Pembrolizumab (Pembro) therapy vs best supportive care (BSC) in advanced hepatocellular carcinoma (HCC): KEYNOTE-240

Abstract

Background: Pembro received accelerated approval for second-line therapy in pts with advanced HCC, based on the phase 2, KEYNOTE-224 trial. KEYNOTE-240 was arandomized, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Method: Eligible pts had radiographic or pathologic diagnoses of HCC, progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to Pembro 200 mg+ BSC or placebo (Pbo) + BSC IV every 3 wk, stratified by geographic region, MVI and AFP levels for ≥35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk (RECIST v1.1, central imaging review). Co-primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR and safety. Data cutoff: OS, final analysis (Jan 2 2019); PFS, first interim (Mar 26 2018) and final analyses. Results: 413 patients were randomized (278 to Pembro,135 to Pbo). After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro, 3.0% on Pbo. Pembro improved OS (HR 0.781, 95% CI 0.611-0.998; one sided p=0.0238) and PFS (HR 0.775, 95% CI 0.609-0.987; one sided p=0.0186 [first interim] and 0.718, 95% CI 0.570-0.904; one sided p=0.0022 [final analysis]) vs Pbo; differences in OS at final and PFS at first interim analyses did not meet significance per the prespecified statistical plan. ORR (95% CI) was 18.3% (14.0-23.4%) and 4.4% (1.6-9.4%) for Pembro vs Pbo at final analysis (one sided p=0.00007); Pembro responses were durable (median DOR: 13.8 mo [1.5+ - 23.6+]). Off study, anticancer therapy use was 42% for Pembro and 47% for Pbo. Safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported for Pembro; no HBV/HCV flares were identified. Conclusion: Pembro reduced the risk of death by 22% and improved PFS vs Pbo in pts with advanced HCC, but significance did not meet prespecified statistical criteria. ORR for Pembro was consistent with that of KEYNOTE-224. New anticancer therapy in the Pbo arm likely impacted OS. The safety profile was comparable to that established for Pembro monotherapy. The results are consistent with those of KEYNOTE-224, further supporting second line therapy with Pembro in HCC pts.