Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA)

Background: GC has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). This phase III study aimed to confirm the superiority of GCS to GC in terms of survival in patients with unresectable or recurrent BTC. Methods: Eligibility criteria included chemotherapy-naïve patients with advanced biliary tract adenocarcinoma (gallbladder, intrahepatic/ extrahepatic biliary tract, or ampulla of Vater), PS of 0–2, and adequate organ function. Enrolled patients were randomly allocated to either GCS arm or GC arm. In the GCS arm, gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m2, respectively, on day 1, and oral S-1 were administered daily at a dose of 80 mg/m2 on days 1-7 every 2 weeks. In the GC arm, 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin were infused on days 1 and 8 and repeated every 3 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response rate (RR), and adverse events (AEs). The sample size was calculated to be 240, assumed 1 year OS rate of 43 % in GC and of 55 % in GCS (one-sided α 0.05, and power 0.8). A total of 39 institutions in Japan participated in this study. Results: From July 2014 to February 2016, 246 patients were enrolled. At the data cutoff (April 16, 2018), median OS and 1-year OS rate was 13.5 months and 59.4 % in the GCS arm and 12.6 months and 53.7 % in the GC arm, respectively (HR 0.79, 95% confidential interval [CI] 0.60-1.04; p = 0.046 [stratified log-rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI 0.58-0.97; p = 0.0015). RR was 41.5 % in the GCS arm, and 15.0 % in the GC arm. AEs except for those related to S-1 did not show significant differences between two arms. Conclusions: This phase III study demonstrated the significant survival benefits of GCS treatment over GC treatment, and indicated that GCS could be a new standard treatment for patients with advanced BTC. Clinical trial identification: NCT02182778, UMIN 000014371. Legal entity responsible for the study: Kansai Hepatobiliary Oncology Group (KHBO). Funding: Kansai Hepatobiliary Oncology Group (KHBO) Taiho Pharmaceutical Co., Ltd. Disclosure: All authors have declared no conflicts of interest.