KEY TAKEAWAYS
- The LEAP-012 phase 3 trial aimed to evaluate if len and pembro with TACE improve PFS vs placebo plus TACE in intermediate-stage HCC.
- The primary endpoints were to determine PFS and OS.
- Researchers observed that len and pembro with TACE improved PFS and suggested a trend toward better OS.
TACE remains the standard of care for intermediate-stage hepatocellular carcinoma (HCC). In this LEAP-012 study, a randomized, multicenter, double-blind, phase 3 trial, Josep Llovet and the team aimed to evaluate the efficacy of lenvatinib (len) combined with pembrolizumab (pembro) and TACE versus placebo plus TACE in this patient population.
They performed an inclusive analysis of eligible patients with HCC who were not candidates for curative treatment, had Child-Pugh class A liver function, had no portal vein invasion, and had an ECOG performance status of 0 or 1. These patients were randomized 1:1 to receive either len (12 mg for body weight ≥60 kg or 8 mg for body weight <60 kg) plus pembro (400 mg every 6 weeks) or placebo plus TACE for up to 2 years. Len or placebo continued until disease progression or discontinuation.
The initial TACE treatment occurred 2-4 weeks after the start of systemic therapy, with a maximum of two treatments per tumor (up to 4 in total) and no more than once per month. Randomization was stratified by study site, alpha-fetoprotein levels, ECOG performance status, ALBI grade, and tumor burden.
The primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS), with hazard ratios (HR) and 95% confidence intervals (CI) estimated using a stratified Cox proportional hazards model with the Efron method for tie handling.
About 480 patients were randomly assigned to receive either len plus pembro (n = 237) or placebo (n = 243), with both groups undergoing TACE. At the first interim analysis, with a median follow-up of 25.6 months (range, 12.6-43.5) from randomization to data cutoff (January 30, 2024), 286 PFS events were recorded.
PFS was significantly improved in the len plus pembro group compared to the placebo group (HR – 0.66; 95%, CI – 0.51-0.84; P = 0.0002; significance threshold, P = 0.025), with median PFS of 14.6 months (95% CI, 12.6-16.7) versus 10.0 months (95% CI, 8.1-12.2).
With 151 OS events (47.5%), OS data were 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 patients in the len plus pembro group versus 31.5% in the placebo group, with TRAEs leading to the discontinuation of both study drugs in 8.4% versus 1.2% of patients, respectively.
The study concluded that len plus pembro combined with TACE demonstrated a statistically significant and clinically meaningful improvement in PFS compared to placebo plus TACE in patients with intermediate-stage HCC.
An early trend towards improved OS was also observed. The adverse event profile was consistent with the known safety profiles of len, pembro, and TACE. OS will be further evaluated in future analyses.
The trial was sponsored by the Merck Sharp & Dohme LLC.
Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/101
Clinical Trial: https://clinicaltrials.gov/study/NCT04246177
Llovet J, Finn R.S, Ren Z, et al. (2024). “Transarterial chemoembolization (TACE) with or without lenvatinib (len) + pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study.” Presented at ESMO 2024 (Abstract LBA3).
