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Pembrolizumab plus Gemcitabine and Cisplatin for Advanced Biliary Tract Cancer
A prior randomized, phase 3 study showed that adding the anti–PD-L1 immune checkpoint inhibitor durvalumab to first-line chemotherapy with gemcitabine and cisplatin significantly improved overall survival in patients with advanced biliary cancer (NEJM JW Oncol Hematol Aug 2022 and NEJM Evid 2022 Jun 1; [e-pub]).
Now, to evaluate the anti–PD-1 immune checkpoint inhibitor pembrolizumab in this setting, investigators conducted an industry-sponsored, international, randomized, phase 3 trial (KEYNOTE-966) in which 1609 untreated patients with advanced biliary cancer received treatment every 3 weeks with gemcitabine (no maximum duration), cisplatin (maximum, 8 cycles), and pembrolizumab or placebo (maximum, 35 cycles). Among the patients, 45% were treated in Asia, 59% had intrahepatic primaries, 88% had metastatic disease, and 68% had a PD-L1 combined positive score of ≥1%.
At a median follow-up of 25.6 months, overall survival (OS; the primary endpoint) was longer with pembrolizumab than with placebo (12.7 vs. 10.9 months; hazard ratio, 0.83; P=0.0034); OS rates were improved with pembrolizumab at 12 months (52% vs. 44%) and 24 months (25% vs. 18%). The level of PD-L1 expression had no impact on OS benefit. Progression-free survival was similar with or without pembrolizumab (6.5 and 5.6 months, respectively). The rate of response was similar in both arms (29%); the median duration of response was 9.7 months with pembrolizumab and 6.9 months with placebo. No new safety signals were identified.
Systemic therapy for patients with advanced biliary cancer improved with the recent approval of durvalumab combined with first-line gemcitabine and cisplatin. Specific molecularly targeted agents in biliary cancer have also recently received regulatory approval based on genomic profiling. The KEYNOTE-966 trial provides further evidence that combining standard-of-care, first-line chemotherapy with immune checkpoint inhibitors targeting PD-1 and PD-L1 improves survival in patients with untreated metastatic or unresectable biliary cancer. Pembrolizumab added to first-line chemotherapy will likely emerge as a new therapeutic option for these patients.
Kelley RK et al.
Title: Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial.
Source: Lancet 2023 Apr 16; [e-pub]. (Abstract/FREE Full Text)