CLINICAL TRIAL / NCT06525220

Inclusion Criteria: 1. Signed ICF before initiation of any study procedures 2. Age ≥ 18 years at signing of ICF 3. Histologically confirmed HNSCC with evidence of metastatic or locally recurrent disease not amenable to local therapy with curative intent. 4. The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. 5. HNSCC patients eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS ≥1. 6. HNSCC patients should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting 7. A baseline new tumor sample unless the patient has an available tumor sample as an FFPE block with sufficient material. 8. Measurable disease as defined by RECIST v1.1 by radiologic methods. 9. ECOG Performance Status (PS) of 0-1 10. Life expectancy ≥ 12 weeks, as per investigator assessment. 11. Left ventricular ejection fraction (LVEF) ≥50% or ≥ institutional normal limit, whichever is higher, by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 12. Adequate organ function as defined per protocol. Exclusion Criteria: 1. Central nervous system metastases that are untreated or already treated but symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 21 days of study entry. 2. Known leptomeningeal involvement 3. Any systemic anticancer therapy within 4 weeks of the first dose of study treatment 4. Major surgery or radiotherapy within 3 weeks of the first dose of study treatment 5. Persistent Grade >1 clinically significant toxicities related to prior cancer therapies (except for alopecia); stable sensory neuropathy Grade ≤2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 is allowed. 6. History of hypersensitivity reaction to any of the excipients of petosemtomab or pembrolizumab. 7. 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 8. History of prior malignancies, with the exception of excised local cancer, or treated cancer deemed at low risk for recurrence with no evidence of disease for ≥3 years 9. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy 10. Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders 11. Patients with known infectious diseases as per protocol. 12. Pregnant or breastfeeding patients. 13. The patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to the first dose 14. The patient has an active autoimmune disease that has required systemic immune suppressive treatment in the past 2 years; replacement therapy is not considered immune suppressive treatment. 15. Patient has a primary tumor site of nasopharynx, or sinonasal carcinoma (any histology) Other protocol defined inclusion/exclusion criteria may apply.