A randomized phase III study of gemcitabine plus cisplatin with S-1 versus gemcitabine plus cisplatin with immune checkpoint inhibitor in unresectable biliary tract cancer.

Abstract

TPS4252 Background: Gemcitabine plus cisplatin (GC) has been established as the standard first-line treatment for unresectable biliary tract cancer (BTC). Recent phase III trials have demonstrated the clinical benefit of adding immune checkpoint inhibitors (ICIs) to GC. Meanwhile, GC combined with S-1 has also shown promising efficacy in East Asian populations. However, no randomized phase III trial has directly compared GC plus ICI with GC plus S-1. This study aims to compare the efficacy and safety of GC plus ICI with GC plus S-1 in patients with unresectable BTC. Methods: This is an ongoing, multicenter, open-label, randomized phase III trial (UMIN000051689). Eligible patients have histologically confirmed unresectable biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, with no prior systemic therapy. Patients are randomized in a 1:1 ratio to receive either Arm A: gemcitabine plus cisplatin plus S-1 or Arm B: gemcitabine plus cisplatin combined with an immune checkpoint inhibitor. Randomization is stratified by primary tumor site, disease status (recurrence vs primary unresectable), and planned immune checkpoint inhibitor regimen for patients assigned to Arm B. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate, disease control rate, safety, and health-related quality of life. The planned sample size is 460 patients (230 per arm), providing 80% power to detect a statistically significant difference in overall survival with a two-sided alpha of 0.05. Current Status: Patient enrollment began in August 2023. As of January 2026, approximately 60% of the planned patients have been enrolled. Enrollment is ongoing, and follow-up continues. Conclusions: This randomized phase III trial will clarify the optimal first-line systemic treatment for unresectable biliary tract cancer by directly comparing GC plus immune checkpoint inhibition with GC plus S-1. Clinical trial information: UMIN000051689.