The LEAP-012 trial met its primary end point demonstrating a statistically significant and clinically meaningful improvement in PFS with the addition of lenvatinib plus pembrolizumab to transarterial chemoembolization (TACE) for patients with intermediate-stage hepatocellular carcinoma (HCC).

These findings were presented by Josep Llovet, MD, PhD, University of Barcelona, Spain, lead investigator of the LEAP-012 trial, at the 2024 ESMO Congress in Barcelona, Spain.

LEAP-012 enrolled patients with HCC not amenable to curative treatment and Child-Pugh class A, no portal vein invasion, and an ECOG performance score (PS) of 0 or 1. Patients were randomized in a 1:1 ratio to receive lenvatinib plus pembrolizumab or placebo and continued treatment until progression or discontinuation. The first TACE occurred 2 to 4 weeks after the start of systemic therapy, with a maximum of 2 treatments per tumor (4 total), no more than once per month.

Study randomization was stratified by site, AFP, ECOG PS, ALBI grade, and tumor burden. The primary end points were PFS by blinded independent central review per RECIST v1.1 and OS. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a stratified Cox proportional hazards model with the Efron method of tie handling.

In total, 480 patients were enrolled and randomized to lenvatinib plus pembrolizumab (n = 237) or placebo (n = 243); both groups received TACE. At the first interim analysis, median time from randomization to data cutoff was 25.6 months (range, 12.6 to 43.5).

Overall, with 286 events, median PFS was 14.6 months (95% CI, 12.6 to 16.7) in the lenvatinib plus pembrolizumab arm vs 10 months (95% CI, 8.1 to 12.2) in the placebo arm (HR, 0.66; 95% CI, 0.51 to 0.84; P = .0002; significance threshold, P = .025). With 151 events, OS data was immature and the significance threshold was not met (HR, 0.80; 95% CI, 0.57 to 1.11; P = 0.0867; significance threshold, P = .0012). 

Regarding safety, grade 3 to 5 treatment-related adverse events (AEs) occurred in 71.3% of patients in the lenvatinib plus pembrolizumab arm and 31.5% of patients in the placebo arm. Treatment-related AEs led to discontinuation of both study drugs in 8.4% vs 1.2% of patients, respectively.

In conclusion, the LEAP-012 trial met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in PFS with the addition of lenvatinib plus TACE for this patient population, and showed an early trend toward improved OS, which will be retested in future analyses.

Source:

Llovet J, Finn RS, Ren Z, et al. Transarterial chemoembolization (TACE) with or without lenvatinib (len) + pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study. Presented at 2024 ESMO Congress. September 13-17, 2024. Abstract LBA3