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.

Study Details

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.

Survival Outcomes

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).

Adverse Events

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.