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 was found to have 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 tumor proportion score of at least 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 up to 35 cycles. Primary end points were progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 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 review (futility bound: one-sided p < 0.4960). Results: A total of 623 patients were randomized. At median follow-up of 15.9 months, median (95% confidence interval [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 (hazard ratio = 1.10 [95% CI: 0.87-1.39], p = 0.79744 [futility criterion met]). Median (95% CI) PFS was 6.6 (6.1-8.2) months versus 4.2 (4.1-6.2) months, respectively (hazard ratio = 0.78 [95% CI: 0.64-0.95]). Grade 3 to 5 treatment- related adverse events occurred in 57.9% of patients (179 of 309) versus 24.4% (76 of 312). Per data and safety monitoring committee 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 programmed cell death-ligand 1 tumor proportion score of at least 1% without EGFR/ALK alterations. (c) 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and The Author(s). Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).