Petosemtamab plus pembrolizumab vs. pembrolizumab alone for first-line (1L) treatment of recurrent/metastatic (r/m) PD-L1–positive 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. Pembrolizumab monotherapy is a current standard of care for 1L treatment of r/m HNSCC in patients (pts) with PD-L1–positive (combined positive score [CPS] ≥1) HNSCC. The combination of petosemtamab 1500 mg every 2 weeks (Q2W) plus pembrolizumab 400 mg every 6 weeks (Q6W) has been explored in a phase II trial. Data were presented at ASCO 2024 (Fayette. Abstr 440434; NCT03526835).Trial designThis is an open-label, global, randomized, controlled phase III trial (EudraCT: 2023-510323-30-00) to compare petosemtamab plus pembrolizumab vs. pembrolizumab monotherapy in pts with PD-L1 positive (CPS ≥1) r/m HNSCC. Key eligibility criteria include age ≥18 years, ECOG PS 0–1, no prior systemic therapy in the r/m setting, measurable disease, and baseline tumor sample for pt selection and stratification. Pts will be randomized 1:1 to receive either petosemtamab intravenously (IV) Q2W plus pembrolizumab IV Q6W, or pembrolizumab IV Q6W only. 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 plus pembrolizumab vs. pembrolizumab. Secondary objectives include evaluation of antitumor activity (measured by progression-free survival, duration of response, clinical benefit rate [all per RECIST v1.1 by BICR and by investigator assessment] and ORR per investigator assessment), safety and tolerability, and health-related quality of life (EuroQol EQ-5D-5L, EORTC QLQ-H&N43, Patient Global Impression of Change).Clinical trial identificationEudraCT 2023-510323-30-00.Editorial acknowledgementMedical writing support was provided by Sophie Houten at LiNK Health Group.Legal entity responsible for the studyMerus N.V.FundingMerus N.V.DisclosureJ. Fayette: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Innate Pharma, Merck Serono, Roche, Seagens, Iteos, Elevar, Hookipa; Non-Financial Interests, Principal Investigator: AstraZeneca. D.R. Adkins: Financial Interests, Personal and Institutional, Advisory Role: Merck, Cue Biopharma, Blueprint Medicine, Exelixis, Immunitas, Kura Oncology, Targimmune Therapeutics, Xilio Therapeutics, Boehringer Ingelheim, Eisai Europe, Coherus Biosciences, Gilead Sciences, Inhibrx; Financial Interests, Institutional, Funding, Local PI: Merus, 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, Xilio, Therapetuics, Alentis, Coherus Biosciences, Inhibrx, Seagen, GSK, Exelixis, Daiichi Sankyo, Janux, Johnson&Johnson; Other, Personal, Member, Member of NCCN Head and Neck Panel: NCCN. A. Psyrri: Financial Interests, Personal, Invited Speaker: MSD, Merck Serono, EPICS; Financial Interests, Personal, Advisory Board: Pfizer, Sanofi, MSD, AstraZeneca, BMS, LEO, RAKUTEN, eTheRNA immunotherapies, Merck Serono, Seagen, Merus; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Pfizer, GSK, Genesis, Incyte, Amgen, Debiopharm, MSD, Jannsen, Lilly, Regeneron, Sanofi, BI, Roche, Peregrine, Oncolytics Biotech; Financial Interests, Coordinating PI: AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Iovance, Pfizer, Roche; Financial Interests, Institutional, Steering Committee Member: Kura Oncology; Financial Interests, Steering Committee Member: Kura Oncology; Financial Interests, Personal and Institutional, Funding: Kura Oncology, BMS, Roche, DEMO, Amgen, BI, Genesis, BMS, Pfizer, Oncolytics Biotech; Financial Interests, Institutional, Funding: Merck Serono, Pfizer; Financial Interests, Personal, Other, Educational activity: Medscape, PrimeOncology; Financial Interests, Institutional, Local PI: Novartis, Replimmune; Non-Financial Interests, Project Lead, Medical Education with honoraria: Medscape. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Voronoi, Arvinas, Navire, Relay Therapeutics, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics, Pangea, GSK, Daiichi Sankyo; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger Ingelheim, GSK, Roche/Genentech, AstraZeneca, Merck, Bayer, Amgen, EMD Serono, Biontech, Gilead, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: EMD Serono; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center, Cancer Grand Challenge, Break Through Cancer. M. Tahara: Financial Interests, Personal, Advisory Board: Merck Biopharma, Ono pharma, MSD, Pfizer, Bayer, Lilly, Rakuten Medical, Boehringer Ingelheim, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Eisai, Novartis; Financial Interests, Institutional, Local PI: MSD, AstraZeneca, Ono Pharma, Novartis, Pfizer, Bristol Myers Squibb, Loxo, GSK, Lilly, Rakuten Medical, Bayer, Merck Biopharma; Financial Interests, Institutional, Research Grant: Bayer. W. Nassib William Junior: Financial Interests, Personal, Invited Speaker: Amgen, Genentceh / Roche, Eli Lilly, BMS, Pfizer, Janssen, United Medical; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Merck, Bayer, Sanofi, Takeda, Novartis. R. Pyle: Financial Interests, Institutional, Full or part-time Employment: Merus N.V.; Financial Interests, Institutional, Stocks/Shares, Unvested: Merus N.V. Y. Shen: Financial Interests, Institutional, Full or part-time Employment: Merus N.V.; Financial Interests, Institutional, Stocks/Shares: 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. E. Pennella: Financial Interests, Institutional, Full or part-time Employment: Merus N.V,. E.E. Vokes: Non-Financial Interests, Institutional, Advisory Board, Data Safety Monitoring Board: 2-BioNTech; Non-Financial Interests, Institutional, Advisory Role, Data Safety Monitoring Board: 2-BioNTech.