Abstract 175P
Background
GEN1042 (DuoBody-CD40x4-1BB) is an investigational, novel, agonistic bispecific antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells. GEN1042 demonstrated biologic and early clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors in the dose escalation part of the ongoing phase 1/2 trial (NCT04083599). Previously presented preclinical data suggest that the immune response generated by GEN1042 treatment (Tx) can be amplified by co-administration of a PD-1 inhibitor. Combination with chemotherapy (CTx) is hypothesized to further enhance antitumor responses by increasing antigen release and PD-L1 expression. We present data from the safety run-in (SRI) and expansion cohorts investigating GEN1042 + pembrolizumab (PEM) ± standard of care (SoC) CTx.
Methods
Tx-naive pts with advanced, metastatic/unresectable/recurrent non-CNS tumors received GEN1042 + PEM ± CTx (nab-paclitaxel + gemcitabine or cis/carboplatin + 5-FU) until disease progression or unacceptable toxicity. Primary endpoint was dose-limiting toxicity (DLT) for SRI and objective response rate (ORR) for the expansion cohorts. Secondary endpoints included AEs, PK, antitumor activity (RECIST v1.1), and pharmacodynamic biomarkers.
Results
As of July 27, 2022, 20 pts (median age, 70.5 y; 12 pts with NSCLC, 3 pts with melanoma, 5 pts with HNSCC) had received GEN1042 + PEM; 17 pts (median age, 64.0 y; 5 pts with HNSCC, 12 pts with PDAC) had received GEN1042 + PEM + CTx. Tx-related AEs in ≥15% of pts (all grades; grade ≥3) were pruritus (20%; 0%), rash (15%; 5%), and pyrexia (15%; 0%) in the GEN1042 + PEM cohorts, and transaminase elevation (23.5%; 5.9%), rash (17.6%; 5.9%), diarrhea (17.6%; 0%), fatigue (23.5%; 0%), and nausea (17.6%; 0%) in the GEN1042 + PEM + CTx cohorts. No DLTs were observed in either group, and irAEs were as expected and manageable. Encouraging preliminary activity was observed in all patients with HNSCC treated with GEN1042 + PEM + CTx; updated results will be presented.
Conclusions
GEN1042 + PEM ± SoC CTx was overall well tolerated and showed initial antitumor activity in pts with advanced/metastatic disease.
Clinical trial identification
NCT04083599; Study Start Date: September 17, 2019.
Editorial acknowledgement
Medical writing and editorial assistance were provided by Peloton Advantage, Llc, an OPEN Health company, Parsippany, NJ, USA, and funded by Genmab.
Legal entity responsible for the study
Genmab A/S.
Funding
Genmab A/S and BioNTech.
Disclosure
I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Monopteros Therapeutics; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. E. Grande Pulido: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGa, Pfizer, Roche; 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, Invited Speaker, Independent research grant: Ipsen; Non-Financial Interests, Personal, Other, AD Board Member: ENETS. M.J. De Miguel Luken: Financial Interests, Personal, Other, Consulting Fees: Roche, MSD, Janssen. M.L. Johnson: Financial Interests, Institutional, Funding: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, 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, Y-mAbs Therapeutics; Financial Interests, Institutional, Other, Consulting/Advisory fees: AbbVie, Achilles Therapeutics, Amgen, AstraZeneca, Axelia Oncology, Atreca, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech / Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Ideaya Biosciences, iTeos, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Oncorus, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics. J.R. Bauman: Financial Interests, Personal, Advisory Board: Kura, Janssen, Pfizer, Blueprint Medicine, Lilly, Merck, Mirati, Turning Point Therapeutics, Beigene. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Personal, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii 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. A.O. Walter: Financial Interests, Personal, Full or part-time Employment: BioNTech. H. Adams III: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. î Türeci: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Member of the Board of Directors: BioNTech. G. Russo: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. U. Sahin: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Member of the Board of Directors: BioNTech. J. Steinberg: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. T. Ahmadi: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Merck Serono, Peptomyc, F. Hoffmann-La Roche, Novartis, Daichii Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono, Sanofi, Takeda, TouchONCOLOGY; Financial Interests, Institutional, Other, Grant for oncology innovation: Merck Healthcare KGAa; Financial Interests, Institutional, Other: Fundaciön Merck Salud; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform).