Randomized, Double-Blind, Phase III LEAP-003 Study of First-Line Lenvatinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab for Unresectable or Metastatic Melanoma
Mené sur 674 patients atteints d'un mélanome non résécable ou métastatique, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de l'ajout du lenvatinib au pembrolizumab en traitement de première ligne
Background: Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti–PD-(L)1 therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma.
Participants and Methods: Participants with unresectable stage III or IV melanoma, previously untreated with PD-1 or PD-L1 checkpoint inhibitors, were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and overall survival (OS). PFS was formally tested at the first interim analysis; OS at the final analysis. An external data monitoring committee regularly reviewed safety and efficacy. Three interim analyses and a final analysis were planned.
Results: Overall, 674 participants were assigned to lenvatinib plus pembrolizumab (n = 334) or placebo plus pembrolizumab (n = 340). Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.88; P = 0.0008). This benefit was not maintained at final analysis (HR, 0.83; 95% CI, 0.69-1.00). Median OS at final analysis was 25.8 months for lenvatinib plus pembrolizumab versus 39.5 months for placebo plus pembrolizumab (HR, 1.20; 95% CI, 0.97-1.48; P = 0.9521). Grade 3-5 treatment-related adverse events occurred in 58.7% of participants receiving lenvatinib plus pembrolizumab versus 29.0% receiving placebo plus pembrolizumab.
Conclusion: Lenvatinib plus pembrolizumab did not provide additional benefit versus placebo plus pembrolizumab in participants with unresectable advanced melanoma. Thus, the trial was terminated early, and the third interim analysis became the final analysis. Immunotherapy remains the standard of care for advanced melanoma.
Annals of Oncology , résumé, 2025