@article{1004a7ed660a40eb9c6323975c1acfc4,
title = "Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR)",
abstract = "The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.",
keywords = "adjuvant chemotherapy, next-generation sequencing, non-squamous non-small cell lung cancer, pemetrexed, tumor mutation burden (TMB)",
author = "Kazuko Sakai and Masahiro Tsuboi and Hirotsugu Kenmotsu and Takeharu Yamanaka and Toshiaki Takahashi and Koichi Goto and Haruko Daga and Tatsuo Ohira and Tsuyoshi Ueno and Tadashi Aoki and Kazuhiko Nakagawa and Koji Yamazaki and Yukio Hosomi and Koji Kawaguchi and Norihito Okumura and Yuichi Takiguchi and Akimasa Sekine and Tomohiro Haruki and Hiromasa Yamamoto and Yuki Sato and Hiroaki Akamatsu and Takashi Seto and Sho Saeki and Kenji Sugio and Makoto Nishio and Kazunori Okabe and Nobuyuki Yamamoto and Kazuto Nishio",
note = "Funding Information: We thank the patients, their families, and the investigators who participated in this study; the data managers and other support staff of West Japan Oncology Group, especially Drs Kazuhiko Sawa, Seiko Tanaka, Shinichiro Nakamura, and Koji Takeda; and technical support staff of Kindai University Faculty of Medicine, especially Yoshihiro Mine and Ayaka Kitano. Funding Information: This research was supported by University Grants for Fundamental Research of Kindai University. Kazuko Sakai reports personal fees from Roche Diagnostics, Bio‐Rad, SRL Diagnostics, AstraZeneca, Chugai Pharmaceutical outside the submitted work. Masahiro Tsuboi reports personal fees from AstraZeneca, MSD, Bristol‐Myers Squibb, Ono Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Johnson & Johnson Japan, Medtronic Japan, Teijin Pharma, Chugai Pharmaceutical, and grants from Boehringer Ingelheim, AstraZeneca, MSD, Bristol‐Myers Squibb, Ono Pharmaceutical outside the submitted work. Hirotsugu Kenmotsu reports personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Kyowa Hakko Kirin, Bristol‐Myers Squibb, MSD, Novartis, Pfizer, and grants from AstraZeneca, Chugai Pharmaceutical, Daiichi‐Sankyo, Boehringer Ingelheim outside the submitted work. Takeharu Yamanaka reports personal fees from Takeda, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi‐Sankyo, Bayer, Pfizer, Sysmex, Huya Biosciences, Gilead Sciences, and grants from Takeda, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi‐Sankyo, Ono Pharmaceutical, Bayer, Merck Serono, Astellas, Eli Lilly outside the submitted work. Toshiaki Takahashi reports personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, and grants from AstraZeneca, Chugai Pharmaceutical outside the submitted work. Koichi Goto reports personal fees from AstraZeneca, Pfizer, Merck Biopharma, Eli Lilly, Thermo Fisher Scientific, MSD, Novartis, AbbVie, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Nippon Kayaku, IQVIA Services, Takeda, Otsuka Pharmaceutical, Astellas, Guardant Health Inc, Life Technologies Japan Ltd., Janssen Pharmaceutical, Kyowa Hakko Kirin, Daiichi‐Sankyo, and grants from AstraZeneca, Pfizer, Merck Biopharma, Eli Lilly, Xcoo, Thermo Fisher Scientific, MSD, Novartis, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Takeda, Astellas, Life Technologies Japan, Janssen Pharmaceutical, Kyowa Hakko Kirin, Daiichi‐Sankyo, Eisai, Sumitomo Dainippon Pharma, Riken Genesis, Ignyta, LOXO Oncology, Sysmex, Medical & Biological Laboratories, Amgen outside the submitted work. Kazuhiko Nakagawa reports grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Kyorin Pharmaceutical, CareNet, Nichi‐Iko Pharmaceutical, Daiichi‐Sankyo, Hisamitsu Pharmaceutical, Yodosha, Clinical Trial, Medicus Shuppan Publishers, Ayumi Pharmaceutical, Nikkei Business Publications, Thermo Fisher Scientific, Nanzando, Medical Review, Yomiuri Telecasting, Reno Medical, MSD, Eli Lilly, Bristol‐Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas, and grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Daiichi‐Sankyo, Merck Serono, ICON, Parexel International, IQVIA Services, A2 Healthcare, AbbVie, EP‐CRSU, Linical, Otsuka Pharmaceutical, EPS, Quintiles, CMIC Shift Zero, Eisai, Kissei Pharmaceutical, Kyowa Hakko Kirin, Bayer, inVentiv Health, Gritstone Oncology, GlaxoSmithKline, Covance, MSD, Eli Lilly, Bristol‐Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas outside the submitted work. Yukio Hosomi reports personal fees from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, MSD, Kyowa Hakko Kirin. Yuichi Takiguchi reports personal fees from Eli Lilly, Kyowa Hakko Kirin, MSD, Boehringer Ingelheim, Ono Pharmaceutical Bristol‐Myers Squibb, Chugai Pharmaceutical, Daiichi‐Sankyo, Pfizer, Novartis, AstraZeneca, Eisai, Merck Serono, and grants from Eli Lilly, Kyowa Hakko Kirin, MSD, Boehringer Ingelheim, Ono Pharmaceutical, Bristol‐Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi‐Sankyo, Takeda outside the submitted work. Akimasa Sekine reports personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, MSD, Bristol‐Myers Squibb. Yuki Sato reports personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical, MSD outside the submitted work. Takashi Seto reports personal fees from Bristol‐Myers Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Roche, Taiho Pharmaceutical, Thermo Fisher Scientific, Yakult, Astellas, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Kissei Pharmaceutical, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda, and grants from Astellas, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Kissei Pharmaceutical, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda, Bayer, Daiichi‐Sankyo, Eisai, LOXO Oncology, Merck Serono outside the submitted work. Makoto Nishio reports consulting fees from Novartis, Daiichi‐Sankyo, Taiho Pharmaceutical, Bristol‐Myers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, AstraZeneca, Merck Serono, MSD, Pfizer, personal fees from Ono Pharmaceutical, Bristol‐Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, and grants from Pfizer, MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Astellas outside the submitted work. Nobuyuki Yamamoto reports personal fees from MSD, AstraZeneca, Eli Lilly, Ono Pharmaceutical, Kyowa Hakko Kirin, Daiichi‐Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Nichi‐Iko Pharmaceutical, Novartis, Pfizer, Bristol‐Myers Squibb, Boehringer Ingelheim, Takeda, and grants from MSD, AstraZeneca, Eli Lilly, Ono Pharmaceutical, Kyowa Hakko Kirin, Daiichi‐Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Nichi‐Iko Pharmaceutical, Novartis, Pfizer, Boehringer Ingelheim, Takeda, Astellas, AbbVie, On‐chip Biotechnologies, Kyorin Pharmaceutical, Toppan, Tosoh, Shionogi, Maruho, Tsumura & Co. outside the submitted work. Kazuto Nishio reports personal fees from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Chugai Pharmaceutical, Eisai, Pfizer, Novartis, MSD, Ono Pharmaceutical, Bristol‐Myers Squibb, SymBio Pharmaceuticals Limited, Solasia Pharma, Yakult Honsha, Roche Diagnostics, AstraZeneca, Sanofi, Guardant Health, Takeda, Kobayashi Pharmaceutical, and grants from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Ignyta, Astellas outside the submitted work. The other authors indicated no financial relationships. Publisher Copyright: {\textcopyright} 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association",
year = "2021",
month = jan,
doi = "10.1111/cas.14730",
language = "English",
volume = "112",
pages = "388--396",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "1",
}
