A Phase 3 Study to Evaluate Petosemtamab Compared With Investigator's Choice Monotherapy in Previously Treated Head and Neck Squamous Cell Carcinoma Patients

Inclusion Criteria: * Signed ICF before initiation of any study procedures. * Age ≥ 18 years at signing of ICF. * Histologically previously confirmed HNSCC with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent. * HNSCC patients progressed on or after anti-PD-1 therapy and platinum-containing therapy. * The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. * Documentation of p16 status (positive or negative) by local laboratory IHC for patients with primary oropharyngeal cancer. * A baseline new tumor sample unless the patient has an available tumor sample as an FFPE block with sufficient material. * Measurable disease as defined by RECIST v1.1 by radiologic methods. * ECOG PS of 0 or 1 * Life expectancy ≥ 12 weeks, as per investigator * Adequate organ function (as per protocol) Exclusion Criteria: * Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 14 days of study entry. * Known leptomeningeal involvement * Any systemic anticancer therapy within 4 weeks of the first dose of study treatment. * Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. * Persistent Grade \>1 clinically significant toxicities related to prior antineoplastic therapies * History of hypersensitivity reaction to any of the excipients of treatment required for this study. * Unstable angina; history of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment or history of myocardial infarction within 6 months of study entry * History of prior malignancies with the exception of excised cervical intraepithelial neoplasia or nonmelanoma skin cancer, or curatively treated cancer deemed at low risk for recurrence with no evidence of disease * Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy * Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders * Patients with known infectious diseases (as per protocol) * Pregnant or breastfeeding patients * Patient has a primary tumor site of nasopharynx (any histology).