Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC).

4004 Background: Pembro received accelerated approval based on results of KEYNOTE-224, a phase 2 trial in pts with advanced HCC in the second line setting. KEYNOTE-240 (NCT02702401) was a randomized, placebo (Pbo) controlled, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Methods: Eligible pts had a radiographic or pathologic diagnosis of HCC, radiographic progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to receive Pembro 200 mg + BSC or Pbo + BSC IV every 3 wk, stratified by geographic region, macrovascular invasion and ɑ-fetoprotein levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk per RECIST v1.1 by central imaging review. Co-primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR and safety. Data cutoff was Jan 2 2019 for OS; Mar 26 2018 for PFS and ORR. Results: 413 patients were randomized; 278 to Pembro and 135 to Pbo. After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro and 3.0% on Pbo. Pembro improved OS (HR: 0.78; one sided p = 0.0238) and PFS (HR: 0.78; one sided p = 0.0209) vs Pbo; these differences did not meet significance per the prespecified statistical plan. ORR was 16.9% (95% CI 12.7-21.8%) for Pembro vs 2.2% (95% CI 0.5-6.4%) for Pbo (nominal one sided p = 0.00001); responses on Pembro were durable (median DOR: 13.8 mo [1.5-23.6+]). Off study, new therapy use was 42% for Pembro and 47% for Pbo. The safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported in Pembro studies; no cases of HBV/HCV flare were identified. Conclusions: Pembro reduced the risk of death by 22% and improved PFS over Pbo in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. ORR in the Pembro arm was consistent with that of KEYNOTE-224. Subsequent anticancer therapy in the Pbo arm likely impacted the OS results. The safety profile was comparable to that established for Pembro monotherapy. These results are overall consistent with those of KEYNOTE-224 further supporting second line therapy with Pembro in HCC pts. Clinical trial information: NCT02702401.