The addition of pembrolizumab and lenvatinib to transarterial chemoembolization (TACE) significantly improves progression-free survival in patients with unresectable, nonmetastatic hepatocellular carcinoma (HCC), according to the first interim analysis of the phase III LEAP-012 trial. The study, presented at the European Society for Medical Oncology (ESMO) Congress 2024, highlights a potential new standard of care for this patient population.
The LEAP-012 trial (NCT04246177) is a multicenter, randomized, double-blind phase III trial evaluating pembrolizumab plus lenvatinib in combination with TACE versus dual placebo plus TACE for the treatment of patients with unresectable, nonmetastatic HCC. The primary endpoint is progression-free survival, assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1.
Progression-Free Survival Improvement
After a median follow-up of 25.6 months, the combination of pembrolizumab plus lenvatinib with TACE demonstrated a statistically significant and clinically meaningful improvement in progression-free survival. The risk of disease progression or death was reduced by 34% (HR = 0.66; 95% 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 versus 10.0 months (95% CI = 8.1–12.2 months) for TACE alone.
Overall Survival Trend
At the time of this interim analysis, a trend toward improvement in overall survival was observed for the pembrolizumab/lenvatinib-based regimen compared to TACE alone (HR = 0.80; 95% CI = 0.57–1.11; P = .0867). However, the overall survival data are not yet mature and did not reach statistical significance.
Study Design and Treatment
The LEAP-012 trial randomly assigned 480 patients 1:1 to receive either:
- Pembrolizumab at 400 mg intravenously 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.
- Intravenous placebo every 6 weeks plus oral placebo once a day in combination with TACE.
Treatment was administered to 237 patients receiving the pembrolizumab/lenvatinib-based regimen and 241 patients receiving TACE alone. Pembrolizumab was administered for up to 2 years (approximately 18 doses), after which lenvatinib could be administered as a single agent until protocol-specified discontinuation criteria were met.
Safety Profile
The safety profile of the pembrolizumab/lenvatinib-based regimen was consistent with that observed in previously reported studies evaluating the combination. Treatment-related adverse events occurred in 98.7% of patients receiving pembrolizumab plus lenvatinib in combination with TACE versus 84.6% of patients receiving TACE alone and led to the discontinuation of both study drugs in 8.4% versus 1.2% of patients, respectively. Serious adverse events were observed in 33.3% of patients receiving pembrolizumab plus lenvatinib in combination with TACE versus 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 versus 31.1% for TACE alone, and treatment-related adverse events led to death in 1.7% (n = 4) versus 0.4% (n = 1) of patients, respectively.
