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. We aimed 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 one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five 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 one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting.

Findings: Between May 22, 2020, and Jan 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 (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 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% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 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 four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage).

Interpretation: 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.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.