A Phase 3 Study to Evaluate Petosemtamab Plus Pembrolizumab Vs Pembrolizumab in First-line Treatment of Head and Neck Cancer

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 baseline new tumor sample unless the patient has an available tumor sample as anFFPE 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 butsymptomatic, or require radiation, surgery, or continued steroid therapy to controlsymptoms 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 cancertherapies (except for alopecia); stable sensory neuropathy Grade ≤2 National CancerInstitute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 isallowed.

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

7. 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 of study entry

8. History of prior malignancies, with the exception of excised local cancer, ortreated cancer deemed at low risk for recurrence with no evidence of disease for ≥3years

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

10. Current serious illness or medical conditions including, but not limited to,uncontrolled active infection, clinically significant pulmonary, metabolic orpsychiatric 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 steroidtherapy or any form of immunosuppressive therapy within 7 days prior to the firstdose

14. 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.

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

Other protocol defined inclusion/exclusion criteria may apply.