Background Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. Patients and methods Patients were randomized (1: 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m 2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m 2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m 2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m 2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Results Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. Conclusion Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. Clinicaltrials.gov ID NCT02746796.
Bibliographical noteFunding Information:
We would like to thank the patients and their families, as well as the investigators and participating study teams, for making this study possible. We thank Shunsuke Hagihara for providing statistical support and the project leader, Mitsunobu Tanimoto (Ono Pharmaceutical). Writing and editorial assistance was provided by Ruhi Ubale, PhD, of Cactus Communications, and was funded by Ono Pharmaceutical Co., Ltd., Osaka, Japan, and Bristol-Myers Squibb Inc., Princeton, NJ.
This study was funded by Ono Pharmaceutical Co., Ltd., Osaka, Japan, and Bristol-Myers Squibb Inc., Princeton, NJ (no grant number is applicable).
NB received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Chugai Pharmaceutical. MHR received research grants from Ono Pharmaceutical; honoraria from DAE HWA Pharmaceutical, Lilly Korea, Bristol-Myers Squibb, and Ono Pharmaceutical; consulting fees from Lilly Korea; and served on the advisory board for Bristol-Myers Squibb and Ono Pharmaceutical. KK received research grants from Ono Pharmaceutical, MSD, Shionogi, and Merck Serono. HCC received research grants from Ono Pharmaceutical, Eli Lilly, GSK, MSD, Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, and Taiho; honoraria from Merck Serono, Eli Lilly, and Foundation Medicine/Roche; and consulting fees from Taiho, Celltrion, MSD, Eli Lilly, Quintiles, Bristol-Myers Squibb, and Merck Serono. KM, KWL, HC, WKK, MT, SF, and MA received research grants from Ono Pharmaceutical. YK received research grants and speaker fees from Ono Pharmaceutical, MSD, Eli Lilly, Merck, AstraZeneca, Daiichi Sankyo, Taiho, Chugai Pharmaceutical, NCC, Kyowa Hakko Kirin, Takeda, Sanofi, Yakult Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, and Novartis, and research grants from Linical and TCOG. KY received research grants from Ono Pharmaceutical and served on the speakers bureau for Ono Pharmaceutical and Bristol-Myers Squibb. HH received research grants from Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Serono, MSD, Taiho, Chugai, Boehringer Ingelheim, Eisai, LSK BioPharma, Incyte, and Pfizer. LTC received research grants from Ono Pharmaceutical, Ministry of Science and Technology (Taiwan), Ministry of Health and Welfare (Taiwan), Novartis, Pfizer, GSK, Merck Serono, TTY Biopharm, OBI Pharma, Polaris Pharma, SynCore Biotechnology, and Celgene, and honoraria from Novartis, Eli Lilly, TTY Biopharm, PharmaEngine, Shire, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, SynCore Biotechnology, Five Prime Therapeutics, and Merrimack. YKK received research grants from DAE HWA Pharmaceutical and consulting fees from Ono Pharmaceutical, Bristol-Myers Squibb, DAE HWA Pharmaceutical, and Blueprint Medicines.
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