Liver and Bile
Lancet. 2025;405(10474):203-215
Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): A multicentre, randomised, double-blind, phase 3 study
Background: Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. The aim of this study was to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma. Methods: In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥ 60 kg: 12 mg; bodyweight < 60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold 1-sided p = 0.025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to 5 target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold 1-sided p = 0.0012) in the intention-to-treat (ITT) population (i.e., all participants randomly assigned to treatment). Safety was assessed in the as-treated population (i.e., all participants who were randomly assigned and received at least 1 dose of any study treatment). Here, results from the first interim analysis (final analysis for progression-free survival) were reported. Findings: Between May 22, 2020, and January 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n = 237) or TACE plus dual placebo (n = 243; ITT population). Median age was 66 years (interquartile range [IQR], 58–73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, 4 (1%) were Black or African American, and 5 (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (January 30, 2024) was 25.6 months (IQR, 19.5–32.4). Median progression-free survival was 14.6 months (95% confidence interval [CI]: 12.6–16.7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10.0 months (95% CI: 8.1–12.2; 154 events [8 deaths and 146 progressions]) with placebo (hazard ratio [HR] = 0.66 [95% CI: 0.51–0.84]; 1-sided p = 0.0002). 69 of 237 (29%) in the lenvatinib plus pembrolizumab group and 82 of 243 (34%) from the placebo group died, with a 24-month overall survival rate of 75% (95% CI: 68–80) in the lenvatinib plus pembrolizumab group and 69% (95% CI: 62–74) in the placebo group (HR = 0.80 [95% CI: 0.57–1.11]; 1-sided p = 0.087). Grade 3 or worse treatment-related adverse events occurred in 169 of 237 participants (71%) in the lenvatinib plus pembrolizumab group and in 76 of 241 (32%) in the placebo group, the most common of which were hypertension (57 [24%] vs. 18 [7%]) and platelet count decreased (27 [11%] vs. 15 [6%]). Deaths due to treatment-related adverse events occurred in 4 (2%) participants in the lenvatinib plus pembrolizumab group (n = 1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and 1 (< 1%) in the placebo group (due to brain stem haemorrhage).
Interpretation: Transarterial chemoembolisation (TACE) plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary.