Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study.

INTRODUCTION: We present the LEAP-006 (NCT03829319) phase 3 study evaluating the addition of lenvatinib to first-line pembrolizumab plus chemotherapy in metastatic nonsquamous NSCLC. METHODS: Adults with previously untreated stage IV nonsquamous NSCLC without targetable genetic alterations were randomized 1:1 to lenvatinib 8 mg/d or placebo once daily plus pembrolizumab 200 mg every 3 weeks with pemetrexed and carboplatin or cisplatin for 4 cycles, followed by pembrolizumab (≤35 total cycles) and pemetrexed until disease progression or intolerable toxicity. Primary end points were progression-free survival and overall survival (OS). Part 1 was an open-label safety run-in of lenvatinib plus pembrolizumab and chemotherapy; part 2 was the randomized, double-blind study. RESULTS: Participants (n = 748) were randomized to the lenvatinib (n = 375) or placebo (n = 373) arms. Median follow-up at final analysis (August 11, 2023) for OS was 36.8 months. Median (95% confidence interval [CI]) progression-free survival was 12.1 (10.4-14.1) versus 9.5 (8.3-10.7) months in the lenvatinib and placebo arms, respectively (hazard ratio, 0.88 [95% CI, 0.74-1.05]; 1-sided p = 0.07976). Median (95% CI) OS was 21.8 (18.6-24.0) versus 22.1 (19.7-24.2) months (hazard ratio, 1.05 [95% CI, 0.88-1.26]; 1-sided p = 0.70818). Grade 3 or higher treatment-related adverse events occurred in 69.7% and 55.6% of participants, respectively (grade 5, 5.6% versus 2.7%). CONCLUSIONS: Adding lenvatinib to first-line pembrolizumab plus chemotherapy did not improve efficacy versus pembrolizumab plus chemotherapy in stage IV nonsquamous NSCLC without targetable genetic alterations. There were no new safety signals. Pembrolizumab plus chemotherapy remains a standard of care for this population. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT03829319.