Phase 3 Data for Pembrolizumab in Hepatocellular Carcinoma Show Significant Improvements in OS, PFS

Merck had previously received accelerated approval for pembrolizumab for patients with advanced hepatocellular carcinoma (HCC); an FDA panel left the approval in place while waiting on results from KEYNOTE-394.

Phase 3 results from the KEYNOTE-394 trial show pembrolizumab (Keytruda) with best supportive care (BSC) offered patients with advanced hepatocellular carcinoma (HCC) significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with placebo and BSC, according to data released today.

The study will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), being held January 20-22 in San Francisco, California.

In KEYNOTE-394 (NCT03062358), 453 patients from Asia were randomized 2:1 to receive the anti-PD-1 antibody pembrolizumab or placebo. Treatment arms were well-balanced; 90.7% of the patients had received sorafenib as a first-line therapy. Patients received 200 mg of pembrolizumab every 3 weeks for up to 35 cycles or placebo with BSC, per local guidelines. Data were cut off June 30, 2021, after a median follow-up of 33.8 months. Results were as follows:

  • Pembrolizumab improved OS vs placebo, with hazard ratio (HR) of 0.79; 95% CI, 0.63-0.99; P = .018.
  • Median OS was 14.6 months (12.6-18.0) for pembrolizumab vs 13.0 months (10.5-15.1) for placebo; the 24-month OS rate was 34.3% vs 24.9%, favoring pembrolizumab.
  • At the second interim analysis, pembrolizumab had significantly improved PFS (HR 0.74, 95% CI, 0.60-0.92; P = .0032), and ORR (estimated difference, 11.4%; 95% CI 6.7-16.0, P = .00004); median PFS was 2.6 months (1.5-2.8) for pembrolizumab vs 2.3 months (1.4-2.8) for placebo; 12-month PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%.
  • At the final analysis, ORR was 13.7% vs 1.3%, and median duration of response was 23.9 months vs 5.6 months.
  • At final analysis, treatment-related adverse event (AEs) had occurred in 66.9% of patients taking pembrolizumab, vs 49.7% in the placebo arm; 14.4% and 5.9% had grade 3-5 events, respectively.
  • Investigators reported that 3 patients (1.0%) in the pembrolizumab arm died of treatment-related AEs; none died of treatment-related AEs in the placebo arm.

“Hepatocellular carcinoma is a leading cause of cancer death across the world, and there are limited treatment options shown to extend survival for patients following treatment with sorafenib,” Shukui Qin, director, Cancer Center of Jinling Hospital, and professor, Nanjing University of Chinese Medicine, said in a statement. “These overall survival data are very encouraging for patients with HCC previously treated with sorafenib and show the potential of KEYTRUDA to extend the lives of these patients.”

Accelerated approval. Pembrolizumab received accelerated approval in November 2018 for patients with HCC who had previously been treated with sorafenib, based on ORR and durability of response data from an earlier trial, KEYNOTE-224. However, a later study, KEYNOTE-240, did not meet primary end points in OS and PFS.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met April 29, 2021, and voted 8-0 to maintain the accelerated approval in the HCC indication. ODAC members discussed the possibility that results from KEYNOTE-394 would confirm the clinical benefits of pembrolizumab in patients previously treated with sorafenib. Merck announced topline results for KEYNOTE-394 in September.


Qin S, Chen Z, Fang W, et al. Pembrolizumab (pembro) plus best supportive care (BSC) versus placebo plus BSC as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI); January 20-22, 2022; San Francisco, CA; Abstract 352788.

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