Merck's Keytruda (pembrolizumab) has shown a statistically significant and clinically meaningful improvement in overall survival (OS) in Asian patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. The Phase 3 KEYNOTE-394 trial, a randomized, double-blind study, demonstrated that Keytruda plus best supportive care (BSC) reduced the risk of death by 21% compared to placebo plus BSC (HR=0.79; 95% CI, 0.63-0.99; p=0.0180). These findings, presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium, highlight the potential of Keytruda as a second-line monotherapy treatment option for HCC.
Efficacy Results
The KEYNOTE-394 trial enrolled 453 patients in Asia with advanced HCC who had previously been treated with sorafenib or oxaliplatin-based chemotherapy. Patients were randomized to receive either Keytruda (intravenously every three weeks for up to 35 cycles) plus BSC or placebo plus BSC. The primary endpoint was OS, with additional endpoints including progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).
Median OS was 14.6 months (95% CI, 12.6-18.0) for patients treated with Keytruda plus BSC compared to 13.0 months (95% CI, 10.5-15.1) for those treated with placebo plus BSC. The percentage of patients alive at two years was 34.3% for the Keytruda arm versus 24.9% for the placebo arm. Keytruda plus BSC also reduced the risk of disease progression or death by 26% (HR=0.74; 95% CI, 0.60-0.92; p=0.0032). Median PFS was 2.6 months for Keytruda plus BSC and 2.3 months for placebo plus BSC. The ORR was 12.7% (95% CI, 9.1-17.0) for Keytruda plus BSC, with a median DOR of 23.9 months, compared to an ORR of 1.3% (95% CI, 0.2-4.6) for placebo plus BSC, with a median DOR of 5.6 months.
Safety Profile
Treatment-related adverse events (TRAEs) occurred in 66.9% of patients in the Keytruda plus BSC arm and 49.7% in the placebo plus BSC arm. Grade 3-5 TRAEs were reported in 14.4% and 5.9% of patients, respectively. Immune-mediated adverse events (AEs) of any grade occurred in 18.1% of patients receiving Keytruda plus BSC and 10.5% receiving placebo plus BSC. Grade 3-5 immune-mediated AEs occurred in 3.0% of patients receiving Keytruda plus BSC. Three deaths in the Keytruda arm were related to the study intervention (gastrointestinal hemorrhage, autoimmune hepatitis, and soft tissue infection).
Clinical Significance
"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," said Dr. Shukui Qin, director, Cancer Center of Jinling Hospital, and professor, Nanjing University of Chinese Medicine. "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."
About Hepatocellular Carcinoma
HCC accounts for 75% to 90% of primary liver cancer cases. Worldwide, major risk factors include chronic hepatitis B and C, alcohol use, and metabolic syndrome. Liver cancer is a leading cause of cancer-related deaths globally, with an estimated 905,000 new cases and 830,000 deaths in 2020.
Regulatory Status
In the U.S., Keytruda is indicated for HCC patients previously treated with sorafenib, based on ORR and DOR data from KEYNOTE-224. This indication is approved under accelerated approval, pending verification of clinical benefit in confirmatory trials. The KEYNOTE-394 data are being discussed with global regulatory authorities and will be evaluated as a potential confirmatory study in the U.S.
