Liver cancer is the second leading cause of cancer deaths worldwide. The tyrosine kinase inhibitor sorafenib is the standard of care for first-line hepatocellular carcinoma (HCC), and there is currently no clear standard of care for second-line HCC. Because most HCC is driven by inflammation, there is a strong rationale to evaluate immunotherapy in patients with this type of cancer. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov, NCT02702401) was designed to compare the efficacy and safety of pembrolizumab, an anti–PD-1 antibody, + best supportive care (BSC) versus placebo + BSC in patients with previously treated advanced HCC.
Eligibility criteria include age ≥18 years, histologically or cytologically confirmed diagnosis of HCC, documented progression after stopping treatment with sorafenib or intolerance to sorafenib, and disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation). Patients must also have measurable disease confirmed by central imaging vendor per RECIST v1.1, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy >3 months. ∼408 patients will be randomized 2:1 to receive pembrolizumab 200 mg IV Q3W + BSC or placebo Q3W + BSC for up to 35 cycles (∼2 years) or until disease progression, unacceptable toxicity, or investigator decision. Randomization will be stratified by geographic region, macrovascular invasion, and α-fetoprotein. BSC will be provided by the investigator per local treatment practices. Response will be assessed every 6 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary objectives are comparison of progression-free survival per RECIST v1.1 by central imaging vendor review and overall survival between treatment arms. Secondary objectives are comparison of objective response rate, duration of response, disease control rate, and time to progression per RECIST v1.1 by central imaging vendor review; and evaluation of safety and tolerability.
Clinical trial identification
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
R. Finn: Consultant: Pfizer, Merck, Bayer, Novartis, Bristol Meyers Squibb.
S.L. Chan: Advisory board member: Novartis, Merck Corporate-sponsored research: Novartis, Celgene, Eli Lilly, SIRTeX, AB Science, Merck, Medimmune.
A. Siegel: Employment, stock ownership at Merck & Co, Inc..
O. Bautista: Employee, shareholder at Merck & Co, Inc. Corporate research funding.
P.A. Watson: Employee, stock owner: Merck & Co, Inc.
M. Kudo: Bayer Co., Lecture fee.
All other authors have declared no conflicts of interest.