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. 2025 Jul;21(16):2007-2016.
doi: 10.1080/14796694.2025.2511470. Epub 2025 Jun 13.

LiGeR-HN phase III trials of petosemtamab + pembrolizumab and petosemtamab monotherapy in recurrent or metastatic HNSCC

Jean-Pascal Machiels  1 , Jérôme Fayette  2 , Robert Haddad  3 , Douglas Adkins  4 , Maura Gillison  5 , Kevin J Harrington  6 , Sung-Bae Kim  7 , Christophe Le Tourneau  8 , Amanda Psyrri  9 , Ari Rosenberg  10 , Lillian L Siu  11 , Makoto Tahara  12 , William N William Jr  13 , Jim Ford  14 , Shekeab Jauhari  15 , Rebecca Pyle  14 , Yu-Ming Shen  16 , David Yao  15 , Fabian Zohren  15 , Everett Vokes  17
Affiliations

LiGeR-HN phase III trials of petosemtamab + pembrolizumab and petosemtamab monotherapy in recurrent or metastatic HNSCC

Jean-Pascal Machiels et al. Future Oncol. 2025 Jul.

Abstract

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated. LGR5 can potentiate the wingless-type integration site (WNT)/β-catenin signaling pathway in response to ligand binding, stimulating cancer stem cell proliferation and self-renewal. This article describes two registration-intent, open-label, randomized phase III trials evaluating efficacy and safety of petosemtamab. LiGeR-HN1 (NCT06525220) evaluates petosemtamab plus pembrolizumab versus pembrolizumab as first-line therapy for patients with programmed cell death ligand 1-positive r/m HNSCC. LiGeR-HN2 (NCT06496178) evaluates petosemtamab versus investigator's choice of monotherapy (cetuximab, methotrexate, or docetaxel) in patients with previously treated r/m HNSCC. Primary endpoints in both trials are objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review, and overall survival. Both trials are recruiting at the time of publication.Clinical Trial Registration: NCT06525220 and NCT06496178 (ClinicalTrials.gov).

Keywords: EGFR; HNSCC; LGR5; LiGeR-HN; LiGeR-HN1; LiGeR-HN2; petosemtamab.

Plain language summary

Head and neck squamous cell carcinoma (HNSCC) is a common cancer located in the head or neck, particularly in the mouth, throat, and nasal cavity. People living with HNSCC whose cancer has come back after treatment (recurrent) or spread to other parts of the body (metastatic) have limited treatment options, especially when their cancer does not respond to available therapies. Petosemtamab is a drug that targets receptors called epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) – two key drivers of tumor cells that contribute to tumor growth and spread. In a phase II trial, petosemtamab showed clinically meaningful benefit with manageable side effects for patients with recurrent or metastatic HNSCC. This article describes two phase III trials studying petosemtamab’s ability to reduce tumors and improve survival. LiGeR-HN1 will include approximately 500 patients who have not yet been treated for recurrent or metastatic HNSCC, and whose tumors have a protein called programmed cell death ligand 1 on the cell surface. Patients will be split into two groups: one group will receive petosemtamab with pembrolizumab, an immunotherapy; the other group will receive only pembrolizumab. LiGeR-HN2 will include approximately 500 patients whose disease has progressed on or after receiving anti-programmed cell death protein 1 and platinum-based treatment for recurrent or metastatic HNSCC. Patients will be split into two groups: one group will receive petosemtamab; the other group will receive either cetuximab (targeted therapy), methotrexate (chemotherapy), or docetaxel (chemotherapy). Both trials are recruiting participants at the time of publication.

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Conflict of interest statement

J. Machiels: Financial interests, institutional, advisory board: ALX Oncology, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cue Pharma, CureVac, Debio, F-star, Genmab, GSK, Incyte, Innate, Janssen, Johnson & Johnson, Merus, MSD, Nanobiotix, Nektar, Novartis, Pfizer, Roche, Seagen; 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 principal investigator (PI): eTheRNA, iTeos, MSD; financial interests, institutional, local PI: AbbVie, Amgen, Bayer, Boehringer Ingelheim, Celyad, GSK, Incyte, Janssen, Johnson & Johnson, Kura, Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis; non-financial interests, leadership role, chair: EORTC Head and Neck Group.

J. Fayette: Financial interests, personal, advisory board: AstraZeneca, Bristol Myers Squibb, Elevar, Hookipa, Innate Pharma, iTeos, Merck Serono, MSD, Roche, Seagen; non-financial interests, PI: AstraZeneca.

R. Haddad: Financial interests, personal, advisory board: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Coherus, Eisai, EMD Serono, Exelixis, Genentech, Genmab, Merck, Merus, Pfizer; financial interests, personal, other, data safety monitoring board: Nanobiotix, PSI, Hookipa; financial interests, personal, royalties: UptoDate; financial interests, institutional, local PI, grant to hospital for clinical trials: AstraZeneca, Bristol Myers Squibb, EMD Serono, Incyte, Kura, Merck; non-financial interests, other, panel chair guidelines: NCCN.

D. Adkins: Financial interests, institutional, consultant, advisory board: Adlai Nortye, Boehringer Ingelheim, Cue Biopharma, Exelixis, Genmab, Immunitas, InhibRx, Kura Oncology, Merck, Merck KGaA, Merus, Natco Pharma, Purple Biotech, Regeneron, Sanofi, Seagen, TargImmune Therapeutics; travel support: Natco Pharma; research funding: Adlai Nortye, Alentis Therapeutics, AstraZeneca, Aveo, BeiGene, BioAtla, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calliditas Therapeutics, Celgene, Cofactor Genomics, Coherus Biosciences, Cue Biopharma, Daiichi Sankyo, Debiopharm Group, Epizyme, Erasca Inc, Exelixis, Genmab, Gilead Sciences, GSK, Hookipa Biotech, Immutep, ISA Pharmaceuticals, Johnson & Johnson, Kura Oncology, InhibRx, Lilly, Merck, Merus, Natco Pharma, Novartis, Pfizer, Rgenta, Roche, Seagen, Takeda, Tempus, Tizona Therapeutics Inc, Vaccinex, Xilio Therapeutics; non-financial interests, leadership committees: NCCN H&N practice guidelines and Chair of Washington University/Barnes Jewish Hospital Pharmacy and Therapeutics (P&T) Committee.

M. Gillison: Financial interests, personal, speaker, consultant, advisor, 2022: Caladrius Biosciences, Debiopharm, Eisai Medical Research, EMD Serono, Exelixis Inc., Gilead Sciences, GSK LLC, Ispen Biopharmaceuticals, Istari Oncology, iTeos Therapeutics, Kura Oncology, Merus N.V., Mirati Therapeutics, Nektar Therapeutics, OncLive, Pilant Therapeutics, Sensei Biotherapeutics, Inc, Shattuck Labs; financial interests, personal, speaker, consultant, advisor, 2022 and 2024: Bicara Therapeutics LLX Solutions; financial interests, personal, speaker, consultant, advisor, 2023: Adaptimmune, AH EPICS Consulting, Aptitude Health, Axiom Healthcare, BioNTech, Bristol Myers Squibb, Coherus Biosciences, Surface Oncology; financial interests, personal, other, editorial role 2023: Journal of Clinical Oncology; financial interests, personal, speaker, consultant, advisor, 2024: AbbVie, Brightly Network, Guidepoint Global, Pfizer; financial interests, personal, funding: Agenus, Bristol Myers Squibb, Cullinan Labs, Genentech, Genocea Biosciences, Inc, Kura, LaRoche, NRG, University of Cincinnati.

K. Harrington: Financial interests, institutional, advisory board: Amgen, Arch Oncology, AstraZeneca, Bicara, Bristol Myers Squibb, Boehringer Ingelheim, Exelixis, GSK, Idera, Merck, Merus, MSD, Pfizer, Replimune, Oncolys, PsiVac, Vyriad; financial interests, institutional, other, honoraria for lectures: Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Replimune; financial interests, institutional, funding, research: AstraZeneca, Boehringer Ingelheim, MSD, Replimune.

S-B. Kim: Financial interests, personal, advisory board: AstraZeneca, BeiGene, DaeHwa Pharma, Daiichi Sankyo, ISU Abx, Lilly, Novartis, OBI Pharma, Samsung Bioepics; financial interests, personal, invited speaker: Legochem Bioscience; financial interests, personal, ownership interest: Genopeaks; financial interests, institutional, research grant: DongKook Pharm Co, Novartis, Sanofi-Genzyme.

C. Le Tourneau: Financial interests, personal, advisory board: ALX Oncology, Bristol Myers Squibb, Celgene, Exscientia, GSK, Merck Serono, MSD, Nanobiotix, Rakuten, Roche, Seattle Genetics.

A. Psyrri: Financial interests, personal, invited speaker: EPICS, Merck Serono, MSD; financial interests, personal, advisory board: AstraZeneca, Bristol Myers Squibb, eTheRNA Immunotherapies, LEO, Merck Serono, Merus, MSD, Pfizer, RAKUTEN, Sanofi, Seagen; financial interests, personal and institutional, local PI: Amgen, AstraZeneca, Boehringer Ingelheim, Debiopharm, Genesis, GSK, Incyte, Jannsen, Lilly, MSD, Oncolytics Biotech, Peregrine, Pfizer, Regeneron, Roche, Sanofi; 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: Amgen, Boehringer Ingelheim, Bristol Myers Squibb, DEMO, Genesis, Kura Oncology, Oncolytics Biotech, Pfizer, Roche; financial interests, institutional, funding: Merck Serono, Pfizer; financial interests, personal, other, educational activity: Medscape, PrimeOncology; financial interests, institutional, local PI: Novartis, Replimune; non-financial interests, project lead, medical education with honoraria: Medscape.

A. Rosenberg: Financial interests, institutional, advisory role: Astellas, Eisai, EMD Serono, Exelixis, Galectin, Geovax, Nanobiotix, Novartis, Privo, Vaccitech.

L.L. Siu: Financial interests, personal, advisory board: Amgen, Arvinas, AstraZeneca, Daiichi Sankyo, GSK, LTZ Therapeutics, Marengo, Medicenna, Merck, Merus, Navire, Pangea, Relay Therapeutics, Roche, Tubulis, Voronoi; 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: Amgen, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, Gilead, GSK, Merck, Novartis, Pfizer, Roche/Genentech; financial interests, institutional, coordinating PI: EMD Serono; non-financial interests, advisory role: Break Through Cancer, Cancer Grand Challenge, Dana-Farber Harvard Cancer Center, ICR.

M. Tahara: Financial interests, personal, advisory board: AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Merck Biopharma, MSD, Ono Pharma, Pfizer, Rakuten Medical; financial interests, personal, invited speaker: Bristol Myers Squibb, Eisai, Novartis; financial interests, institutional, local PI: AstraZeneca, Bayer, Bristol Myers Squibb, GSK, Lilly, Loxo, Merck Biopharma; MSD, Novartis, Ono Pharma, Pfizer, Rakuten Medical; financial interests, institutional, research grant: Bayer.

W.N. William Jr: Financial interests, personal, invited speaker: Amgen, Bristol Myers Squibb, Eli Lilly, Genentech/Roche, Janssen, Pfizer, United Medical; financial interests, personal, advisory board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Sanofi, Takeda.

J. Ford: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares: Merus N.V.

S. Jauhari: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares: Merus N.V.

R. Pyle: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares, unvested: Merus N.V.

Y-M. Shen: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares: Merus N.V.

D. Yao: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares: Merus N.V.

F. Zohren: Financial interests, institutional, full or part-time employment: Merus N.V.; financial interests, institutional, stocks/shares: AbbVie, ImmunoGen Inc., Merus, Pfizer, Inc.

E. Vokes: Financial interests, institutional, consultant, advisory board and honoraria: AbbVie, AstraZeneca, BioNTech, Boehringer Ingelheim, Eikon, Genmab, Merus, MJH Lifesciences, Translational Drug Development LLC; non-financial interests, institutional, advisory board, data safety monitoring board: 2-BioNTech.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
Petosemtamab mechanism of action [23].
Figure 2.
Figure 2.
Petosemtamab monotherapy in previously treated recurrent or metastatic head and neck squamous cell carcinoma: phase II data (NCT03526835) [31].
Figure 3.
Figure 3.
Petosemtamab plus pembrolizumab in first-line programmed cell death ligand 1–positive recurrent or metastatic head and neck squamous cell carcinoma: phase II data (NCT03526835) [30].
Figure 4.
Figure 4.
LiGeR-HN1 trial design.
Figure 5.
Figure 5.
LiGeR-HN2 trial design.
See this image and copyright information in PMC

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