1302P - MET×MET bispecific antibody davutamig (REGN5093) for MET-altered advanced non-small cell lung cancer (aNSCLC): Update from a first-in-human (FIH) study

Background

MET alterations have emerged as actionable targets in aNSCLC. Davutamig (REGN5093) is a novel human bispecific antibody that binds 2 distinct epitopes of MET, blocking ligand binding and inducing MET internalization and degradation. We investigate safety, tolerability, and antitumor activity of davutamig in a FIH study.

Methods

This Phase 1/2, FIH, open-label study includes patients (pts) with MET-altered aNSCLC (unresectable or metastatic) for whom there was no standard therapy option likely to convey clinical benefit. A dose-escalation phase (davutamig 500, 1000, and 2000 mg IV Q3W) was followed by an expansion phase (2000 mg) in cohorts with MET alterations per local testing: exon 14 skipping mutation (ex14 mut), gene amplification, or protein overexpression. MET alterations were also assessed and confirmed retrospectively by a central laboratory. Tumor assessment was performed every 6 weeks until progression or end of study.

Results

As of 8 Dec 2023, 82 pts (median age 67 years; 44% female; 71% Asian; 37% with EGFR mutation) were enrolled, with a median of 2 prior lines of therapy (anti–PD-(L)1 in 61%). Pts received a median of 4 doses of davutamig (range 1–42). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 29% (24/82) of pts, with treatment-related G≥3 TEAEs in 6% (5/82). TEAEs led to treatment discontinuation in 3 pts (4%), and among these, 1 pt had a TEAE (pneumonitis) with a fatal outcome. Peripheral edema occurred in 13% (11/82) of pts, with G≥3 in 1 pt. Of all 74 pts who received the 2000 mg dose, 9 pts (12%) had a partial response per investigator assessment, and 43 pts (58%) demonstrated disease control. Median duration of response was 7.4 months (95% CI 2.2–24.9). Objective response rates (ORR) among MET TKI-naïve pts with a centrally confirmed MET alteration were 25% (4/16) for MET ex14 mut, and 13% (4/32) for MET overexpression and/or MET amplification without MET ex14 alteration. No response was observed in pts with a centrally confirmed MET ex14 mut who had prior MET TKI treatment.

Conclusions

In this FIH study of MET-altered aNSCLC, davutamig showed a favorable safety profile, with early signs of efficacy in pts with aNSCLC with MET alterations.

Clinical trial identification

NCT04077099.

Editorial acknowledgement

Medical writing support was provided by Qing Zhou, PhD, ELS, of Regeneron Pharmaceuticals, Inc., USA.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

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, Medpacto, Blueprint medicines, RandBio, Hanmi, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, Therapex Co., Ltd., Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; 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, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, 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, JINTSbio, Hanmi, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Founder: DAAN Biotherapeutics; Other, Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Liangyihui Network Technology Co., Ltd. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, Bristol Myers Squibb, Roche, Daiichi Sankyo, Merck, Boronoi. T.M. Kim: Financial Interests, Personal, Other, Consultancy: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Janssen, Novartis, Takeda, Samsung Bioepis, Regeneron, Boryng; Non-Financial Interests, Principal Investigator: AstraZeneca/MedImmune, Boryung, Hanmi, Janssen, Boehringer-Ingelheim, Novartis, Takeda, Sanofi, Roche/Genentech, Merck Sharp & Dohme Corp, Merck Serono, REGENERON, Genmab, Bayer, RAPT Therapeutics, Blueprint Medicines Corporation, Black Diamond Therapeutics, AbbVie, Amgen, BEYONDBIO Inc., Fore Biotherapeutics, Dizal Pharmaceutical, Incyte Corporation, BeiGene. J. Han: Financial Interests, Personal, Advisory Board: Norvatis, Lantern, Takeda, Janssen, Merck, Pfizer, Amgen, AstraZeneca, Oncobix, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, Merck, Roche, Yuhan, Pfizer, Norvatis. C. Kim: Financial Interests, Personal, Advisory Board: Novartis, Janssen, AstraZeneca, Sanofi, PierianDx, Diffuse pharmaceuticals, Mirati; Financial Interests, Institutional, Research Funding: AstraZeneca, Bristol Myers Squibb, Novartis, Genentech, Janssen, Regeneron Pharmaceuticals, Inc., Debiopharm, Karyopharm. C. Ricordel: Financial Interests, Personal, Advisory Board: Roche, Takeda, MSD, BMS, Janssen, Sanofi, Astrazeneca. A.E. Drilon: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Speaker, Consultant, Advisor: ArcherDX, AbbVie, BergenBio, Hengrui Therapeutics, Blueprint Medicines, Ignyta/Genentech/Roche, AstraZeneca, MORE Health, Tyra Biosciences, Loxo/Bayer/Lilly, Pfizer, Nuvalent, Merus, AXIS, Medscape, Liberum, Med Learning, PeerView, EPG Health, JNCCN/ Harborside, Ology, Clinical Care Options, TouchIME, Entos, Treeline, Prelude, Applied Pharmaceutical Science, mBrace, i3 Health; Financial Interests, Personal, Other, payments or honoraria: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical, Remedica Ltd., mBrace, AXIS, EPG Health, Harborside Nexus, Liberum, RV More, Ology, Amgen, TouchIME, Janssen, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc., AiCME, I3 Health, MonteRosa; Financial Interests, Personal, Advisory Board: Melendi, 14ner/Elevation Oncology, Novartis, Pfizer, Loxo/Bayer/Lilly, Repare RX, Janssen, Amgen, MonteRosa; Financial Interests, Personal, Stocks/Shares: Treeline Bio; Non-Financial Interests, Personal, Other: Boehringer Ingelheim; Financial Interests, Personal, Other, food and beverages: Merck, Puma, Merus; Non-Financial Interests, Personal, Other, filed or pending copyright: Selpercatinib-Osimertinib. J.E. Gray: Financial Interests, Personal, Other, Consultant / Advisor: AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Inc., EMD Serono - Merck KGaA, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co, Inc., Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners; Financial Interests, Institutional, Full or part-time Employment: Moffitt Cancer Center; Financial Interests, Institutional, Member of Board of Directors: SWOG; Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono - Merck KGaA, Genentech, Gilead Sciences, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co, Inc., Novartis, Panbela Therapeutics, Inc., Pfizer, Regeneron; Non-Financial Interests, Leadership Role, Department Chair, Thoracic Oncology: Moffitt Cancer Center; Non-Financial Interests, Leadership Role, Co-Leader, Molecular Medicine Program: Moffitt Cancer Center; Non-Financial Interests, Leadership Role, Chair, Lung Committee: SWOG; Non-Financial Interests, Member of Board of Directors: IASLC; Non-Financial Interests, Member of Board of Directors, Elected member - service to start on June 4th 2024: ASCO. L. Villaruz: Financial Interests, Personal, Advisory Board: Sanofi, Gilead, Johnson and Johnson, EMD Serono, Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Local PI: Regeneron, GSK, BioAtla, BeiGene, Fujifilm, Amgen, Boehringer Ingelheim, Merck; Financial Interests, Institutional, Coordinating PI: Genentech. G. Blumenschein: Financial Interests, Personal, Advisory Board: AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery,Virogin Biotech, Maverick Therapeutics, BeiGene, Regeneron, Cytomx Therapeutics, Intervenn Biosciences, Onconova Therapeutics, Seagen, Scorpion Therapeutics; Financial Interests, Personal, Full or part-time Employment, Immediate family member employed: Johnson & Johnson/Janssen; Financial Interests, Personal, Stocks/Shares: Viirogin Biotech; Financial Interests, Institutional, Local PI: CytomX Therapeutics, Duality Biologics, Mythic Therapeutics, Takeda, Aulos Bioscience, Seagen, Amgen, Bayer, Exelixis, Daiichi Sankyo, GSK, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myer Squib, Celgene, Genentech, MedImmune, Merck, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, Repertoire Immune Medicines, Verastem; Financial Interests, Institutional, Coordinating PI: Adaptimmune, Novartis; Financial Interests, Institutional, Trial Chair: BeiGene; Non-Financial Interests, Principal Investigator: BeiGene; Non-Financial Interests, Member: ASCO, AACR, SITC, IASLC. J. Perez, D.A. Modi, S. Patel, Y. Hao, E. Kim, H. Magnan: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Kaul: Financial Interests, Institutional, Full or part-time Employment, Global safety Lead for cemiplimab: Regeneron Pharmaceuticals; Financial Interests, Institutional, Stocks/Shares: Regeneron Pharmaceuticals. All other authors have declared no conflicts of interest.