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

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Dr Finn reviews the results from the Leap-002 study which evaluates the use of lenvatinib with pembrolizumab in the front-line setting for patients with advanced hepatocellular carcinoma.



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).


  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.


  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.


  • 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