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

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).