Pembrolizumab Plus Gemcitabine/Cisplatin Provided Significant Improvement in OS in Advanced Biliary Tract Cancer


These data support using this combination therapy as a new first-line treatment option in patients with previously untreated metastatic or unresectable BTC.

The combination therapy pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) provided a statistically significant, clinically meaningful improvement in overall survival (OS) when compared to placebo plus gem/cis in patients with previously untreated metastatic or unresectable biliary tract cancer (BTC), according to investigators in the randomized, double-blind, phase 3 KEYNOTE-966 study (NCT04003636) presented at the AACR Annual Meeting 2023.

Credit: freshidea - Adobe Stock

Credit: freshidea - Adobe Stock

The investigators noted that currently, despite the availability of other treatments for the disease, patients with BTC have a poor prognosis. For this reason, a meaningful improvement in OS is significant for this patient population.

“These results show that pembrolizumab added to chemotherapy provides a meaningful survival benefit for patients with advanced stages of BTC, beyond our historical standard of care with chemotherapy alone,” said study author Robin Kate Kelley, MD, professor, medicine at the Helen Diller Family Comprehensive Cancer Center, Division of Hematology/Oncology, University of California San Francisco, in an interview with Pharmacy Times®.

During the study, patients were eligible for enrollment if they had histologically confirmed, RECIST v1.1-measurable disease with no prior systemic therapy in the unresectable or metastatic setting. These patients were randomized 1:1 to pembro at 200 mg or placebo administered intravenously (IV) on day 1 every 3 weeks (Q3W) for ≤35 cycles added to gemcitabine at 1000 mg/m2 administered IV on days 1 and 8 Q3W until disease progression and cisplatin at 25 mg/m2 administered IV on days 1 and 8 Q3W for ≤8 cycles.

The study was randomized, with the randomization stratified by region (Asia vs non-Asia), stage (metastatic vs locally advanced), and tumor origin (gallbladder vs intrahepatic vs extrahepatic). Further, the primary end point was OS and the secondary end points were progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) per RECIST v1.1 by blinded independent central review and safety.

Per protocol, the final analysis of PFS and ORR was conducted at the first interim analysis point (data cutoff, December 15, 2021), with all other data collected from the protocol-specified final analysis (data cutoff, December 15, 2022). Additionally, one-sided P-value boundaries for significance are 0.0200 for OS, 0.0125 for PFS, and 0.0125 for ORR.

“The KEYNOTE-966 trial substantiates the benefit of adding a checkpoint inhibitor to gemcitabine plus cisplatin chemotherapy in a broad patient population, including Asian and non-Asian subgroups, irrespective of viral hepatitis exposure status,” Kelley said. “It also shows us that an immune checkpoint inhibitor can be continued with or without gemcitabine after 6 months of upfront chemotherapy, noting the different practice patterns.”

In the study, there were 1069 patients randomized to the pembro plus gem/cis group (n = 533) or the placebo plus gem/cis group (n = 536). Among the patients, the baseline characteristics were generally balanced between arms, with 45.5% of patients from Asia, 88.2% with metastatic disease, and 59.2% with intrahepatic origin.

The median study follow-up was 25.6 months (mo), with a range of 18.3 to 38.4 mo at final analysis. At final analysis, median (95% CI) OS was 12.7 mo (11.5-13.6) for pembro plus gem/cis vs 10.9 mo (9.9-11.6) for placebo plus gem/cis (HR 0.83; 95% CI 0.72-0.95; P=0.0034). At 24 mo, the OS was 24.9% vs 18.1%; the OS results were found to be generally consistent across all subgroups.

At the first interim analysis point, median (95% CI) PFS was 6.5 mo (5.7-6.9) for pembro plus gem/cis vs 5.6 mo (5.1-6.6) for placebo plus gem/cis (HR 0.86; 95% CI 0.75-1.00; P=0.0225). Then at 12 mo, the PFS was 25.4% vs 19.8%. Additionally, at first interim analysis point, ORR (95% CI) was 28.7% (24.9-32.8) for pembro plus gem/cis vs 28.5% (24.8-32.6) for placebo plus gem/cis (difference 0.2; 95% CI -5.2 to 5.6; P = 0.4735), with median DOR at 9.7 mo (1.2+ to 22.7+) vs 6.9 mo (0.0+ to 19.2+).

There were grade 3 to 5 AEs reported in 85.3% of the 529 patients who were treated in the pembro plus gem/cis arm vs 84.1% of 534 treated in the placebo plus gem/cis arm (drug related, 71.3% vs 69.3%). Further, grade 5 AE incidence was found to be 5.9% vs 9.2% (drug related, 1.5% vs 0.6%), respectively. Additionally, potentially immune-mediated AEs and infusion reactions occurred in 22.1% vs 12.9%, respectively.

The investigators noted that based on these results, the safety profile of pembro plus gem/cis was as expected and manageable. Further, these data support using pembro plus gem/cis as a new first-line treatment option in patients with previously untreated metastatic or unresectable BTC.

“Next steps include delving into biomarkers and subgroups to understand which factors may impact treatment response; these analyses are ongoing. We hope these data will guide the development of new combinations and next-generation immunotherapies to further improve outcomes in the advanced setting,” Kelley said. “Beyond clinical and translational biomarker analyses, patient-reported outcome data including quality of life analyses will be presented at ASCO 2023.”


Kelley RK, Yoo C, Finn RS, et al. Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC): Phase 3 KEYNOTE-966 study. Presented at: AACR Annual Meeting 2023; April 16, 2023.

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