Transarterial chemoembolization (TACE) with or without lenvatinib (len) plus pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study

초록

Background TACE remains standard of care for intermediate-stage HCC. We present results from LEAP-012, a randomized, multicenter, double-blind, phase 3 trial evaluating len + pembro + TACE vs placebo + TACE in intermediate-stage HCC. Methods Eligible patients (pts) with HCC not amenable to curative treatment and Child-Pugh class A, no portal vein invasion, and ECOG PS of 0 or 1 were randomized 1:1 to len 12 mg (body weight ≥60 kg) or 8 mg (body weight <60 kg) QD PO + pembro 400 mg Q6W IV or to placebo PO + IV for up to 2 years; len/oral placebo alone continued until progression or discontinuation. The first TACE occurred 2-4 weeks after the start of systemic therapy, with a maximum of 2 treatments per tumor (4 total), no more than once per month. Randomization was stratified by study site, AFP, ECOG PS, ALBI grade, and tumor burden. Primary end points were PFS per RECIST v1.1 by BICR and OS; HR and 95% CIs were estimated using a stratified Cox proportional hazards model with the Efron method of tie handling. Results 480 pts were randomly assigned to len + pembro (n = 237) or placebo PO + IV (n = 243); both groups received TACE. At this first interim analysis, median time from randomization to data cutoff (Jan 30, 2024) was 25.6 months (range, 12.6-43.5). With 286 events, PFS was significantly improved for len + pembro vs placebo (HR, 0.66, 95% CI, 0.51-0.84; P = 0.0002; significance threshold, P = 0.025); median PFS was 14.6 months (95% CI, 12.6-16.7) vs 10.0 months (95% CI, 8.1-12.2). With 151 events (47.5%), OS was immature and the significance threshold was not met (HR, 0.80; 95% CI, 0.57-1.11; P = 0.0867; significance threshold, P = 0.0012). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 71.3% of pts in the len + pembro group vs 31.5% in the placebo group; TRAEs led to the discontinuation of both study drugs in 8.4% vs 1.2% of pts, respectively. Conclusions LEAP-012 met its primary end point. Len + pembro + TACE showed a statistically significant, clinically meaningful improvement in PFS and an early trend toward improvement in OS vs placebo + TACE in pts with intermediate-stage HCC. The AE profile was consistent with known safety profiles of len, pembro, and TACE. OS will be retested in future analyses.