Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies.

Background & Aims: We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC).

Methods: Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer stage C or B disease not amenable to or refractory to locoregional therapy, and one or more measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for ≤35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately.

Results: In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (hazard ratio 0.79, 95% CI 0.67-0.93), progression-free survival (per RECIST v1.1 by blinded independent central review [BICR]; hazard ratio 0.76, 95% CI 0.64-0.89), and objective response rate (per RECIST v1.1 by BICR; 15.4% 2.8%, for an estimated treatment difference of 12.5%; 95% CI 8.8-16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region.

Conclusions: Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in overall survival, progression-free survival, and objective response rate. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy.

Impact And Implications: To obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma, we performed a meta-analysis of efficacy using pooled participant data from the phase III KEYNOTE-240 and KEYNOTE-394 studies. Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. This meta-analysis provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced hepatocellular carcinoma.

Clinical Trials Registration: Registered at ClinicalTrials.gov NCT02702401 (KEYNOTE-240) and NCT03062358 (KEYNOTE-394).