A double-blind, phase III KEYNOTE-394 study evaluated the efficacy and safety of pembrolizumab plus best supportive care (BCS) versus placebo plus BCS in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC) and disease progression or intolerance to sorafenib or oxaliplatin-based chemotherapy. Pembrolizumab showed statistically significant improvement in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with placebo. Side effects were manageable and consistent with the known safety profile of pembrolizumab in patients with previously treated advanced HCC. The findings are published by Dr. Shukui Qin of the Jinling Hospital, Nanjing University of Chinese Medicine in Nanjing, China and colleagues on 1 December 2022 in the Journal of Clinical Oncology.
The authors wrote in the study background that HCC is the main histologic type of primary liver cancer. Patients are often diagnosed with advanced stage disease not amenable to curative treatment approaches in most regions of the world. Although advances in antiangiogenic treatment and immunotherapy have improved clinical outcomes in the first- and second-line treatment settings, availability differs across the globe and there is a paucity of data from phase III clinical studies supporting single-agent second-line immune checkpoint inhibitors. The incidence and mortality are especially high in Eastern Asia. Disease burden is also high in Northern America.
Pembrolizumab received accelerated approval from the US Food and Drug Administration in November 2018 based on findings from the global phase II KEYNOTE-224 study conducted in patients with advanced HCC previously treated with sorafenib. A similar favourable benefit-to-risk profile for pembrolizumab when added to BSC compared with placebo plus BSC was observed in the global phase III KEYNOTE-240 study. However, the KEYNOTE-240 study missed prespecified statistical significance criteria for OS or PFS.
The KEYNOTE-394 study was conducted to determine whether pembrolizumab plus BSC would improve efficacy compared with placebo plus BSC in patients from Asia with advanced HCC who were previously treated with sorafenib or oxaliplatin-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus BSC. The primary endpoint was OS, secondary endpoints included PFS and ORR according the RECIST v1.1 evaluated by blinded independent central review.
Median OS was longer in the pembrolizumab group than in the placebo group, 14.6 versus 13.0 months (hazard ratio [HR] for death 0.79; 95% confidence interval [CI] 0.63 to 0.99; p = 0.0180). Median PFS was also longer in the pembrolizumab group than in the placebo group, although not clinically meaningful, 2.6 versus 2.3 months (HR ratio for progression or death 0.74; 95% CI 0.60 to 0.92; p = 0.0032). ORR was greater in the pembrolizumab group, 12.7% (95% CI 9.1 to 17.0) than 1.3% in the placebo group (95% CI 0.2 to 4.6; p < 0.0001).
Treatment-related side effects occurred in 66.9% of patients in the pembrolizumab group with 12.0% being grade 3, 1.3% grade 4 and 1.0% grade 5, and 49.7% of patients in the placebo group with 5.9% being grade 3, and 0% of grade 4 or 5.
The authors wrote that the data in their study reinforce observations in globally conducted studies with pembrolizumab in the second-line treatment of advanced HCC and support it as a single agent in this setting. The proportion of patients who received post-study PD1(-L1) inhibitors following progression was primarily driven by availability of treatment options in Asia at the time of the study. In mainland China, where approximately 80% of patients were enrolled, camrelizumab was approved in 2020 and tislelizumab was approved in 2021. However, the last patient was enrolled in the KEYNOTE-394 study in December 2019. Pembrolizumab is not approved in mainland China for the treatment of advanced HCC.
The findings were previously presented in part at the Gastrointestinal Cancers Symposium (ASCO GI) Annual Meeting in San Francisco, CA, US (20-22 January 2022).
The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ.
Qin S, Chen Z, Fang W, et al. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. JCO; Published online 1 December 2022. DOI: 10.1200/JCO.22.00620