The addition of lenvatinib and pembrolizumab to transarterial chemoembolization (TACE) has shown a significant improvement in progression-free survival for patients with unresectable nonmetastatic hepatocellular carcinoma (HCC), according to results from the phase III LEAP-012 trial. The study, involving 480 patients across 33 countries, compared TACE plus lenvatinib/pembrolizumab against TACE plus placebo, marking a potential shift in the treatment paradigm for intermediate-stage HCC.
LEAP-012 Trial Details
The LEAP-012 trial was a double-blind, active-controlled, multicenter, randomized study. Patients were randomized to receive either TACE in combination with lenvatinib (12 mg daily for patients ≥ 60 kg, 8 mg daily for patients < 60 kg) and pembrolizumab (400 mg every 6 weeks), or TACE plus dual placebos. The choice of TACE method (conventional or drug-eluting beads) and chemotherapy agent was determined by each study site. The primary endpoint was progression-free survival as assessed by blinded independent central review, with overall survival as a key secondary endpoint.
The patient population was diverse, with 72% being Asian, 20% White, and 83% male.
Progression-Free Survival Benefit
The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival with the addition of lenvatinib and pembrolizumab to TACE. The median progression-free survival was 14.6 months (95% CI = 12.6–16.7 months) in the combination arm compared to 10.0 months (95% CI = 8.1–12.2 months) in the placebo arm (HR = 0.66, 95% CI = 0.51–0.84, P = .0002).
Overall Survival Trends
An interim analysis of overall survival showed a numerical improvement in the combination arm, although it did not reach statistical significance. The 2-year overall survival rate was 75% (95% CI = 68%–80%) in the lenvatinib/pembrolizumab group and 69% (95% CI = 62%–74%) in the placebo group (HR = 0.80, 95% CI = 0.57–1.11, P = .087). Longer follow-up is necessary to fully assess the overall survival benefit.
Safety Profile
The combination therapy was associated with a higher incidence of treatment-related adverse events. Grade ≥ 3 treatment-related adverse events occurred in 71% of patients in the lenvatinib/pembrolizumab arm compared to 32% in the placebo arm. Common adverse events included 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 deaths occurred in four patients in the combination arm and one in the placebo arm.
Expert Commentary
The investigators concluded that the addition of lenvatinib and pembrolizumab to TACE provides a significant and clinically meaningful improvement in progression-free survival for patients with unresectable nonmetastatic HCC. While the overall survival data is encouraging, further follow-up is needed. These findings suggest a potential new standard of care for patients with intermediate-stage HCC, addressing a critical unmet need in this population.
