According to results of the first interim analysis of the phase III LEAP-012 trial, the anti–PD-1 therapy pembrolizumab plus the tyrosine kinase inhibitor lenvatinib, in combination with transarterial chemoembolization (TACE), significantly improved progression-free survival compared with TACE alone for the treatment of patients with unresectable, nonmetastatic hepatocellular carcinoma (HCC). These late-breaking data were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2024 (Abstract LBA3).

After a median follow-up of 25.6 months (range = 12.6–43.5 months), pembrolizumab plus lenvatinib in combination with TACE demonstrated a statistically significant and clinically meaningful improvement in progression-free survival, reducing the risk of disease progression or death by 34% (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.51–0.84; P = .0002) compared with TACE alone. Median progression-free survival was 14.6 months (95% CI = 12.6–16.7 months) for the pembrolizumab/lenvatinib–based regimen vs 10.0 months (95% CI = 8.1–12.2 months) for TACE alone.

At this analysis, a trend toward improvement in overall survival, the trial’s other primary endpoint, was observed for the pembrolizumab/lenvatinib–based regimen vs TACE alone (HR = 0.80; 95% CI = 0.57–1.11; P = .0867). The overall survival data are not mature and did not reach statistical significance at the time of this interim analysis. The safety profile of the pembrolizumab/lenvatinib–based regimen was consistent with that observed in previously reported studies evaluating the combination.

LEAP-012 Study Details

LEAP-012 is a multicenter, randomized, double-blind phase III trial (ClinicalTrials.gov identifier NCT04246177) evaluating pembrolizumab plus lenvatinib in combination with TACE vs dual placebo plus TACE for the treatment of patients with unresectable, nonmetastatic HCC. The primary endpoints are progression-free survival as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints include objective response rate, duration of response, disease control rate, and time to disease progression. The study randomly assigned 480 patients 1:1 to receive:

• Pembrolizumab at 400 mg intravenously [IV] every 6 weeks plus lenvatinib at 12 mg (for participants with screening body weight ≥ 60 kg) or 8 mg (for participants with screening body weight < 60 kg) orally once a day) in combination with TACE (conducted as a background procedure of chemotherapeutic and embolic agents injected via hepatic artery 2 to 4 weeks after the start of the study intervention and after the first tumor assessment scan and at least 1 month after the first TACE); or
• IV placebo administered every 6 weeks plus oral placebo administered once a day in combination with TACE.

All study drugs were continued until protocol-specified discontinuation criteria. Pembrolizumab was administered for up to 2 years (approximately 18 doses). After completing 2 years of combination therapy, lenvatinib may have been administered as a single agent until protocol-specified discontinuation criteria were met.

Treatment was administered to 237 patients receiving the pembrolizumab/lenvatinib-based regimen and 241 patients receiving TACE alone. Treatment-related adverse events occurred in 98.7% of patients receiving pembrolizumab plus lenvatinib in combination with TACE vs 84.6% of patients receiving TACE alone and led to the discontinuation of both study drugs in 8.4% vs 1.2% of patients, respectively.

Serious adverse events were observed in 33.3% of patients receiving pembrolizumab plus lenvatinib in combination with TACE vs 12.4% of patients receiving TACE alone. Grade 3 or 4 treatment-related adverse events occurred in 71.3% of patients receiving pembrolizumab plus lenvatinib in combination with TACE vs 31.1% for TACE alone, and treatment-related adverse events led to death in 1.7% (n = 4) vs 0.4% (n = 1) of patients, respectively.