Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study
- PMID: 40419140
- DOI: 10.1016/j.jtho.2025.05.016
Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study
Abstract
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.
Keywords: First-line therapy; Lenvatinib; Metastatic nonsquamous non–small cell lung cancer; NSCLC; Pembrolizumab.
Copyright © 2025 Merck & Co., Inc., Rahway, NJ, USA and its affiliates, The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure Dr. Herbst reports having financial interests, personal, advisory board, and consulting for EGFR and angiogenesis for AstraZeneca, Bolt Biotherapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, I-Mab Biopharma, Immunocore, Ocean Biomedical, Inc.; having financial interests, personal, other, ad hoc consulting-oncology for Bristol Myers Squibb, DynamiCure Biotechnology, LLC, Eli Lilly and Company, Foundation Medicine, Inc., Genentech/Roche, Gilead, Johnson and Johnson, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Oncternal Therapeutics, Pfizer, Sanofi, NextCure; having financial interests, personal - research advisory board for Candel Therapeutics, Inc.; having financial interests, personal, other, clinical advisor for eFFECTOR Therapeutics, Inc.; serving on the data safety monitory committee of EMD Serono, Novartis; having ad hoc consulting-KRAS and angiogenesis for Mirati Therapeutics; serving on the advisory board (clinical) of Ribbon Therapeutics, Xencor, Inc.; Consultant: AbbVie Pharmaceuticals, Loxo Oncology, Oncology: Oncocyte, Regeneron, Seattle Genetics; serving on the advisory board, consultant of Revelar Biotherapeutics; serving as member of board of directors, board member (non-executive/independent) of Immunocore Holdings Limited, Junshi Pharmaceuticals; having stocks/shares, options from Bolt Biotherapeutics, Immunocore, Checkpoint Therapeutics, Normunity; having financial interests, institutional, coordinating PI, research support from AstraZeneca, Genentech/Roche, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; having research support from Eli Lilly and Company; having nonfinancial interests, personal, leadership role, board member/committee chair for American Association for Cancer Research, International Association for the Study of Lung Cancer; having nonfinancial interests, committee chair for Society for Immunotherapy of Cancer, and Southwest Oncology Group. Prof. Cho received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received grant/research support from GIInnovation, AstraZeneca, Champions Oncology, CJ Bioscience, Cyrus, Janssen, MSD, Dong-A ST, Yuhan, ImmuneOncia, Therapex, J INTS Bio, Vertical Bio AG; consultant for BeiGene, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, CJ, Cyrus Therapeutics, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Gilead, Amgen, Daiichi Sankyo, Regeneron, Sanofi, AnHeart Therapeutics, Seagen, Harpoon Therapeutics, GSK, ArriVent; served on advisory boards for KANAPH Therapeutic Inc., Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, Therapex Co., Ltd.; was an invited speaker for American Society of Clinical Oncology (ASCO), AstraZeneca, Guardant, Roche, European Society of Medical Oncology (ESMO), International Association for the Study of Lung Cancer (IASLC), Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Zailab; and holds stocks/shares of TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp., and J INTS Bio; is the founder of DAAN Biotherapeutics; and is a member of the board of directors of J INTS Bio. Dr. Zhou reports receiving honoraria from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, Roche, and Qilu. Dr. Burotto reports receiving speaker fees from BMS, MSD, and Roche; serving on the advisory boards for BMS and MSD; and serving as a steering committee member for Roche. Dr. Dols reports receiving honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Lilly, MSD, Takeda, Kyowa, Pierre-Fabre, Novocure, Sanofi, Janssen; and has served on an advisory board and Data Safety Monitoring committee for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Lilly, MSD, Takeda, Pfizer, Kyowa, Sanofi, and Janssen. Dr. Sendur reports serving on the advisory board of Astellas, AstraZeneca, BMS, Gilead, Lilly, MSD, Novartis, Pfizer, and Takeda; serving as an invited speaker of Pfizer, Novartis, Astellas, BMS, MSD, Lilly, Gilead, and Takeda. Dr. Moiseyenko reports receiving funding to the institution to support study conduct from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Dr. Casarini reports receiving financial interests through institutional support as local principal investigator of multiple clinical studies sponsored by MSD, Bristol Myers Squibb, AstraZeneca, Eli Lilly, Exelixis, Novartis, and Roche; and reports serving as an invited speaker for AstraZeneca. Dr. Nishio reports participating in the speakers’ bureau for Ono Pharmaceuticals, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly Japan K.K, AstraZeneca, MSD, AbbVie, Takeda, Pfizer Japan, Boehringer Ingelheim, Novartis Pharma, Nippon Kayaku, Merck Biopharma, and Janssen. Prof. Hui reports receiving funding to the institution to support study conduct from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; receiving research support or grants from Amgen, AstraZeneca, BMS, Corvus, Eisai, Eli Lilly, Janssen, MSD, Novartis, Oncosec, Olema, Roche, and Seagen; served as an advisor for Amgen, AstraZeneca, BMS, Eisai, Eli Lilly, Janssen, Merck Serono, MSD, Novartis, Olema, Oncosec, Pfizer, Roche, Seagen, Takeda, Zai Lab; and served as a speaker for Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Janssen, Johnson & Johnson, MSD, and Novartis. Dr. Pons-Tostivint reports serving on the advisory board for AstraZeneca, Takeda, BMS, and Sanofi; having financial interests, institutional, local PI from AstraZeneca, BMS, Daiichi Sankyo, Sanofi, PDC line, Takeda, and Amgen. Dr. Dudnik reports receiving funding to the institution to support study conduct from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Prof. Ahmed reports receiving travel grants, lecture fees, and consultancies from MSD, Merck Serono, AstraZeneca, Novartis, Eisai, Lilly, Roche, Pfizer, Daiichi, and Gilead. Dr. Okpara reports serving as an employee of Eisai Ltd., Hatfield, UK. Dr. Dutcus reports serving as an employee of Eisai Inc., Nutley, NJ, USA. Dr. Yin reports serving as an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Dr. Luo reports serving as an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Dr. Chirovsky reports serving as an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Dr. Bhagwati reports serving as an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Dr. Abreu reports receiving personal fees/honoraria for consultancy/having advisory role and lectures from Roche/Genentech, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; receiving travel expenses from Roche, Bristol-Myers Squibb, MSD, Sanofi, Regeneron, and Novartis; and receiving institutional grant support for studies from BMS.
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Medical
