Petosemtamab compared with investigator’s choice monotherapy in previously treated patients (pts) with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): A randomized, open-label, phase III trial

BackgroundEGFR is a known oncogenic driver in HNSCC, and the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a receptor expressed on cancer stem cells, including in HNSCC. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with ADCC-enhanced activity, targeting EGFR and LGR5. This phase III trial (EudraCT: 2023-510322-32) is supported by the ongoing phase II trial (NCT03526835), which demonstrated the promising clinical efficacy and manageable safety profile of petosemtamab monotherapy in pts with r/m HNSCC.Trial designThis is an open-label, global, randomized, controlled phase III trial evaluating petosemtamab vs. investigator’s choice monotherapy in pts with previously treated r/m HNSCC, with disease progression on or after anti-PD-1 therapy and platinum-containing chemotherapy. Key eligibility criteria include age ≥18 years, ≤2 lines of prior therapy in the r/m setting, no prior anti-EGFR therapy (including cetuximab), ECOG PS 0–1, and measurable disease. Pts will be randomized 1:1 to receive either petosemtamab intravenously (IV) every 2 weeks, or investigator's choice monotherapy (cetuximab IV once, then once weekly [QW]; methotrexate IV push QW; or docetaxel IV QW). The primary objectives are to compare overall response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) and overall survival in pts treated with petosemtamab vs. investigator’s choice monotherapy. Secondary objectives include evaluation of antitumor activity (measured by ORR [by investigator assessment], and progression-free survival, duration of response, time to response, clinical benefit rate [all per BICR and investigator; per RECIST v1.1]), the safety and tolerability of petosemtamab, and health-related quality of life (EORTC QLQ-C30, EORTC QLQ-H&N43).Clinical trial identificationEudraCT 2023-510322-32.Editorial acknowledgementMedical writing support was provided by Sophie Houten at LiNK Health Group.Legal entity responsible for the studyMerus N.V.FundingMerus N.V.DisclosureR. Haddad: Financial Interests, Personal, Advisory Board: BMS, Merck, EMD Serono, Boehringer Ingelheim, Eisai, Bayer, Merus, AstraZeneca, Genentech, Pfizer, Genmab, Exelexis, Coherus,; Financial Interests, Personal, Other, Data Safety Monitoring Board (DSMB): Nanobiotix, psi, Hookipa; Financial Interests, Personal, Royalties: up to date; Financial Interests, Institutional, Local PI, Grant To Hospital For Clinical Trials: Merck BMS, EMD, AstraZeneca, Incyte, Kura; Non-Financial Interests, Other, panel chair guidelines: NCCN. M. Gillison: Financial Interests, Personal, Speaker, Consultant, Advisor, 2022: Debiopharm, Sensei Biotherapeutics, Inc, iTeos Therapeutics, Caladrius Biosciences, Exelixis Inc., GSK LLC, Merus N.V, EMD Serono, Gilead Sciences, Kura Oncology, Shattuck Labs, Eisai Medical Research, Istari Oncology, Mirati Therapeutics, Nektar Therapeutics, Pilant Therapeutics, Onclive, Ispen Biopharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor, 2022 & 2024: LLX Solutions, Bicara Therapeutics; Financial Interests, Personal, Speaker, Consultant, Advisor, 2023: Coherus Biosciences, Surface Oncology, Bristol Myers Squibb, BioNTech, Aptitude Health, AH EPICS Consulting, Axiom Healthcare, Adaptimmune; Financial Interests, Personal, Other, Editorial role 2023: Journal of Clinical Oncology; Financial Interests, Personal, Speaker, Consultant, Advisor, 2024: Guidepoint Global, Brightly Network, Pfizer, AbbVie ; Financial Interests, Personal, Funding: Genocea Biosciences, Inc, Bristol Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus, LaRoche, NRG, University of Cincinnati. K.J. Harrington: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Merck, MSD, Pfizer, Replimune, Oncolys, Vyriad, Idera; Financial Interests, Institutional, Other, Honoraria for lectures: Amgen, AstraZeneca, BMS, Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board, Advisory board for CD47 assets: Arch Oncology; Financial Interests, Institutional, Advisory Board, Development of DDR assets: ARTIOS; Financial Interests, Institutional, Advisory Board, Development of exosomal STING agonist: Codiak; Financial Interests, Institutional, Advisory Board, Development of oncolytic adenovirus: PsiVac; Financial Interests, Institutional, Funding, Research: AstraZeneca, Boehringer Ingelheim, MSD; Financial Interests, Institutional, Funding, Development of oncolytic HSV platform: Replimune; Non-Financial Interests, Leadership Role, Chair of Steering Committee: ART NET; Non-Financial Interests, Other, Member of Global Steering Committee: MR - Linac. S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, Daiichi Sankyo, Beigene, Samsung Bioepics, OBI Pharma; Financial Interests, Personal, Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Genzyme, DongKook Pharm Co. C. Le Tourneau: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck Serono, Nanobiotix, Roche, Rakuten, Seattle Genetics, GSK, Celgene, ALX Oncology, Exscientia. A. Rosenberg: Financial Interests, Institutional, Advisory Role: Exelixis, Astellas, Novartis, emd-Serono, Eisai, Vaccitech, Geovax, Nanobiotix, Privo, Galectin. J. Ford, Y. Shen: Financial Interests, Institutional, Full or part-time Employment: Merus N.V,; Financial Interests, Institutional, Stocks/Shares: Merus. D. Yao: Financial Interests, Institutional, Full or part-time Employment: Merus N.V,. F. Zohren: Financial Interests, Institutional, Stocks/Shares: Merus; Financial Interests, Institutional, Stocks/Shares: ImmunoGen Inc.; Financial Interests, Institutional, Stocks/Shares: AbbVie Inc.; Financial Interests, Institutional, Stocks/Shares: Pfizer Inc. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Boerhinger Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, nektar, F-star, Seagen, Astellas, Genmab, Merus, GSK, CureVac; Financial Interests, Institutional, Advisory Board, Education: Merck-Serono; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Ceylad, MSD, Novartis, KURA, Roche, Lilly, Boehringer Ingelheim, Sanofi-Aventis, Incyte, Bayer, Merck-Serono, Janssen, Johnson & Johnson, Amgen, Abbvie, GSK; Non-Financial Interests, Leadership Role, Chair: EORTC head and neck group.