As reported in The Lancet by Kudo et al, the phase III LEAP-012 trial has shown a significant progression-free survival benefit with the addition of lenvatinib and pembrolizumab to transarterial chemoembolization (TACE) in patients with unresectable nonmetastatic hepatocellular carcinoma (HCC). A numeric benefit in overall survival was observed on interim analysis.
Study Details
In the double-blind trial, 480 patients from sites in 33 countries/regions were randomly assigned between May 2020 and January 2023 to receive TACE plus lenvatinib/pembrolizumab (n = 237) or TACE plus dual placebos (n = 243). The selection of TACE method (conventional or with drug-eluting beads) and chemotherapy agent was prespecified by each study site. Lenvatinib was given at 12 mg once daily for patients weighing ≥ 60 kg and 8 mg once daily for those weighing < 60 kg. Pembrolizumab was given at 400 mg once every 6 weeks for up to 2 years. Overall, 72% of enrolled patients were Asian, 20% were White, and 83% were male. The primary endpoints of the study were progression-free survival on blinded independent central review (superiority threshold of P = .025) and overall survival (threshold of P = .0012). The current report provides the final analysis for progression-free survival and the first interim analysis for overall survival.
Key Findings
Median follow-up was 25.6 months (interquartile range = 19.5–32.4 months) at data cutoff (end of January 2024). Median progression-free survival was 14.6 months (95% confidence interval [CI] = 12.6–16.7 months) in the TACE plus lenvatinib/pembrolizumab group vs 10.0 months (95% CI = 8.1–12.2 months) in the TACE plus placebos group (hazard ratio [HR] = 0.66, 95% CI = 0.51–0.84, P = .0002).
At interim analysis, death occurred in 29% of the TACE plus lenvatinib/pembrolizumab group and in 34% of the TACE plus placebos group. Overall survival at 2 years was 75% (95% CI = 68%–80%) vs 69% (95% CI = 62%–74%), with a hazard ratio of 0.80 (95% CI = 0.57–1.11, P = .087).
Grade ≥ 3 treatment-related adverse events occurred in 71% of the TACE plus lenvatinib/pembrolizumab group vs 32% of the TACE plus placebos group. The most common events in both groups were hypertension (24% vs 7%), decreased platelets (11% vs 6%), and increased aspartate aminotransferase (7% vs 5%). Treatment-related adverse events led to discontinuation of both lenvatinib and pembrolizumab in 8% of patients. Treatment-related death occurred in four patients in the TACE plus lenvatinib/pembrolizumab group (due to hepatic failure, gastrointestinal hemorrhage, myositis, and immune-mediated hepatitis in one each) vs one patient in the TACE plus placebos group (due to brain stem hemorrhage).
The investigators concluded, “TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, nonmetastatic [HCC] compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary.”
Josep M. Llovet, MD, PhD, of the Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, and Eisai. For full disclosures of the study authors, visit thelancet.com.
