Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial

Abstract

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

Immune-based therapies for hepatocellular carcinoma

“…Keynote-240 confirmed the ORR observed in other single-agent PD-1 studies (16.9%) with a median duration of response of 13.8 months (95% CI 12.7-23.6). Despite an improvement in the two co-primary endpoints of OS (HR = 0.78, 95%CI: 0.61-0.99; p = 0.0238) and PFS (HR = 0.78, 95%CI: 0.61-0.99; p = 0.0209), the study failed to meet the prespecified threshold for statistical significance [109]. Amongst the reasons considered for the discrepancy between predicted and observed effects of pembrolizumab in this patient population is the rapidly changing landscape of systemic treatment in HCC, with the advent of novel therapies such as regorafenib and cabozantinib having changed the expected survival probability of patients with advanced HCC [110].…”

Systemic therapy in advanced-stage hepatocellular carcinoma

“…The most frequent serious adverse events were increased serum transaminases and adrenal insufficiency. The final analyses of the phase-3 RCT KEYNOTE-240 evaluating pembrolizumab versus placebo as a second-line treatment in western HCC patients showed an improvement in the co-primary endpoints OS and PFS; however, these differences did not reach statistical significance per specified criteria [29].…”

Recent Advances in Immunotherapy for Hepatocellular Carcinoma

“…Based on this data, pembrolizumab was granted accelerated approval by the FDA in November 2018 as a second-line treatment after sorafenib. A phase III trial (KEYNOTE-240) comparing pembrolizumab to a placebo as a second-line treatment demonstrated that pembrolizumab was associated with a longer median OS and PFS; however, these findings were not deemed statistically significant according to the prespecified statistical plan [34]. Two further phase III trials are currently ongoing: KEYNOTE-394 is evaluating pembrolizumab versus a placebo and best supportive care in Asian patients with systemically treated advanced HCC, while KEYNOTE-937 is evaluating pembrolizumab versus a placebo as an adjuvant therapy in HCC patients after curative treatment.…”