4 Courses and 8 Courses of S-1 Adjuvant Chemotherapy for Pathological Stage II Gastric Cancer JCOG1104 (OPAS-1): A Phase 3, Open-Label, Non-Inferiority, Randomised Trial

Background: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to 8 courses) is a standard care for pathological stage II gastric cancer. It remains unclear whether duration of S-1 for 1 year could be shortened to 6 months (corresponding to 4 courses) without worsening the survival. Methods: We conducted a phase 3, open-label, randomized controlled non-inferiority trial at 59 hospitals in Japan. Patients with pathological stage II adenocarcinoma of the stomach were randomly assigned (1:1) to 4 courses S-1 or 8 courses S-1. 80 mg/m2/day of S-1 was administered for 4 weeks with a rest for 2 weeks as one course. Primary endpoint was relapse-free survival (RFS), analyzed by intension to treat. Total sample size was determined to be 1,000, expecting 3-year RFS of 85% with non-inferiority margin of hazard ratio (HR) of 1·37, one-sided alpha of 5% and 80% power. Findings: Between Feb 2012 and Mar 2017, 590 patients were enrolled (8-courses, 295; 4-courses, 295). Among them, 528 patients were analyzed at the first planned interim analysis in Mar 2017. The point estimate of HR of the 4- courses group compared with the 8-courses group was 2·52 (95% CI: 1·11- 5·77), which was greater than 1·37 and met the prespecified criteria for early termination, associated with predictive probability of 2·9% for showing non-inferiority at the final analysis. Updated 3-year RFS analyzed in May 2017 were 93·1% (95% CI 87·8%-96·1%) for the 8-courses group and 89·8% (95% CI 84·2%-93·5%) for the 4-courses group (HR 1·84, 95% CI 0·93-3·63). Interpretation: Postoperative S-1 adjuvant chemotherapy for p-stage II gastric cancer should be continued for 1 year. Clinical Trial Number: This study is registered at UMIN-CTR, number UMIN000007306. Funding Statement: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund. Declaration of Interests: TYo had received reports grants from Japan Agency for Medical Research and Development (AMED) during the conduct of the study, lecture fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol, MSD, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Nippon Kayaku, Kaken Pharmaceutical, Abbott Japan, Medtronic, Johnson & Johnson, and Olympus, and grant supports from Taiho Pharmaceutical, Chugai Pharmaceutical, and Yakult Honsha outside the submitted work. JM had received grants from Ministry of Health, Labour and Welfare, Japan, grants from Japan Agency for Medical Research andÝevelopment (AMED) during the conduct of the study. KY had received grants, personal fees, and non-financial support from Taiho Pharm. Co. during the conduct of the study, grants, personal fees, and non-financial support from Sanofi, grants, personal fees, and non-financial support from Chugai Pharm. Co., Ltd., grants, personal fees, and non-financial support from Yakult Honsha Co., Ltd., grants, personal fees, and non-financial support from Eli Lilly Japan K.K., grants, personal fees, and non-financial support from Daiichi Sankyo Co., Ltd., grants, personal fees, and non-financial support from Merck Serono Co., Ltd., grants, personal fees, and non-financial support from Novartis Pharma, grants, personal fees, and non-financial support from EA Pharma Co., Ltd., grants, personal fees, and non-financial support from Johnson & Johnson K.K., grants, personal fees, and non-financial support from Covidien Japan, grants, personal fees, and non-financial support from Takeda Pharmaceutical Co., Ltd., grants, personal fees, and non-financial support from Ono Pharm. Co.,Ltd, grants and personal fees from Nippon Kayaku Co.,Ltd., grants and personal fees from Otsuka Pharma Co., Ltd., grants from Sumitomo Dainippon Pharma, grants from Bristol Myers Japan, grants from Tsumura, grants from Kyowa Hakko Kirin, grants from Astellas, grants from Toyama Chemical, grants from KCI, grants from Abbott Japan, grants from Asahi Kasei, personal fees from Olympus, personal fees from Terumo, personal fees from Denka, personal fees from MSD K.K., personal fees from Bayer Yakuhin, Ltd, outside the submitted work. SI had received grants from MSD, grants from Ono Pharmaceutical, personal fees from Chugai Pharmaceutical, personal fees from Otsuka Pharmaceutical Factory outside the submitted work. HK had received grants from Ministry of Health, Labour and Welfare, Japan, grants from Japan Agency for Medical Research and Ýevelopment (AMED) during the conduct of the study and personal fees from Johnson & Johnson outside the submitted work. HF had received grants from Ministry of Health, Labour and Welfare, Japan, grants from National Cancer Center, Japan during the conduct of the study, personal fees from Taiho Pharma, and personal fees from Chugai Pharmaceutical outside the submitted work. NB had received honorarium from Taiho, Ono, Chugai, Shionogi, Yakult, Bristol Myers Squibb, Eli Lilly, Merck Serono, and study grant from Taiho, Ono and Bristol Myers Squibb outside of the submitted work. TS had received personal fees from Taiho Pharma outside the submitted work. MS had received personal fees from Taiho Pharmaceutical during the conduct of the study. Ethics Approval Statement: This study was done in accordance with the international ethical recommendations stated in the Declaration of Helsinki, Japanese Ethical Guidelines for Clinical Research. All patients were required to provide written informed consent prior to enrollment.