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

The KEYNOTE-966 Investigators, Robin Kate Kelley, Makoto Ueno, Changhoon Yoo, Richard S. Finn, Junji Furuse, Zhenggang Ren, Thomas Yau, Heinz-Josef Klümpen, Stephen L. Chan, Masato Ozaka, Chris Verslype, Mohamed Bouattour, Joon Oh Park, Olga Barajas, Uwe Pelzer, Juan W. Valle, Li Yu, Usha Malhotra, Abby B. SiegelJulien Edeline, Arndt Vogel

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Abstract

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer has been chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We conducted a study to determine whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in biliary tract cancer.

Methods: The randomised, double-blind, placebo-controlled phase 3 KEYNOTE-966 study enrolled participants with previously untreated unresectable, locally advanced or metastatic biliary tract cancer at 175 medical centres globally. Eligible participants were randomised (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum, 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum, 8 cycles). Randomisation was stratified by geographic region, disease stage, and site of origin. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, number NCT04003636.

Findings: Between October 4, 2019, and June 8, 2021, 1069 participants were randomised to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% confidence interval [CI] 11·5-13·6) in the pembrolizumab group versus 10·9 months (95% CI 9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95], one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3-4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group and was grade 5 in 31 (6%) and 49 (9%) participants, respectively.

Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer.
Original languageEnglish
JournalThe Lancet
Early online date16 Apr 2023
DOIs
Publication statusE-pub ahead of print - 16 Apr 2023

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