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

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 recurrentdisease 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 tumorsexpressing PD-L1, CPS ≥1.

6. HNSCC patients should not have had previous systemic therapy administered in theincurable recurrent or metastatic setting

7. A new tumor biopsy, unless the patient has an available archival tumor sample withsufficient material

8. Measurable disease per Investigator assessment as defined by RECIST v1.1 byradiologic 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.

13. 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 currentlyreceiving highly active antiretroviral therapy

Exclusion Criteria:

1. Central nervous system metastases that are untreated or already treated butsymptomatic, or require radiation, surgery, or continued steroid therapy to controlsymptoms within 21 days prior to randomization

2. Known leptomeningeal involvement

3. Any systemic anticancer therapy or investigational drug within 4 weeks or 5half-lives, whichever is shorter, before randomization

4. Requirement for immunosuppressive medication

5. Major surgery or radiotherapy within 3 weeks of randomization

6. Clinically significant toxicities related to prior anticancer therapies that havenot returned to ≤ Grade 1 or baseline except for Grade ≤2- myalgia, neuropathy,alopecia, and any prior therapy related endocrinopathies

7. History of hypersensitivity reaction to any of the excipients of petosemtomab orpembrolizumab.

8. Unstable angina; history of congestive heart failure of Class II-IV New York HeartAssociation (NYHA) criteria, or serious cardiac arrhythmia requiring treatment; orhistory of myocardial infarction within 6 months prior to randomization

9. History of prior malignancies within the last 5 years, with the exception of excisedlocal cancer

10. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygentherapy

11. Current serious illness or medical conditions including, but not limited to,uncontrolled active infection, clinically significant pulmonary, metabolic orpsychiatric disorders

12. Patients with known infectious diseases as per protocol.

13. Pregnant or breastfeeding patients.

14. The patient has a diagnosis of immunodeficiency or is receiving chronic systemicsteroid therapy of prednisone >10 mg/day or equivalent, or any other form ofimmunosuppressive therapy

15. The patient has an active autoimmune disease that has required systemic immunesuppressive treatment in the past 2 years; replacement therapy is not consideredimmune suppressive treatment

16. The patient has had an allogeneic tissue/solid organ transplant.

17. Patient has a primary tumor site of nasopharynx, or sinonasal carcinoma (anyhistology)

Other protocol defined inclusion/exclusion criteria may apply.