Pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer: longer-term follow-up from the randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-966 trial

Background: At the final analysis of KEYNOTE-966 (median follow-up 25·6 months), pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group) versus placebo plus gemcitabine and cisplatin (placebo group) provided a statistically significant, clinically meaningful improvement in overall survival without any new safety signals in participants with advanced biliary tract cancer. We report results from a median study follow-up of 36·6 months (∼3 years). Methods: intravenously on days 1 and 8 of every 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease status, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was evaluated in the as-treated population, comprising all participants who received at least one dose of study treatment. As the primary endpoint was met at the final analysis, updated data are reported without p values. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1069 participants were randomly assigned to the pembrolizumab group (n = 533) or the placebo group (n = 536). Median follow-up at data cutoff (Nov 14, 2023) was 36·6 months (IQR 32·7-41·4). The hazard ratio for overall survival was 0·86 (95% CI, 0·75-0·98) with pembrolizumab versus placebo; estimated 36-month overall survival rates were 13% (95% CI, 11-17) in the pembrolizumab group and 11% (95% CI, 8-14) in the placebo group. Grade 3 or 4 treatment-related adverse events occurred in 370 (70%) of 529 participants in the pembrolizumab group and 367 (69%) of 534 participants in the placebo group. No new treatment-related deaths occurred since the final analysis. Interpretation: With extended follow-up, the survival benefit of pembrolizumab plus gemcitabine and cisplatin observed at the final analysis persists with approximately 3 years of follow-up, with no new safety signals among participants with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.