As reported in The Lancet Oncology by Josep M. Llovet, MD, and colleagues, the phase III LEAP-002 trial has shown that the addition of pembrolizumab to lenvatinib in the first-line treatment of unresectable hepatocellular carcinoma did not reach statistical superiority thresholds for overall or progression-free survival.

Josep M. Llovet, MD

Study Details

In the global double-blind trial, 794 patients were randomly assigned between January 2019 and April 2020 to receive to pembrolizumab at 200 mg every 3 weeks (n = 395) or placebo (n = 399), both with lenvatinib once daily at 8 mg/day for bodyweight < 60 kg and 12 mg/day for ≥ 60 kg. Treatment was continued for a maximum of 35 cycles or until disease progression or unacceptable toxicity. Overall, 43% of enrolled patients were Asian and 43% were White.

The dual primary endpoints of the trial were overall survival (with a superiority threshold of P = .019) and progression-free survival (with a superiority threshold of P = .002) in the intention-to-treat population.

Overall and Progression-Free Survival

Median follow-up at data cutoff for the final overall survival analysis in June 2022 was 32.1 months (interquartile range [IQR] = 29.4–35.3 months). Median overall survival was 21.2 months (95% confidence interval [CI] = 19.0–23.6 months) in the pembrolizumab group vs 19.0 months (95% CI = 17.2–21.7 months) in the control group (hazard ratio [HR] = 0.84, 95% CI = 0.71–1.00, P = .023)—which failed to meet the efficacy threshold. Rates at 24 and 30 months were 43.7% vs 40.0% and 39.2% vs 31.0%, respectively.

At data cutoff for the final progression-free survival analysis in April 2021, median progression-free survival was 8.2 months (95% CI = 6.4–8.4 months) in the pembrolizumab group vs 8.0 months (95% CI = 6.3–8.2 months) in the control group (HR = 0.87, 95% CI = 0.73–1.02, P = .047)—which also failed to meet the efficacy threshold. Rates at 12 and 24 months were 34.1% vs 29.3% and 16.7% vs 9.3%, respectively.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 61.5% of patients in the pembrolizumab group vs 56.7% of those in the control group, most commonly hypertension (17% vs 17%), increased aspartate aminotransferase (7% vs 4%), and diarrhea (6% vs 4%). Treatment-related serious adverse events occurred in 25% vs 16% of patients.

Treatment-related adverse events led to discontinuation of any drug in 18% vs 11% of patients. Treatment-related death occurred in four patients in the pembrolizumab group (due to gastrointestinal hemorrhage and hepatorenal syndrome in one each and hepatic encephalopathy in two) and in three patients in the control group (due to gastrointestinal hemorrhage, hepatorenal syndrome, and cerebrovascular accident in one each).

The investigators concluded, “In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice.”

Dr. Llovet, of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Eisai US and Merck Sharp & Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit thelancet.com.