A Phase 3 Study to Evaluate Petosemtamab Plus Pembrolizumab vs Pembrolizumab in First-line Treatment of Head and Neck Cancer (LiGeR - HN1)

Inclusion Criteria

• Signed ICF before initiation of any study procedures
• Age ≥ 18 years at signing of ICF
• Histologically confirmed HNSCC with evidence of metastatic or locally recurrent disease not amenable to local therapy with curative intent.
• The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
• HNSCC patients eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS ≥1.
• HNSCC patients should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting
• A new tumor biopsy, unless the patient has an available archival tumor sample with sufficient material
• Measurable disease per Investigator assessment as defined by RECIST v1.1 by radiologic methods
• ECOG Performance Status (PS) of 0-1
• Life expectancy ≥ 12 weeks, as per investigator assessment.
• Left ventricular ejection fraction (LVEF) ≥50% or ≥ institutional normal limit, whichever is higher, by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
• Adequate organ function as defined per protocol.
• HIV-positive patients are eligible only if the cluster of differentiation 4 (CD4+) count is ≥ 300/µl, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy

Exclusion Criteria

• 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 prior to randomization
• Known leptomeningeal involvement
• Any systemic anticancer therapy or investigational drug within 4 weeks or 5 half-lives, whichever is shorter, before randomization
• Requirement for immunosuppressive medication
• Major surgery or radiotherapy within 3 weeks of randomization
• Clinically significant toxicities related to prior anticancer therapies that have not returned to ≤ Grade 1 or baseline except for Grade ≤2- myalgia, neuropathy, alopecia, and any prior therapy related endocrinopathies
• History of hypersensitivity reaction to any of the excipients of petosemtomab or pembrolizumab.
• 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 prior to randomization
• History of prior malignancies within the last 5 years, with the exception of excised local 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
• Patients with known infectious diseases as per protocol.
• Pregnant or breastfeeding patients.
• The patient has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy of prednisone >10 mg/day or equivalent, or any other form of immunosuppressive therapy
• 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
• The patient has had an allogeneic tissue/solid organ transplant.
• Patient has a primary tumor site of nasopharynx, or sinonasal carcinoma (any histology) Other protocol defined inclusion/exclusion criteria may apply.