Pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract cancer: phase 3 KEYNOTE-966 trial in progress

Abstract

Background Biliary tract cancer (BTC) is a rare and heterogeneous malignancy comprising intrahepatic cholangiocarcinoma (CCA), extrahepatic CCA, and gallbladder cancer. Surgery is potentially curative in patients with early disease, but recurrence is common. Combination chemotherapy with gemcitabine and cisplatin is the current standard of care for advanced BTC in most regions as well as S-1 therapy in Japan. Pembrolizumab has demonstrated modest but durable antitumor activity in patients with BTC as monotherapy and improved survival when used in combination with platinum-based chemotherapy in other oncologic indications. KEYNOTE-966 (NCT04003636) is a randomized, double-blind, phase 3 trial evaluating pembrolizumab or placebo plus gemcitabine and cisplatin in patients with advanced BTC. Trial design Eligible patients are ≥18 years old with histologically confirmed metastatic or unresectable BTC, measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function. Patients who have received prior systemic therapy for advanced disease, or prior therapy with an anti-PD-1/PD-L1/PD-L2 or CTLA-4 agent, and those with a history of pneumonitis, HIV infection, or central nervous system metastases will be excluded. Patients with past or ongoing HCV or controlled HBV infection are eligible per protocol-defined criteria, provided they do not have dual active HBV and HCV infection at study entry. Approximately 788 patients will be randomly assigned 1:1 to pembrolizumab 200 mg or placebo IV every 3 weeks in combination with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 IV on days 1 and 8 of every 3-week cycle. Cisplatin will be given for a maximum of 8 cycles; gemcitabine will be given until progression, unacceptable toxicity, or withdrawal. Treatment with pembrolizumab/placebo will be continued for up to 35 cycles (∼2 years of treatment) or until progression, unacceptable toxicity, or withdrawal. Patients will be stratified by region (Asia, non-Asia), stage (locally advanced, metastatic), and tumor origin (gallbladder, intrahepatic, extrahepatic). Imaging will be performed every 6 weeks through week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). Co-primary endpoints are progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary endpoints are objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR, and safety. Exploratory endpoints are disease control rate (DCR) per RECIST v1.1 by BICR; PFS, ORR, DOR, and DCR per immune-modified RECIST; PFS and ORR per RECIST v1.1 by BICR; and health-related quality of life (by EORTC QLQ-C30, EORTC QLQ-BIL21, and EuroQol EQ-5D-5L). Recruitment began in September 2019 and is underway in 19 countries.