Impact of Hepatitis B Virus Infection on the Efficacy and Safety of Pembrolizumab plus Chemotherapy for Advanced Biliary Tract Cancer in the KEYNOTE-966 Study

PURPOSE: In the randomized phase 3 KEYNOTE-966 trial, first-line pembrolizumab plus chemotherapy significantly improved overall survival (OS) versus placebo plus chemotherapy for participants with advanced biliary tract cancer (BTC). This post hoc analysis investigated whether hepatitis B virus (HBV) infection affected the efficacy and safety of pembrolizumab plus chemotherapy. PATIENTS AND METHODS: Eligible participants had histologically confirmed extrahepatic or intrahepatic cholangiocarcinoma or gallbladder cancer, unresectable locally advanced or metastatic disease measurable per RECIST v1.1, known HBV and HCV status (including active HBV), and Eastern Cooperative Oncology Group performance status 0 or 1. Participants were randomly assigned 1:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles plus gemcitabine and cisplatin. HBV-positive participants were monitored for HBV reactivation, and antiviral therapy was required for chronic HBV infection. The primary end point was OS. RESULTS: The intention-to-treat population comprised 1,069 participants (533, pembrolizumab group; 536, placebo group). The median time from randomization to data cutoff (November 14, 2023) was 36.6 months (range, 29.2-49.4). Among 329 HBV-positive participants (30.8%), 30 had chronic and 299 had clinically resolved HBV. The OS HR was 0.87 [95% confidence interval (CI), 0.69-1.10] with pembrolizumab versus placebo for the HBV-positive subgroup and 0.85 (95% CI, 0.73-0.99) for the HBV-negative subgroup. Safety was consistent between the subgroups. Eight participants had HBV reactivation (5, pembrolizumab group; 3, placebo group), and no cases of HBV-associated hepatitis occurred in either group. CONCLUSIONS: Efficacy and safety outcomes were consistent between HBV-positive and HBV-negative participants receiving first-line pembrolizumab compared with placebo plus gemcitabine and cisplatin. SIGNIFICANCE: Chronic HBV infection is a risk factor for BTC, potentially affecting the effectiveness of BTC treatment. In this study, treatment outcomes in participants who received first-line pembrolizumab plus gemcitabine and cisplatin for advanced BTC treatment were consistent regardless of HBV infection status.