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.

Abstract

383 Background: The anti–PD-1 antibody pembro showed efficacy and manageable safety in the global phase 2 KEYNOTE-224 and phase 3 KEYNOTE-240 studies of patients (pts) with previously treated advanced HCC, a population of high unmet need. KEYNOTE-394 is a randomized, double-blind, phase 3 study conducted in Asia to evaluate the efficacy and safety of pembro vs placebo, both given with BSC, as second-line therapy for previously treated advanced HCC (NCT03062358). Methods: Eligible pts in Asia with confirmed advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomized 2:1 to pembro 200 mg or placebo Q3W for ≤35 cycles plus BSC per local guidelines. The primary endpoint was OS. Secondary endpoints were PFS, ORR, DOR, DCR, and TTP, all assessed per RECIST v1.1 by blinded independent central review, and safety. Treatment differences were assessed using the stratified log-rank test (OS and PFS) or the stratified Miettinen & Nurminen method (ORR). The P value boundary for OS superiority at final analysis (FA) was 0.019307. If OS was superior, PFS and ORR superiority at the second interim analysis (IA2; primary analysis timepoint for these endpoints) could be tested at boundaries of 0.013447 and 0.009139, respectively. Results: 453 pts were randomized to pembro (N = 300) or placebo (N = 153). Baseline characteristics were generally balanced between arms; 90.7% had received sorafenib as first-line therapy. As of the June 30, 2021 cutoff date for FA, median study follow-up was 33.8 mo (range 18.7-49.0). At FA, pembro significantly improved OS vs placebo (HR 0.79, 95% CI 0.63-0.99, P = 0.0180); median (95% CI) OS was 14.6 mo (12.6-18.0) for pembro vs 13.0 mo (10.5-15.1) for placebo and 24-mo OS rate was 34.3% vs 24.9%. At IA2, pembro 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 (95% CI) PFS was 2.6 mo (1.5-2.8) for pembro vs 2.3 mo (1.4-2.8) for placebo, 12-mo PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%. At FA, ORR was 13.7% vs 1.3%, median DOR was 23.9 mo vs 5.6 mo, DCR was 52.7% vs 47.7%, and median TTP was 2.7 mo vs 1.7 mo (HR 0.72, 95% CI 0.58-0.90). At FA, treatment-related AEs occurred in 66.9% of pts in the pembro arm and 49.7% in the placebo arm, including 14.4% and 5.9% with grade 3-5 events. 3 pts (1.0%) in the pembro arm and 0 in the placebo arm died of treatment-related AEs. Conclusions: Pembro plus BSC significantly improved OS, PFS, and ORR compared with placebo plus BSC as second-line therapy for patients from Asia with advanced HCC. The pembro safety profile was as expected. Overall, results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and thus add to the body of evidence supporting the use of pembro as second-line therapy for advanced HCC. Clinical trial information: NCT03062358.

Hepatocellular Carcinoma: Pick the Winner—Tyrosine Kinase Inhibitor Versus Immuno-oncology Agent–Based Combinations

“…KEYNOTE 394, which had a similar trial design as KEYNOTE 240 but accrued patients exclusively from Asia, was recently presented. 15 The study reported an improvement in OS with pembrolizumab versus placebo of 14.6 months (12.6-18.0) versus 13.0 months (10.5-15.1) with a HR of 0.79 (95% CI, 0.63 to 0.99; P = .018). It improved the PFS from 2.3 months to 2.6 months (HR 0.74; 95% CI, 0.60 to 0.92; P = .0032) and ORRs from 1.3% to 13.7% with a median duration of response of 23.9 months in the pembrolizumab arm.…”

Immunotherapy and Hepatocellular Cancer: Where Are We Now?

“…Median PFS was 2.6 months for pembrolizumab versus 2.3 months for placebo. The ORR was 13.7% in the pembrolizumab group versus 1.3% in the BSC group, with a median duration of response of 23.9 months versus 5.6 months, “confirming that this agent has a positive effect as monotherapy” [ 14 ].…”

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook

“…The incidence of treatment-related AEs was relatively higher in pembrolizumab arm than that in placebo arm (66.9% vs 49.7%), which was consistent with that in the trial Keynote-224 and Keynote-240. 154 In addition, the post hoc analysis of Keynote-240 revealed that pembrolizumab did not significantly affect liver function in comparison to placebo in aHCC, and exhibited an improved survival regardless of ALBI grade. 155 The HRQOL assessment documented that pembrolizumab could provide a good HRQOL to aHCC patients.…”