As reported in the Journal of Clinical Oncology by Qin et al, the phase III KEYNOTE-394 trial showed overall and progression-free survival benefits with pembrolizumab vs placebo in previously treated Asian patients with advanced hepatocellular carcinoma (HCC).

Study Details

The double-blind trial enrolled 453 patients from sites in mainland China, Hong Kong, the Republic of Korea, Malaysia, and Taiwan. They were randomly assigned 2:1 between May 2017 and December 2019 to receive pembrolizumab at 200 mg (n = 300) or placebo (n = 153) once every 3 weeks for up to 35 cycles plus best supportive care. Patients had disease progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy.

The primary endpoint was overall survival (significance threshold of P = .0193; final analysis). Secondary endpoints included progression-free survival (significance threshold of P = .0134; second interim analysis) and objective response rate (significance threshold of P = .0091; second interim analysis) on blinded independent central review.

Overall Survival and Other Outcomes

Median follow-up at final analysis of overall survival (data cutoff at end June 2021) was 33.8 months (range = 18.7–49.0 months). Median overall survival was 14.6 months (95% confidence interval [CI] = 12.6–18.0 months) in the pembrolizumab group vs 13.0 months (95% CI = 10.5–15.1 months) in the placebo group (hazard ratio [HR] = 0.79, 95% CI = 0.63–0.99, P = .0180), meeting the significance criterion. Estimated rates at 12, 24, and 36 months were 57.0% vs 52.9%, 34.3% vs 24.9%, and 23.4% vs 11.0%, respectively.

At second interim analysis (data cutoff at end of June 2020), median progression-free survival was 2.6 months (95% CI = 1.5–2.8 months) in the pembrolizumab group vs 2.3 months (95% CI = 1.4–2.8 months) in the placebo group (HR = 0.74, 95% CI = 0.60–0.92, P = .0032), meeting the significance criterion. Estimated rates at 12 and 18 months were 15.9% vs 1.4% and 11.8% vs 0%, respectively.

Objective response rates were 12.7% (95% CI = 9.1%–17.0%) in the pembrolizumab group vs 1.3% (95% CI = 0.2%–4.6%) in the placebo group (P < .0001), meeting the significance criterion.

Adverse Events

The most common treatment-related adverse events of any grade in patients in the pembrolizumab group were increased aspartate aminotransferase (12.0% vs 11.1% in the placebo group), increased alanine aminotransferase (11.7% vs 9.2%), and rash (11.7% vs 4.6%). Grade ≥ 3 treatment-related adverse events occurred in 14.3% vs 5.9% of patients. Treatment-related adverse events led to discontinuation of treatment in 4.0% vs 0.7%. Immune-mediated adverse events of any grade irrespective of causality attribution occurred in 18.1% vs 10.5% of patients. Treatment-related adverse events led to death in three patients in the pembrolizumab group (due to gastrointestinal hemorrhage, immune-mediated hepatitis, and soft-tissue infection); no patients in the placebo group died due to treatment-related adverse events.

The investigators concluded, “In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and progression-free survival, and objective response rate was greater [with pembrolizumab] vs placebo.”

Shukui Qin, MD, of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.