A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2)

Abstract

Background: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens.

Methods: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).

Results: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6-7.4 versus 3.6 months, 95% CI 2.8-5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42-0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without.

Conclusions: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.

Keywords: Gastric cancer; Gastro-esophageal junction cancer; Japan; Nivolumab.

Conflict of interest statement

Conflict of interest

Ken Kato received research funds from Ono Pharmaceutical, MSD, Shionogi, and Merck Serono for this study, and research funds from Merck, Shionogi, and Ono Pharmaceutical for activities outside the submitted work. Taroh Satoh received research grants and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb and a department donated by Ono Pharmaceutical for this study; research grants and honoraria from Yakult Honsha, Chugai Pharmaceutical, Eli Lilly, Merck Serono, Takeda Pharmaceutical, Taiho Pharmaceutical, and MSD; and a department donated by Yakult Honsha and Chugai Pharmaceutical for activities outside the submitted work. Kei Muro received a grant from Ono Pharmaceutical for this study; grants from Ono Pharmaceutical, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Shionogi, and Gilead Sciences for activities outside the submitted work; and personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Merck Serono, Eli Lilly, and Yakult Honsha. Takaki Yoshikawa received grants from Ono Pharmaceutical and Bristol-Myers Squibb for this study; grants and honoraria from Chugai Pharmaceutical and Taiho Pharmaceutical; grants and advisory fees from Novartis, Ono Pharmaceutical, Eli Lilly Japan, Johnson & Johnson, and Covidien; and honoraria from Abbott Japan, Kaken, Yakult Honsha, Nippon Kayaku, Takeda Pharmaceutical, and Olympus for activities outside the submitted work. Takao Tamura received grants from Ono Pharmaceutical and Bristol-Myers Squibb for this study, and grants from MSD Pharmaceutical, Merck, and Daiichi Sankyo for activities outside the submitted work. Keiko Minashi received research funding from Ono Pharmaceutical for this study. Kensei Yamaguchi received grants from Ono Pharmaceutical and Bristol-Myers Squibb for this study. Nozomu Machida received a grant from Ono Pharmaceutical for this study, and grants from Taiho Pharmaceutical, MSD, and Eli Lilly for activities outside the submitted work. Taito Esaki received a grant from Ono Pharmaceutical for this study; grants from Dainippon Sumitomo, Novartis, MSD, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bayer, Astellas, Showa, AstraZeneca, and GSK; personal fees from Eisai, Kyowa Hakko Kirin, Chugai Pharmaceutical, and Bristol-Myers Squibb; and grants and personal fees from Taiho Pharmaceutical, Merck Serono, Eli Lilly, Nippon Kayaku, and Takeda Pharmaceutical for activities outside the submitted work. Masahiro Goto received a grant, personal fees, and non-financial support from Ono Pharmaceutical for this study; grants, personal fees, and non-financial support from Taiho Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical, Kyowa Hakko Kirin, and Mochida Pharmaceutical; and personal fees and non-financial support from Takeda Pharmaceutical, Novartis, and Bayer Yakuhin for activities outside the submitted work. Yoshito Komatsu received a grant from Ono Pharmaceutical for this study; lecturer’s fee and research expenses from Ono Pharmaceutical, MSD, Eli Lilly, Merck, AstraZeneca, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, NCC, Kyowa Hakko Kirin, Takeda Pharmaceutical, Sanofi, Yakult Honsha, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, and Novartis; and research expenses from Linical and TCOG for activities outside the submitted work. Takako Eguchi Nakajima received a grant from Ono Pharmaceutical for this study; grants and personal fees from Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Serono, Ono Pharmaceutical, and Dainippon Sumitomo; grants from Yakult Honsha, Eisai, Sanofi, Amgen Astellas BioPharma, and AstraZeneca; and personal fees from Sawai Pharmaceutical, Kyowa Hakko Kirin, Bristol-Myers Squibb, Bayer Yakuhin, and Maruho for activities outside the submitted work. Naotoshi Sugimoto received a grant from Ono Pharmaceutical for this study, and grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, and Dainippon Sumitomo for activities outside the submitted work. Kazuhiro Yoshida received grants, personal fees, and non-financial support from Ono Pharmaceutical for this study; grants, personal fees, and non-financial support from Taiho Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha, Eli Lilly Japan, Daiichi Sankyo, Merck Serono, Novartis Pharma, EA Pharma, Takeda Pharmaceutical, and Sanofi; grants and personal fees from Johnson & Johnson and Covidien Japan; grants from Nippon Kayaku, Otsuka Pharmaceutical, and Dainippon Sumitomo; and personal fees from MSD K.K. and Bayer Yakuhin for activities outside the submitted work. Eiji Oki received a grant from Ono Pharmaceutical for this study, and honoraria for lecturing from Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, Merck Serono, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, and Bristol-Myers Squibb. Akihito Tsuji received a grant from Ono Pharmaceutical for this study, and honoraria from Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Takeda Pharmaceutical, and Bristol-Myers Squibb Japan for activities outside the submitted work. Mizutomo Azuma received a grant and personal fees from Ono Pharmaceutical for this study. Keisei Taku, Masahiro Tsuda, Tomohiro Nishina, Hirofumi Fujii, Kenji Kunieda, Soh Saito, Yasushi Omuro, Yasuo Iwamoto, Sachio Fushida, Yasuo Hamamoto, and Keisho Chin received grants from Ono Pharmaceutical for this study. Li-Tzong Chen received a grant from Ono Pharmaceutical for this study; grants, personal fees, and non-financial support from Novartis, TTY, and Syncore; grants from the Ministry of Science and Technology (Taiwan), Ministry of Health and Welfare (Taiwan), Pfizer, GSK, Merck Serono, OBI, and Polaris; grants and non-financial support from Celgene; and personal fees from Eli Lilly, PharmaEngine, Shire, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Five Prime, and Merrimack for activities outside the submitted work. Yoon-Koo Kang received a grant from Ono Pharmaceutical for this study, and personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Daehwa, and Blueprint for activities outside the submitted work. Narikazu Boku received a grant and personal fees from Ono Pharmaceutical for this study, and personal fees from Chugai Pharmaceutical, Merck Serono, and AstraZeneca for activities outside the submitted work.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent to be included in the study, or the equivalent, was obtained from all patients.

Figures

Fig. 1

Kaplan–Meier plots of a overall survival and b progression-free survival (Japanese ITT population). CI Confidence interval, HR hazard ratio, ITT intention-to-treat

Fig. 2

Kaplan–Meier plots of overall survival in a patients with prior ramucirumab treatment; b patients without prior ramucirumab treatment; and progression-free survival in c patients with prior ramucirumab treatment; d patients without prior ramucirumab treatment (ITT population). CI Confidence interval, HR hazard ratio, ITT intention-to-treat