160TiP - Safety and Antitumor Activity of GEN1042 in Combination with Pembrolizumab _ Chemotherapy in Solid Tumors: Phase 2b Dose-Expansion Trial in Progress

Background

GEN1042 (DuoBody CD40x4-1BB) is a novel, bispecific, agonistic antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells to enhance priming and (re)-activation of tumor-specific immunity. In the phase 1a dose-escalation part of this open-label, multicenter phase 1/2 trial (NCT04083599), single-agent GEN1042 showed biologic and early clinical activity with a manageable safety profile in patients with advanced solid tumors. Preclinical and preliminary clinical results suggest that as a bispecific antibody, GEN1042 can leverage conditional CD40 and 4-1BB agonism in combination with PD-(L)1 blockade ± chemotherapy (CTX) to improve the antitumor response. In the safety run-in and expansion cohorts, GEN1042 in combination with pembrolizumab (PEM) ± CTX was generally well tolerated (no dose-limiting toxicities) with encouraging early clinical activity, including complete responses, observed in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC) receiving GEN1042 + PEM + CTX (Melero I, et al. ESMO IO 2022). Enrolment into the combination therapy expansion cohorts is continuing, with this abstract focused on the evaluation of GEN1042 + PEM + CTX in checkpoint inhibitor (CPI) treatment–naive patients with non-small cell lung cancer (NSCLC) and HNSCC.

Trial Design

The expansion part includes parallel cohorts of patients with NSCLC and HNSCC. Eligible patients with NSCLC will receive GEN1042 + PEM ± CTX. Eligible patients with recurrent/metastatic HNSCC (PD-L1 combined positive score ≥1) will receive GEN1042 + PEM ± cisplatin or carboplatin + 5-fluorouracil. Primary endpoint (phase 2b) is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics. Combination therapy expansion cohorts are recruiting across several countries including Spain, US, and Denmark.

Clinical trial identification

NCT04083599; Release Date: September 10, 2019.

Editorial acknowledgement

Medical writing and editorial support were provided by Stephanie Phan, PharmD, from Peloton Advantage, an OPEN Health company, Parsippany, NJ, USA.

Legal entity responsible for the study

Genmab A/S.

Funding

Genmab A/S and BioNTech SE.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Agneus, Alligator Bioscience, AstraZeneca, BMS, BioLineRx, Boehringer Ingelheim, Boston Pharma, CRISPR Therapeutics, CatalYm GmbH, Crescendo Biologics, Curon BIopharmaceutical, EMD Serono, F-Star, Genentech, Hookipa Pharma, Genmab, Gossamer Bio, Highlight Therapeutics, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Janssen, MSD, Merus N.V., Monopteros Therapeutics, NOXXON Pharma AG, Numab, Phenomic Bio, Pieris Pharmaceuticals GmbH, Pierre Fabre, Roche, Sanofi, Third Rock Ventures, Senti Biosciences, Servier, Shattuck Labs; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, BMS, Genmab, Alligator. E. Grande: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, IPSEN, Janssen, Lilly, Merck KGa, Pfizer, Roche, Dr. Reddy's; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, ONCODNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, Nanostring Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Coordinating PI, Independent research grant: IPSEN; Non-Financial Interests, Personal, Other, AD BOARD member: ENETS; Non-Financial Interests, Personal, Member of Board of Directors: GETNE, GUARD Consortium, Grupo centro de Tumores Genitourinarios. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics. J.R. Bauman: Financial Interests, Personal, Advisory Board: Janssen, Blueprint Medicines, Merck, BeiGene, Turning Point, Pfizer, Mirati; Financial Interests, Personal, Speaker, Consultant, Advisor: Lilly. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, DEBIOPHARM ,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. D.R. Adkins: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Cue Biopharma, Blueprint Medicine, Exelixis, Immunitas, Kura Oncology, Targimmune Therapeutics, TwoXAR, Vaccinex, Xilio Therapeutics, Boehringer Ingelheim, Eisai Europe, Coherus Biosciences, Gilead Sciences, Jazz Pharmaceuticals; Financial Interests, Personal, Principal Investigator: Hookipa, Pfizer, Eli Lilly, Merck, Celgene/BMS, Novartis, AstraZeneca, Blueprint Medicine, Kura Oncology, CUE Biopharma, Cofactor Genomics, Debiopharm, ISA Pharmaceuticals, Gilead Sciences, BeiGene, Roche, Vaccinex, Adlai Nortye, BioAtla, Calliditas, Epizyme, Natco, Immutep, Tizona, Genmab, Boehringer Ingelheim. M.J. De Miguel: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, MSD, Janssen. S. Gattoni-Celli: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. I. Celik: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. J. Steinberg, T.J. Ong: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Personal, Member, Member of the Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. All other authors have declared no conflicts of interest.