Immunotherapy/Chemotherapy Combination Prolongs Survival in Advanced Biliary Tract Cancers

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The addition of the checkpoint inhibitor pembrolizumab to chemotherapy with cisplatin/gemcitabine as first-line therapy improved overall survival in patients with advanced biliary tract cancer, according to results of the KEYNOTE-966 trial presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting.1 At a median follow-up of 25.6 months, patients in the combination therapy arm had a 17% lower risk of death than patients treated with chemotherapy alone.

KEYNOTE-966 was the largest randomized trial conducted to date in biliary tract cancer. Although the improvement in median overall survival was modest, results were hailed as a major achievement in this cancer and were published in The Lancet to coincide with the presentation at the AACR meeting.2

R. Katie Kelley, MD

R. Katie Kelley, MD

“This is one of very few positive trials in this difficult-to-treat population,” said lead author R. Katie Kelley, MD, Professor at the Helen Diller Comprehensive Cancer Center, University of California San Francisco. “We saw a statistically significant and clinically meaningful difference, with a median duration of response that was prolonged. The data support pembrolizumab plus gemcitabine/cisplatin as a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer,” Dr. Kelley told listeners. “We look forward to upcoming analysis of quality of life and biomarkers,” she added.

Study Background

KEYNOTE-966 is the second phase III immunotherapy/chemotherapy combination to improve outcomes in biliary cancers. The phase III TOPAZ-1 trial showed an improvement in survival with the combination of durvalumab plus gemcitabine/cisplatin vs chemotherapy in 658 patients with advanced biliary tract cancer.3

Biliary tract cancers are a complex family of epithelial malignancies that arise from the intrahepatic or extrahepatic bile ducts and the gallbladder. The incidence is increasing worldwide. For the past decade, standard first-line treatment has been chemotherapy with the combination of gemcitabine/cisplatin, leading to a median overall survival of less than 1 year. New treatments are urgently needed.

The majority of these tumors have a “cold” immunogenic environment—ie, they are not likely to trigger a strong immune response. Standard chemotherapy with gemcitabine/cisplatin induces an immune response against biliary tract cancer cells, and the rationale for the addition of pembrolizumab is to boost the immune response and improve outcomes.

KEYNOTE-966 Details

This randomized, double-blind, placebo-controlled trial enrolled 1,069 patients with previously untreated metastatic or unresectable biliary tract cancers. Patients were randomly assigned 1:1 to receive pembrolizumab plus gemcitabine/cisplatin (n = 533) vs placebo plus gemcitabine/cisplatin (n = 536). Pembrolizumab was given at 200 mg intravenously every 3 weeks for up to 35 cycles. In both arms, gemcitabine was given at 1,000 mg/m2 intravenously on days 1 and 8 every 3 weeks (and could be continued), and cisplatin was given at 25 mg/m2 intravenously on days 1 and 8 every 3 weeks for eight cycles.

Patients were stratified for geographic region (Asia vs non-Asia), disease stage (locally advanced vs metastatic), and site of origin (extrahepatic vs gallbladder vs intrahepatic). The primary endpoint was overall survival.

“Unlike other trials [in this setting], gemcitabine could be continued beyond 6 months at the investigator’s discretion, provided there was no disease progression or toxicity,” Dr. Kelley noted.

Key Results

The immunotherapy/chemotherapy combination significantly improved overall survival (P = .0034). Median overall survival was 12.7 months vs 10.9 months, respectively. The 12-month overall survival rate was 52% vs 44%, and the 24-month survival rate was 25% vs 18%, respectively.

Subgroup analysis showed a similar benefit for Asian patients vs non-Asians and for all levels of PD-L1 expression. “We did notice a less pronounced benefit from the combination for extrahepatic vs intrahepatic disease. This may have been due to the fact that these patients have a higher risk of comorbidity,” Dr. Kelley said.

The difference in progression-free survival between treatment arms was not statistically significant, although there was an absolute difference in median progression-free survival of about 1 month favoring the combination arm. Response rates were similar between the two arms, but the duration of response was longer with the pembrolizumab-containing triplet (median = 9.7 vs 6.9 months) at the first interim analysis.

The side-effect profiles of the two treatment arms were well balanced and as expected for each agent. Immune-mediated side effects were mostly mild and manageable. Immune-mediated side effects and infusion reactions of any grade occurred in 22% of the experimental arm vs 13% of the control arm. Grade 3 to 4 immune-related adverse events occurred in 7% and 4%, respectively. One death in the pembrolizumab-containing arm was attributed to immune-related side effects vs none in the control arm. Treatment discontinuation rates were similar: 19% and 15%, respectively.

“Adding immunotherapy to chemotherapy does improve survival. This larger study adds confidence to the results with its broadly representative, global patient population. Importantly, the study allowed continuing gemcitabine beyond 6 months, reflecting practice patterns in many parts of the world,” Dr. Kelley noted during the discussion following her presentation at a press conference. 

DISCLOSURE: The study was funded by Merck, Sharp & Dohme. Dr. Kelley has served as a consultant or advisor (with fees going to her institution) to Agios, AstraZeneca, BMS, Exelixis, Ipsen, and MSD; a consultant or advisor (with fees going to herself) to Compass Therapeutics, Exact Sciences, Kinnate, Regeneron, Tyra Biosciences; and has received institutional research support from Agios, AstraZeneca, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Loxo Oncology, MSD, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho.


1. Kelley RK, Yoo C, Finn RS, et al: Pembrolizumab in combination with gemcitabine and cisplatin for advanced biliary tract cancer: Phase 3 KEYNOTE-966 study. AACR Annual Meeting 2023. Abstract CT008. Presented April 16, 2023.

2. Kelley RK, Ueno M, Yoo C, et al: 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. Lancet. April 14, 2023 (early release online).

3. Oh DY, He AR, Qin S, et al: Durvalumab plus gemcitabine and cisplatin in advanced biliary cancer. N Engl J Med. June 1, 2022 (early release online).

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