A Phase 3 Open-label, Randomized Controlled Study to Evaluate the Efficacy and Safety of Petosemtamab Compared With Investigator's Choice Monotherapy Treatment in Previously Treated Patients With Incurable, Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma

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 participants 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 participants with primary oropharyngeal cancer. * A baseline new tumor sample unless the participant 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 prior to randomization. * Known leptomeningeal involvement * Any systemic anticancer therapy within 4 weeks prior to randomization. * Major surgery within 3 weeks or palliative radiotherapy within 2 weeks prior to randomization. * 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 localized cancer with curative resection (e.g. cervical intraepithelial neoplasia or nonmelanoma skin cancer) * 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 * Participants with known infectious diseases (as per protocol) * Pregnant or breastfeeding participants * Participant has a primary tumor site of nasopharynx (any histology).