Richard S. Finn, MD
As reported in the Journal of Clinical Oncology by Richard S. Finn, MD, and colleagues, the phase III KEYNOTE-240 trial has shown no statistically significant progression-free or overall survival benefit with pembrolizumab vs placebo in patients with advanced hepatocellular carcinoma who were previously treated with sorafenib. Outcomes were numerically better with pembrolizumab.
The double-blind trial included 413 patients from 119 sites in 27 countries enrolled between May 2016 and November 2017. Patients were randomly assigned 2:1 to receive 200 mg of pembrolizumab every 3 weeks for at least 35 cycles (approximately 2 years) plus best supportive care (n = 278) or placebo plus best supportive care (n = 135).
The coprimary endpoints were overall survival and progression-free survival on independent central review in the intention-to-treat population, with significance thresholds of P = .0174 for final analysis and P = .002 for first interim analysis.
Median follow-up was 13.8 months in the pembrolizumab group and 10.6 months in the placebo group. Median overall survival at final analysis was 13.9 months (95% confidence interval [CI] = 11.6–16.0 months) vs 10.6 months (95% CI = 8.3–13.5 months), with a hazard ratio (HR) favoring pembrolizumab of 0.781 (95% CI = 0.611–0.998, P = .0238). Median progression-free survival was 3.0 months (95% CI = 2.8–4.1 months) vs 2.8 months (95% CI = 2.5–4.1 months) at first interim analysis (HR = 0.775, 95% CI = 0.609–0.987, P = .0186) and 3.0 months (95% CI = 2.–-4.1 months) versus 2.8 months (95% CI = 1.6–3.0 months) at final analysis (HR = 0.718, 95% CI = 0.570–0.904, P = .0022).
Grade ≥ 3 adverse events occurred in 52.7% of the pembrolizumab group vs 46.3% of the placebo group and were considered treatment-related in 18.6% vs 7.5%. Adverse events led to discontinuation of treatment in 17.2% vs 9.0% of patients, with the most common causes being ascites (4.3% vs 2.2%) and increased aspartate transaminase and bilirubin (1.4% and 0.7% in each group). Immune-mediated adverse events occurred in 18.3% vs 8.2% of patients, with the most common of any grade being hypothyroidism (5.0% vs 5.2%), hyperthyroidism (3.2% vs 0%), and pneumonitis (3.6% vs 0.7%); immune-mediated adverse events were grade ≥ 3 in 7.2% vs 0.7%. Immune-mediated hepatitis events occurred in 3.6% vs 0% of patients; no cases of hepatitis B or C viral flares were observed in either group.
The investigators concluded, “In this study, [overall survival] and [progression-free survival] did not reach statistical significance per specified criteria. The results are consistent with those of [the phase II] KEYNOTE-224 [trial], supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.”
Dr. Finn, of the University of California, Los Angeles, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.