64O - Lenvatinib plus pembrolizumab, pemetrexed, and a platinum (len + pembro + chemo) as first-line therapy for metastatic nonsquamous non-small cell lung cancer (NSCLC): phase 3 LEAP-006 study

Background

LEAP-006 is a 2-part phase 3 study of len + pembro + chemo as first-line therapy for metastatic nonsquamous NSCLC (NCT03829319). Part 1 established len 8 mg/d as the recommended starting dose when added to pembro + chemo. We present results of part 2, a randomized, double-blind study of len + pembro + chemo vs placebo (pbo) + pembro + chemo.

Methods

Pts with stage IV nonsquamous NSCLC and no indication for EGFR-, ALK-, or ROS1-directed primary therapy were randomized 1:1 to len 8 mg/d or matching pbo PO QD until progression or intolerable toxicity; all pts received IV pembro 200 mg Q3W plus standard doses of pemetrexed and carboplatin or cisplatin for 4 cycles, followed by pembro (≤35 total cycles) and pemetrexed given until progression or intolerable toxicity. Dual primary endpoints were PFS per RECIST 1.1 by blinded, independent central review (BICR) and OS. Secondary endpoints included ORR per RECIST 1.1 by BICR and safety. Per the prespecified analysis plan, testing was complete at interim analysis (IA) 1 for ORR, IA3 for PFS, and final analysis (FA) for OS. All P values are one-sided.

Results

748 pts were randomized to len + pembro + chemo (n = 375) or pbo + pembro + chemo (n = 373). At FA, median study follow-up was 36.8 mo (28.4-46.4). At IA3, median (95% CI) PFS was 12.1 mo (10.4-14.1) in the len arm vs 9.5 mo (8.3-10.7) in the pbo arm (HR 0.88 [95% CI 0.74-1.05], P = 0.080). At FA, median (95% CI) OS was 21.8 mo (18.6-24.0) in the len arm vs 22.1 mo (19.7-24.2) in the pbo arm (HR 1.05 [95% CI 0.88-1.26], P = 0.708). At IA1, ORR (95% CI) was 57.1% (50.1-63.8) in the len arm vs 50.7% (43.8-57.6) in the pbo arm (difference 6.3 [95% CI -2.8 to 15.4], P = 0.086). At FA, treatment-related AEs were grade ≥3 in 69.7% in the len arm vs 55.6% in the pbo arm, led to death in 5.6% vs 2.7%, and led to discontinuation of ≥1 drug in 37.3% vs 27.7%.

Conclusions

Adding len to pembro + pemetrexed and a platinum did not improve on the efficacy of pembro + pemetrexed and a platinum as first-line therapy for stage IV nonsquamous NSCLC without targetable genetic alterations. There were no new safety signals. Pembro + chemo remains a standard-of-care for this population.

Clinical trial identification

NCT03829319, first posted February 4, 2019.

Editorial acknowledgement

Medical writing assistance was provided by Melanie A. Leiby, PhD, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Legal entity responsible for the study

Eisai Inc., Nutley, NJ, USA and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Eisai Inc., Nutley, NJ, USA and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

R.S. Herbst: Financial Interests, Personal, Advisory Board, Advisory board and consulting EGFR and angiogenesis: AstraZeneca; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Bolt Biotherapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, I-Mab Biopharma, Immunocore, Ocean Biomedical, Inc.; Financial Interests, Personal, Other, Ad hoc consulting-oncology: Bristol Myers Squibb, DynamiCure Biotechnology, LLC, Eli Lilly and Company, Foundation Medicine, Inc., Genentech/Roche, Gilead, Johnson and Johnson, Merck and Company, Oncternal Therapeutics, Pfizer, Sanofi, NextCure; Financial Interests, Personal, Advisory Board, Advisory Board - Research Advisory Board: Candel Therapeutics, Inc.; Financial Interests, Personal, Other, Clinical Advisor: eFFECTOR Therapeutics, Inc.; Financial Interests, Personal, Advisory Board, Data safety monitory committee: EMD Serono, Novartis; Financial Interests, Personal, Other, Ad hoc consulting-KRAS and angiogenesis: Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board (clinical): Ribbon Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board: Xencor, Inc; Financial Interests, Personal, Other, Consultant: AbbVie Pharmaceuticals, Loxo Oncology; Financial Interests, Personal, Other, Consultant - Ad-Hoc Consulting - Oncology: Oncocyte, Regeneron, Seattle Genetics; Financial Interests, Personal, Advisory Board, Consultant: Revelar Biotherapeutics; Financial Interests, Personal, Member of Board of Directors, Board Member (non-executive/ independent): Immunocore Holdings Limited, Junshi Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, Options: Bolt Biotherapeutics; Financial Interests, Personal, Stocks/Shares: Immuocore, Checkpoint Therapeutics, Normunity; Financial Interests, Institutional, Coordinating PI, Research Support: AstraZeneca, Genentech/Roche, Merck and Company; Financial Interests, Institutional, Funding, Research Support: Eli Lilly and Company; Non-Financial Interests, Personal, Leadership Role, Board Member/ Committee Chair: American Association for Cancer Research, International Association for the Study of Lung Cancer; Non-Financial Interests, Personal, Leadership Role, Committee Chair: Society for Immunotherapy of Cancer; Non-Financial Interests, Personal, Leadership Role, Committee Chair/ Principal Investigator: Southwest Oncology Group. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc. Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Other, Advisory role: Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS Bio; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, Kanaph Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS Bio; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine., Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Personal, Other, Founder: Daan Biotherapeutics. C. Zhou: Financial Interests, Personal, Invited Speaker, Honoraria: Eli Lily, Roche, Sanofi, Qilu Pharma, Hengrui, Innovent Biologics, C-Stone, Luye Pharma, TopAlliance Biosciences Inc; Financial Interests, Personal, Invited Speaker, BI: BI; Financial Interests, Personal, Invited Speaker, MSD: MSD; Financial Interests, Personal, Advisory Board, Advisor: Amoy Diagnositics. M. Burotto: Financial Interests, Personal, Advisory Board: Roche, Merck; Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca. M.A.N. Sendur: Financial Interests, Personal, Advisory Board: BMS, Pfizer, Takeda, Roche, Astellas; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer, BMS, MSD, Roche. V. Moiseyenko, B. Zurawski: Financial Interests, Institutional, Sponsor/Funding, Study funding to the institution to support study conduct: MSD. I.A. Casarini: Financial Interests, Institutional, Local PI, Principal investigator of multiple clinical studies of the company: MSD, Bristol, AstraZeneca, Lilly, Exelixis, Novartis; Financial Interests, Institutional, Local PI, Principal investigator in one study of the company: Roche. M. Nishio: Financial Interests, Personal, Invited Speaker, lectures fee: Ono Pharmaceuticals; Financial Interests, Personal, Invited Speaker, lectures: Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, Janssen; Financial Interests, Personal, Invited Speaker, lectures,: Lilly. R. Hui: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Eisai, Merck, Oncosec, Amgen, Takeda, Zai Lab; Financial Interests, Personal, Invited Speaker: MSD, Novartis, AstraZeneca, Eli Lilly, Janssen; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Novartis, Oncosec, Roche, Seagen, Corvus; Financial Interests, Personal, Steering Committee Member: MSD, AstraZeneca; Non-Financial Interests, Personal, Member: ASCO, IASLC, Medical Oncology Group of Australia (MOGA); Non-Financial Interests, Personal, Other, Member of IASLC Education Committee: IASLC. E. Pons-Tostivint: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, BMS, Sanofi; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Daiichi Sankyo, Sanofi, PDC line, Takeda, Amgen. S. Ahmed: Financial Interests, Personal and Institutional, Coordinating PI: MSD. C.E. Okpara: Financial Interests, Personal, Full or part-time Employment: Eisai Ltd. L. Yin, Y.Luo: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. N. Bhagwati: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. D. Rodriguez Abreu: Financial Interests, Personal, Advisory Board: MSD, Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Incyte, Merck Serono; Financial Interests, Personal, Invited Speaker: MSD, Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Merck Serono; Financial Interests, Personal, Other, Travel expenses: MSD, Novartis, Roche/Genentech, Pfizer. All other authors have declared no conflicts of interest.