Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial

Introduction Lenvatinib plus pembrolizumab demonstrated antitumor activity and acceptable safety in previously treated metastatic NSCLC. We evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in metastatic NSCLC in the LEAP-007 study (NCT03829332/NCT04676412). Methods Patients with previously untreated stage IV NSCLC with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1% without targetable EGFR/ROS1/ALK aberrations were randomized 1:1 to lenvatinib 20 mg or placebo once daily; all patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles. Primary endpoints were progression-free survival (RECIST version 1.1) and overall survival (OS). We report results from a prespecified nonbinding futility analysis of OS performed at the fourth independent data and safety monitoring committee (DMC) review (futility bound: 1-sided P<0.4960). Results 623 patients were randomized. At median follow-up of 15.9 months, median (95% CI) OS was 14.1 (11.4‒19.0) months in the lenvatinib plus pembrolizumab group versus 16.4 (12.6‒20.6) months in the placebo plus pembrolizumab group (HR, 1.10 [95% CI, 0.87‒1.39]; P=0.79744 [futility criterion met]). Median (95% CI) progression-free survival was 6.6 (6.1‒8.2) versus 4.2 (4.1‒6.2) months, respectively (HR, 0.78 [95% CI, 0.64‒0.95]). Grade 3‒5 treatment-related adverse events (AEs) occurred in 57.9% of patients (179/309) versus 24.4% (76/312). Per DMC recommendation, the study was unblinded and lenvatinib and placebo were discontinued. Conclusions Lenvatinib plus pembrolizumab did not have a favorable benefit‒risk profile versus placebo plus pembrolizumab. Pembrolizumab monotherapy remains an approved treatment option in many regions for first-line metastatic NSCLC with PD-L1 TPS ≥1% without EGFR/ALK alterations.