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Clinical Trial
. 2025 Oct;20(10):1489-1504.
doi: 10.1016/j.jtho.2025.05.020. Epub 2025 Jun 3.

LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-Programmed Cell Death Protein 1 or Anti-Programmed Cell Death Ligand 1 Plus Platinum Chemotherapy

Natasha B Leighl  1 , Luis Paz-Ares  2 , Delvys Rodriguez Abreu  3 , Rina Hui  4 , Sofia Baka  5 , Frédéric Bigot  6 , Makoto Nishio  7 , Alexey Smolin  8 , Samreen Ahmed  9 , Adam J Schoenfeld  10 , Sameh Daher  11 , Diego L Cortinovis  12 , Vincenzo Di Noia  13 , Helena Linardou  14 , Justin F Gainor  15 , Corina Dutcus  16 , Chinyere E Okpara  17 , Xuan Deng  18 , Debra Kush  18 , Ashwini Arunachalam  18 , Andrew Song  18 , Byoung Chul Cho  19
Affiliations
Free article
Clinical Trial

LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-Programmed Cell Death Protein 1 or Anti-Programmed Cell Death Ligand 1 Plus Platinum Chemotherapy

Natasha B Leighl et al. J Thorac Oncol. 2025 Oct.
Free article

Abstract

Background: LEAP-008 (NCT03976375) was an open-label, randomized, phase 3 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic NSCLC that progressed on anti‒programmed cell death protein 1 or anti‒programmed cell death ligand 1 therapy and platinum-containing chemotherapy.

Methods: Participants were randomized 4:4:1 to once-daily lenvatinib 20 mg plus pembrolizumab 200 mg every 3 weeks (maximum 35 cycles), docetaxel 75 mg/m2 every 3 weeks, or once-daily lenvatinib 24 mg. Primary end points were overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by central review. The superiority of lenvatinib plus pembrolizumab versus docetaxel was assessed at interim analysis 2 for PFS and final analysis for OS.

Results: Participants (N = 422) were randomized to lenvatinib plus pembrolizumab (n = 185), docetaxel (n = 189), or lenvatinib monotherapy (n = 48). The median (95% confidence interval [CI]) PFS was 5.6 (4.2‒6.5) months with lenvatinib plus pembrolizumab and 4.2 (3.2‒5.2) months with docetaxel (hazard ratio, 0.89 [95% CI: 0.70‒1.12]; p = 0.164). The median (95% CI) OS was 11.3 (9.4‒13.2) versus 12.0 (9.6‒13.7) months (hazard ratio, 0.98 [95% CI: 0.78‒1.23]; p = 0.434). Rates of treatment-related adverse events were 91.7%, 91.0%, and 89.4% with lenvatinib plus pembrolizumab, docetaxel, and lenvatinib, respectively; the rates of grade 3 to 5 treatment-related adverse events were 59.7%, 48.6%, and 57.4%. Health-related quality of life scores were similar between treatment arms.

Conclusion: Lenvatinib plus pembrolizumab did not improve efficacy versus docetaxel in participants with stage IV NSCLC that progressed on anti‒programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy and platinum-containing chemotherapy. There were no unexpected safety signals. More effective therapies are needed for this patient population.

Keywords: Docetaxel; Lenvatinib; NSCLC; Non–small-cell lung cancer; Pembrolizumab; Phase 3 clinical trial.

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Conflict of interest statement

Disclosure Dr. Leighl reports receiving grants or contracts (institution) from AstraZeneca, GlaxoSmithKline, Lilly, Janssen, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), Neogenomics, Novartis, Pfizer, and Takeda; received honoraria (unrelated Continuing Medical Education [CME] lectures) from Beigene, Bristol-Myers Squibb, Janssen, MSD, Novartis, and Takeda; received support for meeting travel from AstraZeneca, Eisai, Guardant Health, Janssen, MSD, Roche, and Sanofi; and participated in Data Safety Monitoring Boards (uncompensated) for Mirati and Daiichi Sankyo. Dr. Paz-Ares reports receiving consulting fees from Lilly, MSD, Roche, PharmaMar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Pfizer, Sanofi, Bayer, Bristol-Myers Squibb, Mirati, GlaxoSmithKline, Janssen, Takeda, Regeneron, Sanofi, Gilead, Roche, AbbVie, and Daiichi Sankyo; grants or contracts from MSD, AstraZeneca, Bristol-Myers Squibb, and Pfizer; and honoraria for lectures/speakers bureau from AstraZeneca, Janssen, Merck Serono, Mirati, and Sanofi. Dr. Rodriguez Abreu reports receiving personal fees/honoraria for consultancy/advisory roles and lectures from Roche/Genentech, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; travel expenses from Roche, Bristol-Myers Squibb, MSD, Sanofi, Regeneron, and Novartis; and institutional grant support for studies from Bristol-Myers Squibb. 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; research support or grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Corvus, Eisai, Eli Lilly, Janssen, MSD, Novartis, Oncosec, Olema, Roche, and Seagen; served as an advisor for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Eli Lilly, Janssen, Merck Serono, MSD, Novartis, Olema, Oncosec, Pfizer, Roche, Seagen, Takeda, and Zai Laboratory; and served as speaker for Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Janssen, Johnson & Johnson, MSD, and Novartis. Dr. Baka reports receiving honoraria and participating in advisory board for AstraZeneca, Bristol-Myers Squibb, Servier, MSD, Novartis, and Roche; and received institutional research funding from GlaxoSmithKline, AstraZeneca, MSD, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck KGaA, Novartis, Takeda, Roche, Sanofi-Aventis, Daiichi Sankyo, Astellas, Parexel, PPD, IQVIA, Amgen, and Regeneron. Dr. Bigot reports receiving honoraria (institution) from AstraZeneca, Bristol-Myers Squibb, Regeneron, Takeda, MSD, and Sanofi; and received support for congress or meetings and accommodation from MSD, Janssen, and AstraZeneca. Dr. Nishio reports participating at 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. Dr. Smolin reports receiving grants or contracts (institution) from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Takeda, MSD, BIOCAD, and R-Farm; and received honoraria (unrelated CME lectures) from Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, Pfizer, and R-Farm. Prof. Ahmed reports receiving travel grants, lecture fees, and consultancies from MSD, Merck Serono, AstraZeneca, Novartis, Eisai, Lilly, Roche, Pfizer, Daichi, and Gilead. Dr. Schoenfeld reports having consulting/advising roles to Johnson & Johnson, KSQ therapeutics, Bristol-Myers Squibb, MSD, AstraZeneca, Synthekine, cTRL therapeutics, Regeneron, Enara Bio, Perceptive Advisors, Oppenheimer and Co., Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Obsidian Therapeutics, Prelude Therapeutics, Immunocore, Lyell Immunopharma, Amgen, and Heat Biologics; and received institutional research funding from GlaxoSmithKline, PACT Pharma, Iovance Biotherapeutics, Achilles therapeutics, MSD, Synthekine, Bristol-Myers Squibb, Harpoon Therapeutics, AffiniT therapeutics, Legend Therapeutics, Synthekine, and Amgen. Dr. Daher received honoraria from Bristol-Myers Squibb, Takeda, MSD, Roche, Merck KGaA, AstraZeneca, Pfizer, and Medison. Dr. Cortinovis received honoraria/participated in the speaker bureau/served as a scientific advisor from Roche, AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, Boehringer Ingelheim, Amgen, Novartis, Seagen, Takeda, GlaxoSmithKline, Beigene, Pfizer, and Johnson & Johnson. Dr. Di Noia reports receiving speakers’ fees from AstraZeneca, MSD, Bristol-Myers Squibb, Istituto Gentili, and Boehringer Ingelheim; grants from consultancies by AstraZeneca, MSD, Bristol-Myers Squibb, Boehringer Ingelheim, and Novartis; travel fees from MSD, Roche, and Boehringer Ingelheim; institutional research grants from Roche and F.C.; and is a member of the advisory board of GlaxoSmithKline, Roche, AstraZeneca, Eli Lilly, and Regeneron. Dr. Linardou received honoraria or fees for serving as a consultant or as member as an advisory board for Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Takeda, and Institutional research funding from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Health Data Specialist, Lilly, MSD, Novartis, Parexel, PPD, Qualitis, and Roche. Dr. Gainor is a compensated consultant for Amgen, AstraZeneca, Mariana Therapeutics, Mirati Therapeutics, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Silverback Therapeutics, Sanofi, Blueprint Medicines, Bristol-Myers Squibb, Genentech, Gilead Sciences, ITeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly/Loxo, MSD, Moderna Therapeutics, and Takeda; has received honoraria from Novartis, MSD, Novartis, Pfizer, and Takeda; has received institutional research funding from Adaptimmune, Alexo Therapeutics, AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Genentech, Jounce Therapeutics, MSD, Moderna Therapeutics, Novartis, NextPoint Therapeutics, and Palleon Pharmaceuticals; received research support from Novartis, Genentech, and Takeda; has equity in AI Proteins; and has an immediate family member who has equity in and is employed by Ironwood Pharmaceuticals. Dr. Dutcus is an employee of Eisai Inc., Nutley, NJ, USA. Dr. Okpara is an employee of Eisai Ltd., Hatfield, United Kingdom. Dr. Deng, Ms. Kush, Dr. Arunachalam, and Dr. Song are employees 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. Prof. Cho received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received grant/research support from GIInnovation, AstraZeneca, Champions Onoclogy, CJ Bioscience, Cyrus, Janssen, MSD, Dong-A ST, Yuhan, ImmuneOncia, Therapex, J INTS bio, and Vertical Bio AG; served as a consultant for BeiGene, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol-Myers Squibb, CJ, Cyrus therapeutics, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Gliead, Amgen, Daiichi Sankyo, Regeneron, Sanofi, AnHeart Therapeutics, Seagen, Harpoon Therapeutics, GlaxoSmithKline, ArriVent; served on advisory boards for KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, and Therapex Co., Ltd.; was an invited speaker for American Society of Clinical Oncology (ASCO), Astra Zeneca, 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; 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.

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