LEAP-012: Lenvatinib Plus Pembrolizumab Improves PFS in Intermediate-Stage HCC

In a study presented at the European Society for Medical Oncology Congress 2024 by lead author Josep Llovet, MD, PhD, of the University of Barcelona, the combination of lenvatinib and pembrolizumab with transarterial chemoembolization (TACE) was evaluated against TACE plus placebo in patients with intermediate-stage hepatocellular carcinoma (HCC). TACE remains the standard of care in this population.

The phase 3 LEAP-012 study explored the potential benefit of adding systemic therapy to enhance treatment outcomes.

LEAP-012 is a randomized, double-blind, multicenter study that enrolled 480 patients with HCC that was not responsive to curative treatment, Child-Pugh class A liver function, no portal vein invasion, and ECOG performance status of 0 or 1.

Participants were randomized 1:1 to receive lenvatinib (12 mg or 8 mg, depending on body weight) plus pembrolizumab (400 mg every 6 weeks) or placebo alongside TACE. Patients were treated with systemic therapy before and after TACE, with no more than two treatments per tumor and four TACE procedures. The primary endpoints were progression-free survival (PFS) and overall survival (OS), assessed by independent radiology review (BICR).

At the first interim analysis, after a median follow-up of 25.6 months, the trial met its primary endpoint, showing a significant improvement in PFS. The combination of lenvatinib and pembrolizumab plus TACE resulted in a median PFS of 14.6 months (95% CI, 12.6-16.7) compared to 10 months (95% CI, 8.1-12.2) with placebo plus TACE, with a hazard ratio (HR) of 0.66 (95% CI, 0.51-0.84; P=.0002), indicating a 34% reduction in the risk of progression.

Overall survival data remained immature, with 47.5% of events occurring at the time of analysis. The median OS had not been reached, and the HR for OS was 0.80 (95% CI, 0.57-1.11; P=.0867), falling short of the prespecified significance threshold (P=.0012).

The safety analysis revealed that treatment-related adverse events (TRAEs) of grade 3-5 occurred in 71.3% of patients in the lenvatinib plus pembrolizumab group versus 31.5% in the placebo group. In addition, 8.4% of patients receiving the combination discontinued treatment due to TRAEs, compared to 1.2% in the placebo arm. These events were consistent with the known safety profiles of lenvatinib, pembrolizumab, and TACE.

The LEAP-012 study demonstrated a statistically significant and clinically meaningful improvement in PFS with lenvatinib and pembrolizumab combined with TACE compared to TACE alone in patients with intermediate-stage HCC. While OS improvement was not statistically significant at this interim analysis, further follow-up is needed to assess the long-term survival benefit.