Primary Results from the Phase 3 Leap-002 Study: Lenvatinib plus Pembrolizumab versus Lenvatinib as First-Line Therapy for Advanced Hepatocellular Carcinoma

Background

The global, randomized, double-blind, Ph3 LEAP-002 study (NCT03713593) evaluated the efficacy and safety of lenvatinib + pembrolizumab (lenva + pembro) vs lenvatinib (lenva) + placebo as 1L therapy for advanced hepatocellular carcinoma (aHCC).

Methods

1. Eligible pts with aHCC were randomized 1:1 to lenvatinib (8 mg/day if BW<60 kg or 12 mg/day if BW≥60 kg) plus pembrolizumab (200 mg IV Q3W) or lenvatinib plus placebo.
2. Dual primary endpoints OS and PFS (per RECIST 1.1 by BICR) were assessed using the stratified log-rank test. ORR (per RECIST 1.1 by BICR) was a key secondary endpoint.
3. The protocol specified 2 interim analyses (IAs) and a final analysis (FA) for OS. Prespecified efficacy boundaries were one-sided P = 0.002 for PFS at IA1 (prespecified final PFS analysis) and 0.0185 for OS at FA.

Results

1. 794 pts were randomized (lenvatinib+ pembrolizumab, 395; lenvatinib, 399).
2. At FA (data cutoff 21 June 2022; median follow-up 32.1 months), 534 OS events had occurred and 36 pts (9.1%) in the lenvatinib + pembrolizumab arm and 24 pts (6.1%) in the lenvatinib arm remained on study treatment.
3. The median OS with lenvatinib + pembrolizumab was 21.2 months vs 19.0 months with lenvatinib, and the HR was 0.840 (95% CI: 0.708-0.997, P=0.0227).
4. HR for PFS at IA1 (data cutoff 5 April 2021) was 0.867 (95% CI: 0.734-1.024, P=0.0466,)
5. ORR at FA was 26.1% for lenvatinib + pembrolizumab vs 17.5% for lenvatinib.
6. Grade 3-5 treatment-related adverse events (TRAEs) were 62.5% in the lenvatinib + pembrolizumab arm and 57.5% in the lenvatinib arm (grade 5 TRAEs, 1.0% vs 0.8%).
7. Post-study systemic anti-cancer treatments were used in 44.1% vs 52.1% of pts, in each arm, respectively.

Conclusions

• LEAP-002 primary endpoints of OS (at FA) and PFS (at IA1) did not meet pre-specified statistical significance.
• The combination of lenvatinib+ pembrolizumab achieved the longest median OS ever reported in 1L HCC Ph3 studies (21.2 months) with no new safety signals observed.
• The median OS of 19.0 months with lenvatinib monotherapy supports its role as a standard of care in 1L aHCC.

Finn RS, Kudo M, Merle P et al. Primary Results from the Phase 3 LEAP-002 Study: Lenvatinib plus Pembrolizumab versus Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma Abstract presented at: 2022 European Society of Medical Oncology, September 9-13, 2022; Paris, France & Online. Abstract # LBA34 https://oncologypro.esmo.org/meeting-resources/esmo-congress/primary-results-from-the-phase-iii-leap-002-study-lenvatinib-plus-pembrolizumab-versus-lenvatinib-as-first-line-1l-therapy-for-advanced-hepatoce