Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study.

Summary

In the phase 3 LEAP-012 trial, adding lenvatinib plus pembrolizumab to TACE prolonged progression-free survival versus TACE plus placebo in unresectable, non-metastatic HCC (median 14.6 vs 10.0 months; HR 0.66; one-sided p=0.0002). Overall survival showed a favorable trend at 24 months, with higher toxicity in the combination group.

Key Findings

• Progression-free survival improved with TACE plus lenvatinib plus pembrolizumab vs TACE plus placebo (median 14.6 vs 10.0 months; HR 0.66; one-sided p=0.0002).
• At 24 months, overall survival rates were 75% vs 69% (HR 0.80; one-sided p=0.087), indicating a favorable trend but not yet statistically significant.
• Grade ≥3 treatment-related adverse events occurred in 71% vs 32%, with hypertension and thrombocytopenia most common; treatment-related deaths were 2% vs <1%.

Clinical Implications

If longer follow-up confirms an overall survival benefit, TACE plus lenvatinib and pembrolizumab could become a new standard for unresectable, non-metastatic HCC in Child-Pugh A patients, with careful management of hypertension and other toxicities.

Limitations

• Overall survival was not yet statistically significant at interim; longer follow-up is required.
• Higher toxicity with the combination and eligibility limited to Child-Pugh A may constrain generalisability.

Future Directions

Mature OS analysis, biomarker-driven selection, toxicity mitigation strategies, and cost-effectiveness analyses will inform adoption.