suppl.)  282  -282  2019/02
• Alectinibによる長期の腫瘍制御が可能であった末期腎不全合併ALK融合遺伝子陽性肺腺癌の1例

  鈴木 慎一郎; 原谷 浩司; 渡邉 諭美; 高濱 隆幸; 武川 直樹; 林 秀敏; 武田 真幸; 米阪 仁雄; 中川 和彦  日本内科学会雑誌  108-  (Suppl.)  283  -283  2019/02
• 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; 高濱隆幸; 坂井和子; 西尾和人  肺癌(Web)  59-  (4)  2019
• 当院におけるオシメルチニブの使用成績と血漿中cfDNAの有用性に関する検討

  加藤了資; 林秀敏; 米阪仁雄; 原谷浩司; 酒井瞳; 高濱隆幸; 谷崎潤子; 岩朝勤; 田中薫; 吉田健史; 武田真幸; 金田裕靖; 中川和彦; 清水重喜; 伊藤彰彦; 坂井和子; 西尾和人  肺癌(Web)  59-  (2)  2019
• 肉芽腫様所見を伴った縦隔腫瘍の2例

  大谷 知之; 清水 重喜; 榎木 英介; 佐藤 隆夫; 伊藤 彰彦; 林 秀敏; 中川 和彦; 武本 智樹; 光冨 徹哉  肺癌  58-  (5)  380  -381  2018/10
• A phase II study on the efficacy of Nivolumab in Japanese patients with cancer of unknown primary (CUP) (NivoCUP)

  Junko Tanizaki; Hidetoshi Hayashi; Hironobu Minami; Makoto Arai; Shin Takahashi; Yoshihiko Segawa; Yukinori Ozaki; Hiroki Ueda; Kohei Akiyoshi; Yasuo Iwamoto; Kan Yonemori; Yasuhiro Kidera; Kazuya Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa  ANNALS OF ONCOLOGY  29-  2018/10
• 非小細胞肺癌における免疫チェックポイント阻害剤再投与の安全性と効果に関する後方視検討

  高濱 隆幸; 武田 真幸; 林 秀敏; 米阪 仁雄; 田中 薫; 岩朝 勤; 吉田 健史; 原谷 浩司; 加藤 了資; 鈴木 慎一郎  肺癌  58-  (6)  699  -699  2018/10
• ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討

  田中 薫; 谷崎 潤子; 野長瀬 祥兼; 原谷 浩司; 酒井 瞳; 林 秀敏; 中川 和彦; 坂井 和子; 西尾 和人  肺癌  58-  (5)  373  -373  2018/10
• 希少肺癌(Ret、ROS1、BRAF陽性)の治療 EGFRまたはHER2のエクソン20遺伝子変異を有する非小細胞肺癌の臨床的特徴(Clinical characteristics of non-small cell lung cancer harboring exon 20 mutation of EGFR or HER2)

  武田 真幸; 坂井 和子; 林 秀敏; 高濱 隆幸; 田中 薫; 西尾 和人; 中川 和彦  肺癌  58-  (6)  451  -451  2018/10
• 当院におけるオシメルチニブの使用成績と血漿中cfDNAの有用性に関する検討

  加藤 了資; 林 秀敏; 米阪 仁雄; 原谷 浩司; 酒井 瞳; 高濱 隆幸; 谷崎 潤子; 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  58-  (6)  519  -519  2018/10
• 肺癌個別化医療に向けた取り組み

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 高濱 隆幸; 原谷 浩司; 福岡 和也; 中川 和彦; 西尾 和人  日本癌治療学会学術集会抄録集  56回-  O2  -2  2018/10
• 肉芽腫様所見を伴った縦隔腫瘍の2例

  大谷 知之; 清水 重喜; 榎木 英介; 佐藤 隆夫; 伊藤 彰彦; 林 秀敏; 中川 和彦; 武本 智樹; 光冨 徹哉  肺癌  58-  (5)  380  -381  2018/10
• Relationship between checkpoint molecule B7-H3 and refractoriness to anti-PD-1 therapy in non-small cell lung cancer.

  Kimio Yonesaka; Keita Kudo; Shiki Takamura; Hitomi Sakai; Ryoji Kato; Koji Haratani; Takayuki Takahama; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyuki Kaneda; Masayuki Takeda; Osamu Maenishi; Michiko Yamato; Masaaki Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa  JOURNAL OF CLINICAL ONCOLOGY  36-  (15)  2018/05
• EGFR遺伝子変異陽性肺癌における血漿検体と組織検体でのT790M変異検査の比較検討

  田中薫; 加藤了資; 高濱隆幸; 谷崎潤子; 岩朝勤; 林秀敏; 武田真幸; 中川和彦  気管支学  40-  (Suppl.)  S239  -S239  2018/05
• 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  2018/04
• 免疫チェックポイント阻害薬のバイオマーカーとしてのPD-L1(その問題点)

  Ryoji Kato; Hidetoshi Hayashi  がん分子標的治療  16-  (1)  61  -65  2018/03
• 原発不明がんにおける腫瘍微小免疫環境と予後の関連性

  原谷浩司; 林秀敏; 高濱隆幸; 澤田貴宏; 中村靖司; 伊藤彰彦; 千葉康敬; 谷崎潤子; 藤田至彦; 坂井和子; 西尾和人; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  16th-  2018
• ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討

  田中薫; 谷崎潤子; 野長瀬祥兼; 原谷浩司; 酒井瞳; 林秀敏; 中川和彦; 坂井和子; 西尾和人  肺癌(Web)  58-  (5)  2018
• 【がん免疫療法の展開】がん免疫療法の展開 抗PD-1抗体の臨床成績と問題点

  林 秀敏  Vita  35-  (1)  58  -63  2018/01
• heregulin発現HER2陽性乳癌・胃癌における抗HER2薬ラパチニブ,トラスツズマブ,T‐DM1の感受性に関する研究

  野長瀬祥兼; 米阪仁雄; 川上尚人; 渡邉諭美; 原谷浩司; 高濱隆幸; 武川直樹; 植田勲人; 谷崎潤子; 林秀敏; 吉田健史; 武田真幸; 千葉康敬; 田村孝雄; 中川和彦; 鶴谷純司  日本乳癌学会学術総会プログラム・抄録集  42-  (3-4)  25A  -25A  2017/12
• ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例

  武田 真幸; 林 秀敏; 田中 薫; 中川 和彦; 坂井 和子; 西尾 和人  肺癌  57-  (7)  880  -881  2017/12
• Trousseau症候群とDICを合併した肺腺癌にgefitinibが奏功した1例

  野長瀬 祥兼; 武田 真幸; 田中 薫; 吉田 健史; 林 秀敏; 中川 和彦  肺癌  57-  (7)  879  -879  2017/12
• ニボルマブ投与後に腫瘍周囲のすりガラス陰影とともにpseudoprogressionを呈した肺腺癌の1例

  加藤 了資; 林 秀敏; 谷崎 潤子; 田中 薫; 武田 真幸; 中川 和彦  肺癌  57-  (7)  885  -885  2017/12
• S-1 as an option for second-line treatment of NSCLC. Is the 'East Side Story' applicable in the West?

  H. Hayashi; T. Mitsudomi  ANNALS OF ONCOLOGY  28-  (11)  2627  -2629  2017/11
• 注目の新薬 キイトルーダ(ペムブロリズマブ)

  原谷 浩司; 林 秀敏  診断と治療 = Diagnosis and treatment  105-  (11)  1465  -1470  2017/11
• Combined Safety Analysis for Japanese in Domestic Phase 1, Phase 1b and International Phase 2/3 Trials of Pembrolizumab

  Atsushi Horiike; Hideo Saka; Hiroshi Tanaka; Terufumi Kato; Naoya Yamazaki; Kazuhiko Yamada; Kenji Yokota; Shunichi Sugawara; Kazuo Noguchi; Hidetoshi Hayashi  ANNALS OF ONCOLOGY  28-  2017/10
• Gene expression and mutation profiling for cancer of unknown primary

  Hidetoshi Hayashi; Shuta Tomida; Yoshihiko Fujita; Yosuke Togashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa  ANNALS OF ONCOLOGY  28-  2017/10
• Phase I study of TAS-121, a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC)

  H. Murakami; Y. Ohe; T. Hida; H. Sakai; K. Kasahara; F. Imamura; T. Baba; K. Kubota; Y. Hosomi; T. Shimokawa; H. Hayashi; K. Miyadera; T. Tamura; M. Nishio  ANNALS OF ONCOLOGY  28-  2017/09
• ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例

  武田 真幸; 林 秀敏; 田中 薫; 坂井 和子; 西尾 和人; 中川 和彦  肺癌  57-  (5)  545  -545  2017/09
• 【複合がん免疫療法】 肺がんにおけるEGFR遺伝子変異と免疫チェックポイント阻害薬

  林 秀敏; 光冨 徹哉  癌と化学療法  44-  (9)  722  -726  2017/09
• まれなEGFR遺伝子変異L861QおよびS768I陽性非小細胞性肺癌に対する最適なEGFR阻害剤の選択

  坂野 恵里; 冨樫 庸介; 中村 雄; 千葉 眞人; 小林 祥久; 林 秀敏; 谷崎 潤子; 寺嶋 雅人; デ・ベラスコ・マルコ A; 坂井 和子; 藤田 至彦; 光冨 徹哉; 西尾 和人  日本癌学会総会記事  76回-  YSA  -4  2017/09
• ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例

  武田 真幸; 林 秀敏; 田中 薫; 坂井 和子; 西尾 和人; 中川 和彦  肺癌  57-  (5)  545  -545  2017/09
• heregulin発現HER2陽性乳癌・胃癌における抗HER2薬ラパチニブ、トラスツズマブ、T-DM1の感受性に関する研究

  野長瀬 祥兼; 米阪 仁雄; 川上 尚人; 渡邉 諭美; 原谷 浩司; 高濱 隆幸; 武川 直樹; 植田 勲人; 谷崎 潤子; 林 秀敏; 吉田 健史; 武田 真幸; 千葉 康敬; 田村 孝雄; 中川 和彦; 鶴谷 純司  日本乳癌学会総会プログラム抄録集  25回-  (3)  559  -559  2017/07
• Emerging strategies for the treatment of advanced non-small cell lung cancer with EGFR mutation

  林 秀敏  近畿大学医学雑誌 = Medical Journal of Kindai University  42-  (1)  49  -53  2017/06
• osimertinibが奏効したEGFR T790M変異陽性肺腺癌、癌性髄膜炎の1例

  酒井 瞳; 林 秀敏; 岩朝 勤; 武田 真幸; 中川 和彦  肺癌  57-  (3)  242  -242  2017/06
• 進行非小細胞肺癌に対する微量心嚢水の予後に関する検討

  加藤 了資; 林 秀敏; 酒井 瞳; 原谷 浩司; 高濱 隆幸; 岩朝 勤; 田中 薫; 武田 真幸; 中川 和彦; 千葉 康敬  肺癌  57-  (3)  253  -253  2017/06
• Alectinib(Alec)に耐性化したALK陽性肺癌にCeritinib(Ceri)が奏効した1例

  幕内 陽介; 林 秀敏; 原谷 浩司; 谷崎 潤子; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人; 清水 重喜; 伊藤 彰彦  肺癌  57-  (3)  237  -237  2017/06
• EGFR遺伝子変異陽性非小細胞肺癌におけるニボルマブの有効性と効果予測因子の解析

  原谷 浩司; 林 秀敏; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖  肺癌  57-  (3)  239  -239  2017/06
• Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation positive non-small cell lung cancer.

  Shunichi Sugawara; Koichi Azuma; Makoto Nishio; Hidetoshi Hayashi; Katsuyuki Kiura; Miyako Satouchi; Toyoaki Hida; Atsushi Nakamura; Yasuo Iwamoto; Akira Inoue; Koji Takeda; Satoshi Ikeda; Tomoki Nakagawa; Seitaro Asahina; Kanji Komatsu; Satoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa  JOURNAL OF CLINICAL ONCOLOGY  35-  2017/05
• Estimated risks of recurrence and mortality in lung cancer: comprehensive analysis by a population-based study

  Junko Tanizaki; Hidetoshi Hayashi; Kazuhiko Nakagawa  TRANSLATIONAL CANCER RESEARCH  6-  S39  -S41  2017/02
• EGFR遺伝子変異陽性非小細胞肺癌におけるEGFR-TKI耐性後T790M変異有無によるニボルマブ治療効果と腫瘍微小免疫環境の後向き検討

  原谷浩司; 林秀敏; 田中妙; 金田裕靖; 冨樫庸介; 坂井和子; 吉岡弘鎮; 光冨徹哉; 西尾和人; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  15th-  2017
• EGFR遺伝子変異陽性非小細胞肺癌におけるニボルマブの有効性と効果予測因子の解析

  原谷浩司; 林秀敏; 武田真幸; 中川和彦; 坂井和子; 西尾和人; 金田裕靖  肺癌(Web)  57-  (3)  2017
• Alectinib(Alec)に耐性化したALK陽性肺癌にCeritinib(Ceri)が奏効した1例

  幕内陽介; 林秀敏; 原谷浩司; 谷崎潤子; 武田真幸; 中川和彦; 坂井和子; 西尾和人; 清水重喜; 伊藤彰彦  肺癌(Web)  57-  (3)  2017
• ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例

  武田真幸; 林秀敏; 田中薫; 中川和彦; 坂井和子; 西尾和人  肺癌(Web)  57-  (7)  2017
• The Association between the Percentage of Anaplastic Lymphoma Kinase(ALK)-Positive Cells and Efficacy of ALK Inhibitor

  Tae Tanaka; Hiroshige Yoshioka; Koji Haratani; Hidetoshi Hayashi; Kunio Okamoto; Toshihiko Kaneda; Toshihide Yokoyama; Masayuki Takeda; Hiroyasu Kaneda; Kazuhiko Nakagawa; Tadashi Ishida  JOURNAL OF THORACIC ONCOLOGY  12-  (1)  S1162  -S1162  2017/01
• ASP8273 Tolerability and Antitumor Activity in TKI-Naive Japanese Subjects with EGFRmut plus NSCLC: Preliminary Results

  Makoto Nishio; Koichi Azuma; Hidetoshi Hayashi; Toyoaki Hida; Akira Inoue; Yasuo Iwamoto; Satoshi Ikeda; Katsuyuki Kiura; Miyako Satouchi; Shunichi Sugawara; Koji Takeda; Desai Bhardwaj; Anne Keating; Kanji Komatsu; Maiko Morishita; Kentaro Takeda; Satoshi Morita; Masahiro Fulmoka; Kazuhiko Nakagawa  JOURNAL OF THORACIC ONCOLOGY  12-  (1)  S1243  -S1244  2017/01
• Clinical Outcome of Node-Negative Oligometastatic Non-Small Cell Lung Cancer

  Masayuki Takeda; Kiyohiro Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Tetsuya Mitsudomi; Atsuko Koyama; Kazuhiko Nakagawa  JOURNAL OF THORACIC ONCOLOGY  12-  (1)  S892  -S893  2017/01
• 尿崩症を初発症状とした肺小細胞癌下垂体転移の1例

  加藤了資; 酒井瞳; 原谷浩司; 高濱隆幸; 谷崎潤子; 吉田健史; 岩朝勤; 田中薫; 林秀敏; 武田真幸; 中川和彦; 古川健太郎; 奥田武司  肺癌(Web)  56-  (7)  1072(J‐STAGE)  -1072  2016/12
• ニボルマブ投与でpseudoprogressionを認めた肺腺癌の2例

  谷崎 潤子; 林 秀敏; 田中 薫; 岩朝 勤; 武田 真幸; 中川 和彦  肺癌  56-  (7)  1067  -1067  2016/12
• 尿崩症を初発症状とした肺小細胞癌下垂体転移の1例

  加藤 了資; 酒井 瞳; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 吉田 健史; 岩朝 勤; 田中 薫; 林 秀敏; 武田 真幸; 中川 和彦; 古川 健太郎; 奥田 武司  肺癌  56-  (7)  1072  -1072  2016/12
• ニボルマブ投与でpseudoprogressionを認めた肺腺癌の2例

  谷崎 潤子; 林 秀敏; 田中 薫; 岩朝 勤; 武田 真幸; 中川 和彦  肺癌  56-  (7)  1067  -1067  2016/12
• 尿崩症を初発症状とした肺小細胞癌下垂体転移の1例

  加藤 了資; 酒井 瞳; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 吉田 健史; 岩朝 勤; 田中 薫; 林 秀敏; 武田 真幸; 中川 和彦; 古川 健太郎; 奥田 武司  肺癌  56-  (7)  1072  -1072  2016/12
• FGFR T790M変異陽性肺腺癌、癌性髄膜炎にosimertinibを投与した1例

  酒井 瞳; 林 秀敏; 岩朝 勤; 武田 真幸; 中川 和彦  肺癌  56-  (7)  1077  -1077  2016/12
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 西尾 和人; 中川 和彦  近畿大学医学雑誌  41-  (3-4)  19A  -19A  2016/12
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人  近畿大学医学雑誌  41-  (3-4)  20A  -20A  2016/12
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 西尾 和人; 中川 和彦  近畿大学医学雑誌  41-  (3-4)  19A  -19A  2016/12
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人  近畿大学医学雑誌  41-  (3-4)  20A  -20A  2016/12
• EGFR‐TKI既治療EGFR遺伝子変異陽性非小細胞肺癌におけるニボルマブの治療成績

  林秀敏; 原谷浩司; 田中薫; 長谷川喜一; 工藤慶太; 金田裕靖; 武田真幸; 中川和彦  日本肺癌学会総会号  57th-  (6)  801  -801  2016/11
• 局所進行性NSCLC患者におけるCDDPとTRTを併用したnab-パクリタキセル療法の第I/II相試験(Phase I/II study of nab-paclitaxel with CDDP and TRT in patients with locally advanced NSCLC)

  倉田 宝保; 林 秀敏; 小倉 昌和; 丹羽 崇; 横井 崇; 田村 洋輔; 藤阪 保仁; 金田 裕靖; 吉岡 弘鎮; 中川 和彦  肺癌  56-  (6)  540  -540  2016/11
• 組織型転化を来したEGFR・ALK陽性肺癌症例の臨床的検討

  田中薫; 谷崎潤子; 加藤了資; 原谷浩司; 武川直樹; 高濱隆幸; 岩朝勤; 林秀敏; 武田真幸; 中川和彦  日本肺癌学会総会号  56-  (6)  572  -572  2016/11
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 西尾 和人; 中川 和彦  肺癌  56-  (6)  637  -637  2016/11
• Current status of 3rd generation EGFR-TKI, osimertinib : results of clinical trials

  林 秀敏  腫瘍内科 = Clinical oncology  18-  (4)  357  -361  2016/10
• 原発不明癌の治療のための標的分子の探索

  藤田 至彦; 坂井 和子; 倉田 宝保; 寺嶋 雅人; 林 秀敏; 中川 和彦; 西尾 和人  日本癌学会総会記事  75回-  P  -2111  2016/10
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 高濱 隆幸; 吉田 健史; 岩朝 勤; 光冨 徹哉; 伊藤 彰彦; 西尾 和人; 中川 和彦  日本癌学会総会記事  75回-  J  -1063  2016/10
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 高濱 隆幸; 吉田 健史; 岩朝 勤; 光冨 徹哉; 伊藤 彰彦; 西尾 和人; 中川 和彦  日本癌学会総会記事  75回-  J  -1063  2016/10
• 原発不明癌の治療のための標的分子の探索

  藤田 至彦; 坂井 和子; 倉田 宝保; 寺嶋 雅人; 林 秀敏; 中川 和彦; 西尾 和人  日本癌学会総会記事  75回-  P  -2111  2016/10
• Heregulin-induced resistance against HER2-targeted therapies in HER2 positive breast and gastric cancer in vitro and in vivo

  Yoshikane Nonagase; Kimio Yonesaka; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Haruka Sakamoto; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani  CANCER RESEARCH  76-  2016/07
• 下咽頭癌頸部リンパ節転移に対して先行頸部郭清術を施行した症例の検討

  北野 睦三; 木村 隆幸; 西原 美沙子; 白石 功; 森川 大樹; 小林 孝光; 速水 康介; 藤原 良平; 石川 一樹; 横川 正樹; 高濱 隆幸; 吉田 健史; 林 秀敏; 田中 薫; 土井 勝美  頭頸部癌  42-  (2)  170  -170  2016/05
• s状結腸がん肝転移治癒切施行後,StageI小細胞肺癌を合併した1例

  奥野達哉; 野長瀬祥兼; 武川直樹; 植田勲人; 田中薫; 林秀敏; 武田真幸; 清水俊雄; 鶴谷純司; 田村孝雄; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  14th-  2016
• HER2陽性乳癌・胃癌における抗HER2薬に対するHeregulinによる薬剤耐性に関する研究

  野長瀬祥兼; 米阪仁雄; 渡邉諭美; 武川直樹; 川上尚人; 林秀敏; 武田真幸; 田村孝雄; 中川和彦; 鶴谷純司  日本臨床腫瘍学会学術集会(CD-ROM)  14th-  2016
• ニボルマブ投与でpseudoprogressionを認めた肺腺癌の2例

  谷崎潤子; 林秀敏; 田中薫; 岩朝勤; 武田真幸; 中川和彦  肺癌(Web)  56-  (7)  1067(J‐STAGE)  2016
• Successful treatment with HER2-targeting therapy beyond progression for HER2-positive Extramammary Paget's disease

  WATANABE Satomi; TAKEDA Masayuki; TAKAHAMA Takayuki; TANIZAKI Junko; IWASA Tsutomu; TSURUTANI Junji; HAYASHI Hidetoshi; SHIMIZU Toshio; WADA Yoshitaka; NAKAGAWA Kazuhiko  日本臨床腫瘍学会学術集会(CD-ROM)  14th-  ROMBUNNO.PF1‐045  2016
• 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; 岡本邦男; 岡本邦男; 金田裕靖; 金田裕靖; 田中薫; 武田真幸; 中川和彦; 藤原季美子; 長谷川喜一  肺癌(Web)  56-  (7)  1064(J‐STAGE)  2016
• アレクチニブ耐性後に小細胞癌転化をしたALK融合遺伝子陽性の肺腺癌の一例

  武川直樹; 林秀敏; 飯塚徳重; 高濱隆幸; 植田勲人; 田中薫; 武田真幸; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  14th-  ROMBUNNO.PF1‐032  2016
• Afatinib activity against head-and-neck or esophageal squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in head-and-neck squamous cell carcinoma

  Y. Togashi; Y. Nakamura; S. Tomida; H. Hayashi; M. A. de Velasco; K. Sakai; Y. Fujita; S. Hamada; K. Nishio  ANNALS OF ONCOLOGY  26-  97  -97  2015/12
• Safety and yield of real time ultrasound-assisted cutting needle biopsy performed by medical oncologist

  Kunio Okamoto; Satoru Mutsuo; Tae Tanaka; Souichi Fumita; Ryota Shintani; Hirofumi Kiyokawa; Genichi Kato; Hidetoshi Hayashi  ANNALS OF ONCOLOGY  26-  107  -108  2015/11
• Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS)

  Hidetoshi Hayashi; Shuta Tomida; Yosuke Togashi; Kazuko Sakai; Yoshihiko Fujita; Junji Tsurutani; Issei Kurahashi; Takayasu Kurata; Kazuhiko Nakagawa; Kazuto Nishio  ANNALS OF ONCOLOGY  26-  86  -86  2015/11
• Re-biopsy of twelve non small cell lung cancer (NSCLC) cases

  Tae Tanaka; Soichi Fumita; Kunio Okamoto; Ryota Shintani; Hirohumi Kiyokawa; Hidetoshi Hayashi  ANNALS OF ONCOLOGY  26-  113  -114  2015/11
• Bevacizumab beyond disease progression in advanced non-squamous NSCLC (WJOG 5910L): a randomized phase II trial

  Takashi Seto; Masayuki Takeda; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Takeharu Yamanaka; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto  ANNALS OF ONCOLOGY  26-  91  -91  2015/11
• Kinases and lung cacer 非小細胞肺癌における受容体チロシンキナーゼ遺伝子変異の探索と機能解析・問題点

  冨樫 庸介; 水内 寛; 林 秀敏; 小林 祥久; 中川 和彦; 光冨 徹哉; 西尾 和人  肺癌  55-  (5)  367  -367  2015/10
• 3. 当院における非小細胞肺癌に対するre-biopsyの検討(第97回 日本呼吸器内視鏡学会近畿支部会)

  田中 薫; 西田 諭美; 原谷 浩司; 野長瀬 祥兼; 高濱 隆幸; 吉田 健史; 岩朝 勤; 林 秀敏; 武田 真幸; 金田 裕靖; 中川 和彦  気管支学 : 日本気管支研究会雑誌  37-  (5)  2015/09
• Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinoma

  Y. Togashi; Y. Yoshioka; T. Chikugo; M. Terashima; T. Mizukami; H. Hayashi; K. Sakai; M. De Velasco; S. Tomida; Y. Fujita; K. Okuno; K. Nishio  EUROPEAN JOURNAL OF CANCER  51-  S390  -S390  2015/09
• 肺がんの治療法を知る 免疫療法 (特集 肺がん患者の治療とケア最前線)

  林 秀敏; 長崎 礼子; 中川 和彦  がん看護  20-  (6)  619  -622  2015/09
• Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

  T. Mizukami; Y. Togashi; E. Banno; M. Terashima; M. A. De Velasco; K. Sakai; H. Hayashi; Y. Fujita; S. Tomida; T. Eguchi Nakajima; N. Boku; A. Ito; K. Nakagawa; K. Nishio  EUROPEAN JOURNAL OF CANCER  51-  S46  -S46  2015/09
• Receptor tyrosine kinase mutations in non-small cell lung cancer

  H. Hayashi; Y. Togashi; M. Terashima; K. Sakai; H. Mizuuchi; Y. Kobayashi; K. Suda; K. Nakagawa; K. Nishio; T. Mitsudomi  EUROPEAN JOURNAL OF CANCER  51-  S601  -S601  2015/09
• Phase 2: Docetaxel with or without ramucirumab as therapy for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations after prior EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy

  K. Kasahara; K. Kiura; N. Nogami; K. Takayama; Y. Takiguchi; T. Hirashima; K. Aoe; H. Hayashi; H. Saka; K. Takahashi; F. Imamura; S. Oizumi; A. Inoue; M. Satouchi; M. Tatsumi; T. Nakamura; S. Enatsu; T. Tamura; K. Nakagawa  EUROPEAN JOURNAL OF CANCER  51-  S620  -S620  2015/09
• Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

  Yosuke Togashi; Akihiro Kogita; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Masayuki Kitano; Masatoshi Kudo; Kazuto Nishio  CANCER RESEARCH  75-  2015/08
• Melanoma transition is frequently accompanied by a loss of cytoglobin, a putative tumor suppressor, in melanocytes

  Yoshihiko Fujita; Satoshi Koinuma; Marco De Velasco; Bolz Jan; Yosuke Togashi; Masato Terashima; Hidetoshi Hayashi; Takuya Matsuo; Kazuto Nishio  CANCER RESEARCH  75-  2015/08
• ROS1融合遺伝子陽性肺腺癌に対してCBDCA+PTX+Bevacizumabによって長期奏効が得られた1例

  岡本 邦男; 文田 壮一; 金田 裕靖; 林 秀敏; 武田 真幸; 清水 俊雄; 中川 和彦  肺癌  55-  (4)  310  -310  2015/08
• Alectinibによる治療後に小細胞肺癌・扁平上皮癌への形質転換を認めたALK融合遺伝子陽性肺癌の1例

  高濱 隆幸; 林 秀敏; 武川 直樹; 植田 勲人; 吉田 健史; 岩朝 勤; 田中 薫; 武田 真幸; 中川 和彦  肺癌  55-  (4)  316  -316  2015/08
• 活性型ALK遺伝子変異を有するALK免疫染色陽性/FISH陰性のまれな肺腫瘍

  冨樫 庸介; 寺嶋 雅人; 坂井 和子; 林 秀敏; 西尾 和人; 水内 寛; 小林 祥久; 光冨 徹哉  肺癌  55-  (4)  304  -304  2015/08
• KRAS遺伝子変異陽性肺癌の臨床的特徴

  林 秀敏; 武田 真幸; 金田 裕靖; 鶴谷 純司; 中川 和彦; 寺嶋 雅人; 坂井 和子; 西尾 和人  肺癌  55-  (4)  311  -311  2015/08
• FOLFIRINOX療法におけるコリン作動性症状の発現調査

  中野由紀; 中川雅史; 泉本裕美; 岡本邦男; 文田壮一; 田中妙; 西出貴義; 井出朋子; 上田祥子; 林秀敏; 樫葉利人  医療薬学フォーラム講演要旨集  23rd-  317  2015/06
• Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy inadvanced nonsquamous non-small cell lung cancer (WJOG 5910L): An open-label, randomized, phase II trial.

  Masayuki Takeda; Takashi Seto; Hidetoshi Hayashi; Morihito Okada; Koichi Azuma; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Haruhiro Saito; Akihito Kubo; Toshiyuki Sawa; Eiji Miyahara; Naoyuki Nogami; Takeharu Yamanaka; Yoichi Nakanishi; Kazuhiko Nakagawa; Isamu Okamoto  JOURNAL OF CLINICAL ONCOLOGY  33-  (15)  2015/05
• 非小細胞肺癌 基礎研究 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 坂井 和子; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 岡部 崇記; 林 秀敏; 岡本 邦男; 金田 裕靖; 清水 俊雄; 西尾 和人; 中川 和彦  日本呼吸器学会誌  4-  (増刊)  146  -146  2015/03
• 間質性肺炎合併非小細胞肺癌(NSCLC with IP)に対するnab-Paclitaxel投与例の検討

  新谷 亮多; 清川 寛文; 加藤 元一; 林 秀敏; 田中 妙; 文田 壮一; 岡本 邦男  肺癌  55-  (1)  69  -69  2015/02
• 活性型ALK遺伝子変異を有するALK免疫染色陽性/FISH陰性のまれな肺腫瘍

  冨樫庸介; 寺嶋雅人; 坂井和子; 林秀敏; 西尾和人; 水内寛; 小林祥久; 光冨徹哉  肺癌(Web)  55-  (4)  2015
• KRAS遺伝子変異陽性肺癌の臨床的特徴

  林秀敏; 武田真幸; 金田裕靖; 鶴谷純司; 中川和彦; 寺嶋雅人; 坂井和子; 西尾和人; 金田裕靖  肺癌(Web)  55-  (4)  2015
• 当院における非小細胞肺癌に対するre‐biopsyの検討

  田中薫; 西田諭美; 原谷浩司; 野長瀬祥兼; 高濱隆幸; 吉田健史; 岩朝勤; 林秀敏; 武田真幸; 金田裕靖; 中川和彦  気管支学  37-  (5)  607  -607  2015
• 非小細胞肺癌に対するre‐biopsy症例の検討

  田中妙; 文田壮一; 岡本邦男; 新谷亮多; 清川寛文; 林秀敏  日本臨床腫瘍学会学術集会(CD-ROM)  13th-  ROMBUNNO.P1-4-53  2015
• ROS1融合遺伝子陽性肺腺癌に対してCBDCA+PTX+Bevacizumabによって長期奏効が得られた1例

  岡本邦男; 文田壮一; 金田裕靖; 林秀敏; 武田真幸; 清水俊雄; 中川和彦  肺癌(Web)  55-  (4)  310(J‐STAGE)  2015
• 転移性脳腫瘍との鑑別を要した脳膿瘍の1症例

  田中 妙; 岩下 和真; 岡 尚宏; 文田 壮一; 岡本 邦男; 林 秀敏  腫瘍内科  14-  (5)  514  -517  2014/11
• MEK INHIBITORS ARE EFFECTIVE AGAINST GASTRIC CANCER CELL LINES WITH ONCOGENIC MEK1 GENE MUTATIONS

  Yosuke Togashi; Shunsuke Sogabe; Hiroaki Kato; Masato Terashima; Hidetoshi Hayashi; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Takushi Yasuda; Kazuto Nishio  ANNALS OF ONCOLOGY  25-  2014/10
• THE RETROSPECTIVE STUDY FOR UNPLANNED HOSPITAL ADMISSION OF PATIENTS WITH CANCER WHO VISITED THE EMERGENCY DEPARTMENT

  Tae Tanaka; Hidetoshi Hayashi; Masataka Taguri; Soichi Fumita; Yoshio Matsuo  ANNALS OF ONCOLOGY  25-  2014/10
• CHRONIC NICOTINE EXPOSURE MEDIATES RESISTANCE TO EGFR-TKI IN EGFR-MUTATED LUNG CANCER VIA EGFR SIGNAL

  Hidetoshi Hayashi; Yosuke Togashi; Kunio Okamoto; Soichi Fumita; Masato Terashima; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio  ANNALS OF ONCOLOGY  25-  2014/10
• Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

  Yosuke Togashi; Hiroki Sakamoto; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Yoshihiko Fujita; Yasuo Kodera; Kazuko Sakai; Shuta Tomida; Masayuki Kitano; Masatoshi Kudo; Kazuto Nishio  CANCER RESEARCH  74-  (19)  2014/10
• CPFE合併肺癌に対する根治的化学放射線療法の安全性・有効性に関する後ろ向きコホート研究

  清川 寛文; 林 秀敏; 小倉 昌和; 田中 妙; 新谷 亮多; 文田 壮一; 内田 泰樹; 岡本 邦男; 三浦 幸樹; 松本 和也; 加藤 元一  肺癌  54-  (5)  405  -405  2014/10
• PS不良ALK陽性肺癌にCrizotinibを投与したが早期治療中止に至った2症例

  田中 妙; 林 秀敏; 新谷 亮多; 文田 壮一; 岡本 邦男; 清川 寛文; 三浦 幸樹; 松本 和也; 川島 正裕; 加藤 元一  肺癌  54-  (5)  472  -472  2014/10
• 肺扁平上皮がんの現状と展望 切除不能局所進行肺扁平上皮癌に対するDE-766+CDDP+VNR+胸部放射線療法の無作為化第III相試験

  田中 薫; 林 秀敏; 軒原 浩; 益田 典幸; 久保田 馨; 澤 祥幸; 高橋 利明; 野上 尚之; 高田 昇平; 早川 和重; 西村 泰昌; 山本 信之; 田村 友秀; 福岡 正博; 浅見 由美子; 井上 悟; 中川 和彦  肺癌  54-  (5)  286  -286  2014/10
• 肺癌に於ける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定

  武田 真幸; 清水 俊雄; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野長瀬 祥兼; 岡部 崇記; 林 秀敏; 岡本 邦男; 坂井 和子; 西尾 和人; 中川 和彦  肺癌  54-  (5)  364  -364  2014/10
• 新規ALK阻害剤であるアレクチニブはMET阻害剤との併用で効果が高まる

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人  肺癌  54-  (5)  403  -403  2014/10
• 低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人  肺癌  54-  (5)  470  -470  2014/10
• 喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺がんにおいてEGFR-TKIの耐性因子である

  林 秀敏; 冨樫 庸介; 岡本 邦男; 田中 妙; 文田 壮一; 新谷 亮多; 清川 寛文; 坂本 洋一; 寺嶋 雅人; de Velasco Marco A; 坂井 和子; 藤田 至彦; 冨田 秀太; 加藤 元一; 中川 和彦; 西尾 和人  肺癌  54-  (5)  626  -626  2014/10
• メラノサイトからメラノーマへの移行は、しばしばがん抑制因子であるサイトグロビンの発現低下を伴う(Cytoglobin, a putative tumor suppressor, is frequently lost in melanocyte during melanoma transition)

  藤田 至彦; 鯉沼 聡; デベラスコ・マルコ; ボルツ・ヤン; 富樫 庸介; 寺嶋 雅人; 林 秀敏; 松尾 拓哉; 西尾 和人  日本癌学会総会記事  73回-  P  -3066  2014/09
• MEK遺伝子変異を有する胃がんに対するMEK阻害剤の有効性(MEK inhibitor for gastric cancer with MEK1 gene mutations)

  冨樫 庸介; 加藤 寛章; 林 秀敏; 寺嶋 雅人; デベラスコ・マルコ; 坂井 和子; 藤田 至彦; 冨田 秀太; 安田 卓司; 西尾 和人  日本癌学会総会記事  73回-  P  -2349  2014/09
• Overview of PD-1 and PD-L1 inhibition

  林 秀敏; 岡本 勇  腫瘍内科  13-  (6)  767  -772  2014/06
• The retrospective study for unplanned hospital admission of patients with cancer who visited the emergency department

  Tae Tanaka; Hidetoshi Hayashi; Masataka Taguri; Soichi Fumita; Yoshio Matsuo  JOURNAL OF CLINICAL ONCOLOGY  32-  (15)  2014/05
• 転移性骨腫瘍が疑われ、放射線治療がなされた脊椎カリエスの1例

  内田 泰樹; 林 秀敏; 文田 壮一; 加藤 元一; 清川 寛文; 新谷 亮多; 三浦 幸樹; 松本 和也  結核  89-  (5)  584  -584  2014/05
• An open-label, dose-escalation, safety, and pharmacokinetics phase I study of ombrabulin, a vascular disrupting agent, administered as a 30-min intravenous infusion every 3 weeks in Japanese patients with advanced solid tumors

  H. Murakami; T. Kurata; Y. Onozawa; J. Watanabe; A. Ono; T. Takahashi; N. Yamamoto; Y. Fujisaka; H. Kiyota; H. Hayashi; K. Tanaka; K. Nakagawa; S. Kuroda  CANCER CHEMOTHERAPY AND PHARMACOLOGY  73-  (3)  623  -630  2014/03
• 扁平上皮癌に転化を来たしたT790M変異陽性肺癌に第3世代EGFR-TKI(CO-1686)が奏効した症例

  林秀敏; 林秀敏; 金田裕靖; 吉田健史; 清水俊雄; 古下義彦; 古下義彦; 飯塚徳重; ROLFE Lindsey; 加藤元一; 中川和彦  日本肺癌学会総会号  55th-  2014
• MEK1遺伝子変異を有する胃がん細胞株に対するMEK阻害剤の有効性と臨床サンプルの検討

  冨樫庸介; 曽我部俊介; 加藤寛章; 寺嶋雅人; 林秀敏; 林秀敏; 坂井和子; 藤田至彦; 冨田秀太; 安田卓志; 西尾和人  日本臨床腫瘍学会学術集会(CD-ROM)  12th-  2014
• 救急外来を受診した担癌患者の入院適応についての検討

  田中妙; 林秀敏; 田栗正隆; 文田壮一; 松尾吉郎  日本臨床腫瘍学会学術集会(CD-ROM)  12th-  ROMBUNNO.O1-16-3  2014
• 大阪泉州地域における原発不明癌の診療状況

  文田壮一; 林秀敏  日本臨床腫瘍学会学術集会(CD-ROM)  12th-  ROMBUNNO.P3-2-1  2014
• EGFR遺伝子変異陽性患者におけるEGFR阻害剤の耐性後の投与期間についての検討

  岡本邦男; 林秀敏; 高濱隆幸; 文田壮一; 田中薫; 加藤元一; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  12th-  ROMBUNNO.P3-15-4  2014
• ORAOV1 IS AMPLIFIED IN ESOPHAGEAL SQUAMOUS CELL CANCER AND RELATED TO TUMOR GROWTH AND POORLY DIFFERENTIATED TUMOR

  Y. Togashi; T. Arao; H. Kato; K. Matsumoto; M. Terashima; H. Hayashi; Y. Fujita; T. Yasuda; H. Shiozaki; K. Nishio  ANNALS OF ONCOLOGY  24-  2013/11
• PHASE I PHARMACOKINETIC STUDY OF S-1 GRANULE AND NEDAPLATIN FOR PATIENTS WITH RECURRENT/METASTATIC HEAD AND NECK CANCER

  K. Tanaka; H. Hayashi; I. Okamoto; S. Ueda; K. Okamoto; H. Kawakami; S. Nishina; M. Takeda; K. Doi; K. Nakagawa  ANNALS OF ONCOLOGY  24-  2013/11
• Metastatic apocrine carcinoma : long duration response to systemic chemotherapy

  林 秀敏  腫瘍内科  12-  (4)  487  -490  2013/10
• cIII期N2非小細胞肺癌の診断と治療戦略 EGFR遺伝子変異もしくはALK転座陽性、局所進行非小細胞肺癌における放射線治療の治療成績

  林 秀敏; 岡本 勇; 木村 英晴; 西村 恭昌; 西尾 和人; 中川 和彦  肺癌  53-  (5)  388  -388  2013/10
• 肺癌生物像に基づいた、新しい肺癌治療の戦略 EGFR遺伝子変異を有する肺癌においてβカテニンを阻害することでEGFR-TKIの効果が増強する

  冨樫 庸介; 林 秀敏; 寺嶋 雅人; 藤田 至彦; 坂井 和子; 冨田 秀太; 中川 和彦; 西尾 和人  肺癌  53-  (5)  397  -397  2013/10
• Prospective cohort study of serum sialylated glycoprotein (KL-6) as a prognostic marker in patients (pts) with non-small cell lung cancer (NSCLC) receiving gefitinib monotherapy: Okayama Lung Cancer Study Group 0703.

  Hiroshige Yoshioka; Katsuyuki Hotta; Isao Oze; Yoshiro Fujiwara; Hidetoshi Hayashi; Akihiro Nishiyama; Yohei Korogi; Nagio Takigawa; Mitsune Tanimoto; Katsuyuki Kiura  JOURNAL OF CLINICAL ONCOLOGY  31-  (15)  2013/05
• 中枢気道狭窄に対する気道ステントの症状緩和とQOLに対する有用性の検討

  田中 薫; 宮崎 昌樹; 岡本 邦男; 林 秀敏; 金田 裕靖; 鶴谷 純司; 岡本 勇; 中川 和彦  気管支学  35-  (Suppl.)  S245  -S245  2013/05
• 中枢気道狭窄に対する気道ステントの症状緩和とQOLに対する有用性の検討

  田中薫; 宮崎昌樹; 岡本邦男; 林秀敏; 清田秀美; 上田眞也; 金田裕靖; 鶴谷純司; 岡本勇; 中川和彦  日本内科学会雑誌  102-  (Suppl.)  282  -282  2013/02
• 進行・再発頭頸部扁平上皮癌に対するネダプラチン・S-1顆粒製剤の第I相臨床試験

  林 秀敏; 上田 眞也; 田中 薫; 岡本 勇; 中川 和彦  日本内科学会雑誌  102-  (Suppl.)  282  -282  2013/02
• Potential of combined-modality treatment using radiotherapy and molecular targeted agents for locally advanced NSCLC

  林 秀敏; 岡本 勇  腫瘍内科  11-  (1)  61  -66  2013/01
• 食道扁平上皮癌で高頻度に増幅しているORAOV1遺伝子は腫瘍増大と低分化な組織型に関与している

  冨樫庸介; 荒尾徳三; 加藤寛章; 松本和子; 寺嶋雅人; 林秀敏; 藤田至彦; 安田卓司; 塩崎均; 西尾和人  日本臨床腫瘍学会学術集会(CD-ROM)  11th-  2013
• EGFR,HER2及びHER3阻害剤AZD8931の第1相試験-進行固形癌患者対象の単独投与及び進行再発乳癌患者対象のパクリタキセル併用-

  鶴谷純司; 倉田宝保; 藤阪保仁; 岡本渉; 林秀敏; 川上尚人; 辛栄成; 林暢哉; 中川和彦  日本臨床腫瘍学会学術集会(CD-ROM)  11th-  2013
• 気管食道科領域における発癌のrisk factor : 気道系について : 肺がん,悪性胸膜中皮腫

  林 秀敏; 中川 和彦  専門医通信  (45)  1  -4  2012/11
• 【分子標的薬-がんから他疾患までの治癒をめざして-】 総論 分子標的治療薬とは

  林 秀敏; 西尾 和人  日本臨床  70-  (増刊8 分子標的薬)  7  -11  2012/11
• POSTPROGRESSION SURVIVAL FOR FIRST-LINE CHEMOTHERAPY IN PATIENTS WITH ADVANCED GASTRIC CANCER

  H. Kawakami; I. Okamoto; H. Hayashi; M. Taguri; S. Morita; K. Nakagawa  ANNALS OF ONCOLOGY  23-  95  -95  2012/10
• AMPLIFICATION OF OCT4-PSEUDOGENE POU5F1B IS A POOR PROGNOSTIC FACTOR IN GASTRIC CANCER

  H. Hayashi; T. Arao; K. Matsumoto; T. Nagai; H. Kimura; M. A. De Velasco; Y. Fujita; Y. Yamada; K. Nakagawa; K. Nishio  ANNALS OF ONCOLOGY  23-  112  -112  2012/10
• POSTPROGRESSION SURVIVAL FOR ADVANCED NSCLC

  H. Hayashi; I. Okamoto; M. Taguri; S. Morita; K. Nakagawa  ANNALS OF ONCOLOGY  23-  95  -95  2012/10
• CHARACTERISTICS OF HS6ST2 EXPRESSION IN COLORECTAL CANCER

  H. Kimura; S. Hatabe; T. Arao; H. Hayashi; K. Matsumoto; T. Nagai; Y. Fujita; H. Kato; K. Okuno; K. Nishio  ANNALS OF ONCOLOGY  23-  160  -160  2012/10
• PHASE I STUDY OF OMBRABULIN, A VASCULAR DISRUPTING AGENT (VDA), ADMINISTERED EVERY 3 WEEKS TO JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS

  T. Kurata; H. Murakami; Y. Fujisaka; H. Kiyota; H. Hayashi; K. Tanaka; K. Nakagawa; Y. Onozawa; J. Watanabe; N. Yamamoto; T. Aoyama  ANNALS OF ONCOLOGY  23-  110  -110  2012/10
• Evaluation of the Usefulness of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration in the Diagnosis of Hilar or Mediastinal Lymphadenopathy

  KANEDA Hiroyasu; MIYAZAKI Masaki; KIYOTA Hidemi; TANAKA Kaoru; HAYASHI Hidetoshi; TSURUTANI Junji; KURATA Takayasu; OKAMOTO Isamu; NAKAGAWA Kazuhiko  気管支学 : 日本気管支研究会雑誌 : the journal of the Japan Society for Bronchology  34-  (5)  423  -427  2012/09
• PHARMACOKINETICS (PK) AND SAFETY OF TESETAXEL, A NOVEL ORAL TAXANE, IN JAPANESE PATIENTS (PTS) WITH ADVANCED SOLID TUMORS

  K. Tanaka; T. Kurata; Y. Fujisaka; H. Kawakami; H. Hayashi; T. Cousin; W. Okamoto; T. Kudoh; T. Satoh; K. Nakagawa  ANNALS OF ONCOLOGY  23-  167  -167  2012/09
• FINAL RESULTS OF A JAPANESE PHASE 1 TRIAL EVALUATING A C-MET INHIBITOR TIVANTINIB IN COMBINATION WITH AN EGFR INHIBITOR ERLOTINIB IN ADVANCED/METASTATIC NON-SMALL CELL LUNG CANCER (ARQ 197-003/005 STUDY)

  N. Yamamoto; H. Murakami; T. Takahashi; H. Hayashi; Y. Fujisaka; T. Hirashima; K. Takeda; M. Satouchi; K. Nakagawa  ANNALS OF ONCOLOGY  23-  424  -424  2012/09
• 進行肺腺癌を対象としたGefitinib/S-1併用療法第I相臨床試験

  清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋 応顕; 藤阪 保仁; 鶴谷 純司; 宮崎 昌樹; 倉田 宝保; 中川 和彦  近畿大学医学雑誌  37-  (3)  139  -147  2012/09
• OCT4偽遺伝子であるPOU5F1Bの増殖は胃がんにおいて予後不良因子である(Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer)

  林 秀敏; 荒尾 徳三; 松本 和子; 永井 知行; 木村 英晴; デベラスコ・マルコ; 藤田 至彦; 山田 康秀; 中川 和彦; 西尾 和人  日本癌学会総会記事  71回-  186  -186  2012/08
• 大腸がんにおけるHS6ST2発現とその臨床的意義(Characteristics of HS6ST2 expression in colorectal cancer)

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人  日本癌学会総会記事  71回-  348  -348  2012/08
• 食道扁平上皮癌におけるEGFR、HER2、FGFR2、METの遺伝子増幅(Gene amplification of EGFR, HER2, FGFR2, and MET in esophageal squamous cell carcinoma)

  加藤 寛章; 荒尾 徳三; 林 秀敏; 吉田 修平; 永井 知行; 松本 和子; 藤田 至彦; 木村 英晴; 安田 卓司; 奥野 清隆; 塩崎 均; 西尾 和人  日本癌学会総会記事  71回-  369  -369  2012/08
• EGFR-Mutation

  林 秀敏; 岡本 勇  最新医学  67-  1433  -1442  2012/06
• 中枢気道狭窄に対する気道ステントの症状緩和とQOLに対する有用性の検討

  田中 薫; 宮崎 昌樹; 谷崎 潤子; 牧村 ちひろ; 岡本 邦男; 清田 秀美; 林 秀敏; 松岡 弘道; 上田 眞也; 鶴谷 純司; 中川 和彦  日本緩和医療学会学術大会プログラム・抄録集  17回-  307  -307  2012/06
• 【分子標的治療薬の服薬指導のポイント】 分子標的治療薬とは

  林 秀敏; 西尾 和人  調剤と情報  18-  (6)  819  -822  2012/06
• Detection of EGFR T790M mutation in non-small-cell lung cancer patients using colony hybridization assay

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Hidetoshi Hayashi; Kazuyuki Furuta; Hiroaki Kato; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; Kazuto Nishio  CANCER RESEARCH  72-  2012/04
• Amplification of OCT4-pseudogene POU5F1B is a poor prognostic factor in gastric cancer

  Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Tomoyuki Nagai; Hideharu Kimura; Marco A. De Velasco; Yoshihiko Fujita; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio  CANCER RESEARCH  72-  2012/04
• Characteristics of HS6ST2 expression in colorectal cancer

  Hideharu Kimura; Shigeru Hatabe; Tokuzo Arao; Hidetoshi Hayashi; Tomoyuki Nagai; Kazuko Matsumoto; Yoshihiko Fujita; Masao Fukushima; Akihiko Ito; Kiyotaka Okuno; Kazuto Nishio  CANCER RESEARCH  72-  2012/04
• 【肺癌UPDATE】 肺癌の分子生物学 分子標的治療のバイオマーカー

  林 秀敏; 西尾 和人  医学のあゆみ  240-  (13)  1072  -1077  2012/03
• 【癌の抗血管新生療法】 抗血管新生薬の開発

  林 秀敏; 西尾 和人  血管医学  13-  (1)  11  -17  2012/02
• FGFR阻害薬によるCD133の発現制御機構の解析

  松本和子; 荒尾徳三; 吉田修平; 林秀敏; 藤田至彦; 加藤寛章; 永井知行; 木村英晴; 西尾和人  日本臨床腫瘍学会学術集会プログラム・抄録集  10th-  2012
• ソラフェニブの上皮間葉移行阻害効果

  永井知行; 永井知行; 木村英晴; 荒尾徳三; 松本和子; 藤田至彦; 吉田修平; 林秀敏; 工藤正俊; 西尾和人  日本臨床腫瘍学会学術集会プログラム・抄録集  10th-  2012
• Snailに誘導される上皮間葉移行とチュブリン作用系抗癌剤の感受性

  吉田修平; 田村大介; 荒尾徳三; 松本和子; 木村英晴; 藤田至彦; 林秀敏; 林秀敏; 永井知行; 金田裕靖; 西尾和人  日本臨床腫瘍学会学術集会プログラム・抄録集  10th-  2012
• インフォームドコンセントのための図説シリーズ「肺がん：抗悪性腫瘍薬（改訂版）」

  西條 長宏; 岡本 勇; 西村 恭昌; 林 秀敏; 静岡県静岡がんセンター副院長; 呼吸器内科部長; 国立がん研究センター東病院; 呼吸器内科外来医長  2011/10
• 大腸がんにおけるHS6ST2発現とその臨床的特徴(Characteristics of HS6ST2 Expression in Colorectal Cancer)

  木村 英晴; 波多邉 繁; 荒尾 徳三; 林 秀敏; 永井 知行; 松本 和子; 工藤 可苗; 藤田 至彦; 伊藤 彰彦; 奥野 清隆; 西尾 和人  日本癌学会総会記事  70回-  235  -235  2011/09
• First-in-human phase I study of the antiangiogenic vaccine (OTS11101) targeting VEGFR-1 in patients with solid tumors.

  H. Hayashi; T. Kurata; Y. Fujisaka; T. Satoh; M. Takeda; M. Miyazaki; T. Okabe; H. Kiyota; K. Tanaka; T. Tsunoda; K. Nakagawa  JOURNAL OF CLINICAL ONCOLOGY  29-  (15)  2011/05
• Treatment of non-small cell lung cancer, critical role of histology

  林 秀敏; 岡本 勇  Respiratory medicine  19-  (4)  293  -299  2011/04
• 化学療法--非小細胞癌の治療 (肺がんのすべて) -- (肺がんの病態と治療)

  林 秀敏; 岡本 勇  からだの科学  (270)  93  -97  2011
• 切除不能・進行再発胃癌に対するXP療法の検討

  川上尚人; 上田眞也; 工藤敏啓; 佐藤太郎; 岡部崇記; 林秀敏; 清田秀美; 寺嶋応顕; 武田真幸; 藤阪保仁; 宮崎昌樹; 鶴谷純司; 倉田宝保; 岡本勇; 中川和彦  日本臨床腫瘍学会学術集会プログラム・抄録集  9th-  2011
• 当科におけるEBUS-TBNA症例の検討(EBUS-TBNAで確定診断に至らなかった症例を中心に)

  清田 秀美; 宮崎 昌樹; 谷崎 潤子; 文田 壮一; 牧村 ちひろ; 岡本 邦男; 竹澤 健; 吉田 健史; 田中 薫; 林 秀敏; 岡部 崇記; 岡本 渉; 寺嶋 応顕; 金田 裕靖; 武田 真幸; 上田 眞也; 藤阪 保仁; 鶴谷 純司; 佐藤 太郎; 岡本 勇; 倉田 宝保; 中川 和彦  気管支学  33-  (0)  S185  -S185  2011
• 根治切除・照射不能進行食道がんに対する化学療法と局所食道放射線併用療法

  上田眞也; 佐藤太郎; 川上尚人; 工藤敏啓; 林秀敏; 清田秀美; 武田真幸; 宮崎昌樹; 岡本勇; 中川和彦  日本消化管学会総会学術集会プログラム・抄録集  7th-  287  2011
• State of the Art 非小細胞肺癌の治療戦略 EGFR-TKIに関する最近の知見

  林 秀敏; 岡本 勇  外来癌化学療法  1-  (2)  102  -106  2010/10
• PHASE II STUDY OF IRINOTECAN (CPT-11) IN PATIENTS (PTS) WITH PREVIOUSLY TREATED METASTATIC BREAST CANCER (MBC): KMBOG0601

  H. Hayashi; J. Tsurutani; T. Satoh; J. Sakamoto; N. Masuda; Y. Tokunaga; M. Yamaguchi; S. Tominaga; M. Fukuoka; K. Nakagawa  ANNALS OF ONCOLOGY  21-  121  -121  2010/10
• 進行肺腺癌を対象としたゲフィチニブ/S-1併用療法第I相臨床試験

  清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋 応顕; 東 公一; 武田 真幸; 米坂 仁雄; 藤坂 保仁; 鶴谷 純司; 宮崎 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦; 駄賀 晴子; 武田 晃司; 内藤 立暁; 山本 信之  肺癌  50-  (5)  502  -502  2010/10
• 外来化学療法は安全に施行可能である

  藤阪保仁; 林秀敏; 清田秀美; 牧村ちひろ; 田中薫; 武田真幸; 東公一; 上田眞也; 米阪仁雄; 宮崎昌樹; 鶴谷純司; 佐藤太郎; 岡本勇; 倉田宝保; 中川和彦  日本癌治療学会誌  45-  (2)  582  -582  2010/09
• 根治切除・照射不能進行食道がんに対する化学療法と局所食道放射線併用療法

  上田眞也; 佐藤太郎; 川上尚人; 田中薫; 林秀敏; 清田秀美; 武田真幸; 東公一; 米坂仁雄; 藤阪保仁; 鶴谷純司; 宮崎昌樹; 岡本勇; 倉田宝保; 中川和彦  日本癌治療学会誌  45-  (2)  990  -990  2010/09
• 進行肺腺癌を対象としたゲフィチニブ/S‐1併用療法第I相臨床試験

  清田秀美; 岡本勇; 谷崎潤子; 文田壮一; 岡本邦男; 牧村ちひろ; 竹澤健; 田中薫; 林秀敏; 岡本渉; 寺嶋応顕; 東公一; 金田裕靖; 武田真幸; 上田眞也; 米坂仁雄; 藤坂保仁; 鶴谷純司; 宮崎昌樹; 佐藤太郎; 倉田宝保; 中川和彦; 駄賀晴子; 武田晃司  肺癌  50-  (4)  400  -400  2010/08
• Molecular target therapy for elderly cancer patients (特集 高齢化社会における癌治療最前線)

  林 秀敏; 中川 和彦  成人病と生活習慣病  40-  (5)  479  -483  2010/05
• TS-1が有効であったPS不良の重症転移性乳癌の一例

  牧村 ちひろ; 東 公一; 林 秀敏; 田中 薫; 清田 秀美; 倉田 宝保; 藤阪 保仁; 佐藤 太郎; 鶴谷 純司; 橋本 幸彦; 乾 浩己; 綿谷 正弘; 岡本 勇; 中川 和彦  日本乳癌学会総会プログラム抄録集  18回-  571  -571  2010/05
• 外来化学療法は安全に施行可能である

  林秀敏; 藤阪保仁; 岡本勇; 倉田宝保; 佐藤太郎; 宮崎昌樹; 鶴谷純司; 中川和彦  日本内科学会雑誌  99-  (Suppl.)  247  -247  2010/02
• 原発不明がん (がん治療最前線--米国癌学会(ASCO)のトピックスを中心に) -- (臓器部位別の治療戦略)

  林 秀敏; 中川 和彦  がん治療レクチャー  1-  (1)  157  -161  2010
• ゾレドロン酸単剤で多臓器転移巣に対して抗腫瘍効果を認めた原発不明がんの一例

  鶴谷純司; 岡本邦男; 牧村ちひろ; 東公一; 武田真幸; 竹澤健; 岡本渉; 清田秀美; 林秀敏; 田中薫; 谷崎潤子; 岡本勇; 西條長宏; 福岡正博; 中川和彦  日本臨床腫瘍学会学術集会プログラム・抄録集  8th-  2010
• 前化学療法歴を有する切除不能・再発頭頚部癌に対するDoc療法

  上田眞也; 佐藤太郎; 中川和彦; 倉田宝保; 岡本勇; 鶴谷純司; 宮崎昌樹; 米坂仁雄; 藤坂保仁; 清水俊雄; 武田真幸; 田中薫; 東公一; 清田秀美; 林秀敏  日本臨床腫瘍学会学術集会プログラム・抄録集  8th-  2010
• EGFR遺伝子変異を認めない再発肺非小細胞癌患者に対するエルロチニブ療法の第2相試験

  堀田 勝幸; 木浦 勝行; 瀧川 奈義夫; 田端 雅弘; 八杉 昌幸; 尾瀬 功; 越智 宣昭; 原田 大二郎; 吉岡 弘鎮; 林 秀敏; 岩破 将博; 久山 彰一; 張田 信吾; 岡田 俊明; 畝川 芳彦; 野上 尚之; 梅村 茂樹; 亀井 治人; 別所 昭宏; 谷本 光音  肺癌  49-  (5)  593  -593  2009/10
• 再発肺非小細胞癌に対するドセタキセルとドセタキセル+S-1併用の無作為化第2相試験

  吉岡 弘鎮; 林 秀敏; 畝川 芳彦; 野上 尚之; 尾瀬 功; 加藤 有加; 新海 哲; 川井 治之; 前田 忠志; 細川 忍; 松尾 恵太郎; 瀧川 奈義夫; 田端 雅弘; 木浦 勝行; 谷本 光音  日本癌治療学会誌  44-  (2)  537  -537  2009/09
• Phase II study of amrubicin (AMR) in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy: preliminary results of West Japan Thoracic Oncology Group study (WJTOG0401)

  Shigeki Mitsuoka; Hiroyasu Kaneda; Hidetoshi Hayashi; Toshiyuki Sawa; Isao Goto; Kenji Akita; Hiroshi Saito; Kazuhiko Shibata; Isamu Okamoto; Kazuhiko Nakagawa  JOURNAL OF THORACIC ONCOLOGY  4-  (9)  S449  -S449  2009/09
• Phase II study of amrubicin (AMR) in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy: WJTOG0401

  H. Hayashi; H. Kaneda; I. Okamoto; M. Miyazaki; S. Kudoh; T. Sawa; K. Takeda; S. Negoro; Y. Iwamoto; K. Nakagawa  JOURNAL OF CLINICAL ONCOLOGY  27-  (15)  2009/05
• Evaluation of erlotinib treatment after gefitinib failure in Japanese recurrent non-small cell lung cancer patients

  A. Hata; S. Nanjo; R. Kaji; S. Hujita; N. Katakami; T. Nishimura; K. Ishihara; H. Yoshioka; H. Hayashi; T. Ishida  JOURNAL OF CLINICAL ONCOLOGY  27-  (15)  2009/05
• P-128 既治療進行非小細胞肺癌に対するCPT-11+TS-1併用化学療法の検討(化学療法2,第49回日本肺癌学会総会号)

  横山 俊秀; 吉岡 弘鎮; 岩破 将博; 山本 正樹; 林 秀敏; 橋本 徹; 石田 直  肺癌  48-  (5)  521  -521  2008/10
• P-100 進行非小細胞肺癌におけるゲフィチニブ使用にて画像および腫瘍マーカー上にて奏効が得られた症例の検討(分子標的治療2,第49回日本肺癌学会総会号)

  林 秀敏; 吉岡 弘鎮; 山本 正樹; 横山 俊秀; 石田 直  肺癌  48-  (5)  514  -514  2008/10
• P-308 前縦隔非セミノーマ性胚細胞腫瘍3症例の検討(縦隔腫瘍3,第49回日本肺癌学会総会号)

  山本 正樹; 吉岡 弘鎮; 岩破 将博; 横山 俊秀; 林 秀敏; 橋本 徹; 石田 直  肺癌  48-  (5)  566  -566  2008/10
• 36.既治療進行非小細胞肺癌に対するCPT-11+TS-1併用化学療法の検討(第47回日本肺癌学会中国・四国支部会,中国・四国支部,支部活動)

  横山 俊秀; 吉岡 弘鎮; 岩破 将博; 三枝 美香; 福山 一; 山本 正樹; 林 秀敏; 野山 麻紀; 橘 洋正; 有田 真知子; 橋本 徹; 石田 直  肺癌  48-  (4)  357  -357  2008/08
• O-66 高齢者切除不能非小細胞肺癌未治療例に対するGemcitabine+Carboplatin(GC)の併用第ll相試験(一般演題(口演)12 高齢者・合併症肺癌1,第48回日本肺癌学会総会号)

  吉岡 弘鎮; 西村 尚志; 片上 信之; 林 秀敏; 山本 正樹; 横山 俊秀; 野山 麻紀; 時岡 史明; 永井 宏樹; 石田 直; 瀬尾 龍太郎; 竹嶋 好; 林 三千雄; 富井 啓介; 石原 享介; 秦 明登; 東 陽一郎; 加地 玲子; 久保田 未央; 坂口 才  肺癌  47-  (5)  495  -495  2007/10
• 13.高齢者切除不能非小細胞肺癌未治療例に対するGemcitabine (GEM)+Carboplatin (CBDCA)の併用第II相試験 : 中間報告(第46回日本肺癌学会中国・四国支部会)

  林 秀敏; 吉岡 弘鎮; 岩破 将博; 三枝 美香; 福山 一; 山本 正樹; 横山 俊秀; 時岡 史明; 永井 宏樹; 野山 麻紀; 安田 武洋; 石井 知也; 橘 洋正; 有田 真知子; 橋本 徹; 石田 直; 西村 尚志; 富井 啓介; 石原 享介; 片上 信之  肺癌  47-  (4)  375  -375  2007/08
• 87.ダブルバルーン小腸内視鏡にて診断された肺癌小腸転移の2症例(第46回日本肺癌学会中国・四国支部会)

  吉岡 弘鎮; 林 秀敏; 岩破 将博; 三枝 美香; 福山 一; 山本 正樹; 横山 俊秀; 時岡 史明; 永井 宏樹; 野山 麻紀; 安田 武洋; 石井 知也; 橘 洋正; 有田 真知子; 橋本 徹; 石田 直  肺癌  47-  (4)  389  -389  2007/08
• 33.倉敷中央病院における胸部3次元定位放射線治療(3DSRT)の有用性と安全性の検討(第45回 日本肺癌学会中国・四国支部会,支部活動)

  吉岡 弘鎮; 坂口 才; 山本 正樹; 横山 俊秀; 林 秀敏; 野山 麻紀; 時岡 史明; 永井 宏樹; 丸毛 聡; 安田 武洋; 石井 知也; 橘 洋正; 有田 眞知子; 橋本 徹; 石田 直; 百々 義廣  肺癌  46-  (6)  780  -780  2006/10
• MODULATION OF THE MALIGNANT PHENOTYPE BY THE EXPRESSION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I GENES

  K TANAKA; H HAYASHI; G JAY  DNA-A JOURNAL OF MOLECULAR & CELLULAR BIOLOGY  5-  (1)  58  -58  1986/02

Industrial Property Rights

• 特開2023-082015:免疫チェックポイント阻害剤の奏効性の判定を補助する方法、試薬キット、装置及びコンピュータプログラム  2023/06/13

  本庶 佑, 茶本 健司, 林 秀敏, 中川 和彦, 後藤 恵, 宇賀 均  国立大学法人京都大学, 学校法人近畿大学, 小野薬品工業株式会社, シスメックス株式会社  202303018173419351
• 特許第7251738号:免疫チェックポイント阻害剤の奏効性の判定を補助する方法、試薬キット、装置及びコンピュータプログラム  

  本庶 佑, 茶本 健司, 林 秀敏, 中川 和彦, 後藤 恵, 宇賀 均  国立大学法人京都大学, 学校法人近畿大学, 小野薬品工業株式会社, シスメックス株式会社  202303009020898570

Awards & Honors

• 2022/12 日本肺癌学会 篠井・河合賞
  
• 2015/07 日本臨床腫瘍学会 日本臨床腫瘍学会奨励賞
   

  受賞者: 林 秀敏
• 2008/06 西日本がん研究機構 西日本がん研究機構賞
  

Research Grants & Projects

• Validation study of a model to estimate the primary organ of cancer of unknown primary

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2023/04 -2026/03 

  Author : 西尾 和人; 林 秀敏; デベラスコ マルコ; 坂井 和子
• Analysis of the risk factors for the development and severity of immune-related adverse events by immune checkpoint inhibitors

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2022/04 -2025/03 

  Author : 谷崎 潤子; 林 秀敏; 磯本 晃佑; 鈴木 慎一郎; 金村 宙昌
• Immune related gene-expression profiling for the combination of chemotherapy and PD-1/PD-L1 inhibition.

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2019/04 -2022/03 

  Author : HAYASHI Hidetoshi

   

  After approval of the research protocol by the institutional review board at multiple institutions, including Kinki University, registration of cases and collection of clinical information were conducted at each institution, and a total of 125 cases were registered from four institutions. Tumor tissue samples (FFPE) obtained by biopsy or surgery were collected from 90 of the registered cases, and RNA/DNA was extracted at our institution, and tumor immunity-related gene expression was evaluated using nCounter, PanCancer, and IO360 Panel. Part of the analysis is still in progress, and the final analysis is expected to include 60 patients. We found that response to combination therapy with immune checkpoint inhibitors and chemotherapy correlated with PD-L1 expression and some immune-related gene expression.
• Resistance mechanis of molecular targeted therapy and tumor micro environment as the immune-checkpoint inhibitor's biomarker

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2016/04 -2018/03 

  Author : HAYASHI Hidetoshi

   

  The efficacy of PD-1 blockade in EGFR mutated NSCLC with different mechanisms of acquired resistance to EGFR-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.We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. Efficacy of nivolumab 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 of10% or50% was higher among T790M-negative patients than among -positive patients. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. 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.
• 未治療原発不明癌に対する次世代シークエンスを用いた原発巣推定に基づく治療 効果の意義を問う第 II 相試験

  日本医療研究開発機構(AMED)：革新的がん医療実用化研究事業 領域6：ライフステージやがんの特性に着目した重点研究

  Date (from‐to) : 2014/04 -2017/03

Committee Membership

• 2022/03 - Today   Japanese Society of Medical Oncology   Vice chair of the Specialist Examination Subcommittee
• 2020/02 - Today   International Association for the Study of Lung Cancer   Membership committee

Other link

researchmap

https://researchmap.jp/hayashi_h