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

This is a Phase 3 randomized, open-label study to evaluate the efficacy and safety of petosemtamab plus pembrolizumab vs pembrolizumab in first-line treatment of recurrent or metastatic PD-L1+ head and neck squamous cell carcinoma.

This is a Phase 3 randomized, open-label study to evaluate the efficacy and safety of petosemtamab plus pembrolizumab vs pembrolizumab in first-line treatment of recurrent or metastatic PD-L1+ HNSCC. HNSCC patients should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advanced disease is allowed if PD was ≥6 months after the last platinum-containing therapy dose. Previous treatments with anti PD-(L)1 or anti-EGFR therapies are not allowed. In the case of cetuximab, patients who have received cetuximab with radiotherapy as a local treatment and PD was \>1 year after the last dose of cetuximab are eligible.

Eligibility Criteria:
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 new tumor biopsy, unless the patient has an available archival tumor sample with sufficient material
8. Measurable disease per Investigator assessment 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.
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 currently receiving highly active antiretroviral therapy

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 prior to randomization
2. Known leptomeningeal involvement
3. Any systemic anticancer therapy or investigational drug within 4 weeks or 5 half-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 have not 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 or pembrolizumab.
8. 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
9. History of prior malignancies within the last 5 years, with the exception of excised local cancer
10. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy
11. Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric 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 systemic steroid therapy of prednisone \>10 mg/day or equivalent, or any other form of immunosuppressive therapy
15. 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
16. The patient has had an allogeneic tissue/solid organ transplant.
17. Patient has a primary tumor site of nasopharynx, or sinonasal carcinoma (any histology)

Other protocol defined inclusion/exclusion criteria may apply.