The phase 3 study, KEYNOTE-394, demonstrated significant benefit of using pembrolizumab in combination with best supportive care for Asian patients with advanced hepatocellular carcinoma (HCC) in second-line treatment.
The anti-PD-1 antibody pembrolizumab showed efficacy and manageable safety in the KEYNOTE-224 (phase 2) and KEYNOTE-240 (phase 3) studies in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-394 is a randomized, double-blind, phase 3 study conducted in Asia to evaluate the efficacy and safety of pembrolizumab vs placebo, both administered with best supportive care (BSC), as second-line therapy for previously treated advanced HCC. It is important to highlight that the study was carried out in a population with unmet medical needs.
Eligible patients with confirmed and progressing advanced HCC or who were intolerant to sorafenib, or oxaliplatin-based chemotherapy were randomized 2:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles or less in combination with BSC, per local guidelines. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and time to progression (TTP) – all assessed using the RECIST v1.1, by blinded, safety and independent central review. The dep value threshold for SG superiority in the final analysis was 0.019307. If the OS was superior, the superiority of PFS and ORR at the second intermediate analysis could be tested at boundaries of 0.013447 and 0.009139, respectively.
453 patients were randomized to receive pembrolizumab (300) or placebo (153). Baseline characteristics were generally balanced between groups; 90.7% received sorafenib as first-line therapy. At the cut-off date – June 30, 2021, for the final analysis, the median study follow-up was 33.8 months. In the final analysis, pembrolizumab significantly improved OS vs placebo (HR 0.79, 95% CI 0.63-0.99, P = 0.0180); median OS was 14.6 months for pembrolizumab vs 13.0 months for placebo, and the 24-month OS rate was 34.3% vs 24.9%.
In the second interim analysis, pembrolizumab significantly improved PFS (HR 0.74, 95% CI 0.60-0.92, P = 0.0032) and ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P = 0.00004); median PFS was 2.6 months for pembrolizumab vs 2.3 months for placebo. The 12-month PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%. In the final analysis, ORR was 13.7% vs 1.3%, median DOR was 23.9 months vs 5.6 months, DCR was 52.7% vs 47.7% and median TTP was 2.7 months versus 1.7 months (HR 0.72, 95% CI 0.58-0.90). In the final analysis, treatment-associated adverse events occurred in 66.9% of patients receiving pembrolizumab and 49.7% in the placebo group, including 14.4% and 5.9% with grade 3-5 events. 3 patients in the pembrolizumab arm died from these treatment-related events.
The pembrolizumab + BSC regimen significantly improved OS, PFS and ORR compared with placebo + BSC as second-line therapy for patients from Asian with advanced HCC. The safety profile of pembrolizumab was as expected. Overall, the results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and corroborate with evidence supporting the use of pembrolizumab as a second-line therapy for advanced HCC.
1. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study (https://meetings.asco.org/abstracts-presentations/205255 )