Zanzalintinib with Pembrolizumab and Cetuximab for Head and Neck Cancer

Inclusion Criteria: * Histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), which is considered incurable by local therapies. * Primary tumor locations: oropharynx, oral cavity, hypopharynx, larynx, nasopharynx, and sinonasal. Unknown primary is also eligible. * Age: Participants must be at least 18 years old. * ECOG Performance Status: Must be 0-1. * Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. * For oropharyngeal cancer: HPV (p16) testing is required. p16 Immunohistochemistry (IHC) is sufficient for Human Papillomavirus (HPV) testing. * Programmed cell death ligand 1 (PD-L1) combined positive score (CPS) : For patients with previously untreated R/M disease, a combined positive score (CPS) of 1 or greater is required. There is no PD-L1 restriction for patients who have previously received anti-PD(L)1 therapy. * Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from any adverse events (AEs), including immune-related AEs from prior treatments. * Adequate organ and marrow function, including: * Absolute neutrophil count (ANC) ≥ 1500/mm3. * Platelets ≥ 100,000/mm3. * Hemoglobin ≥ 9 g/dL. * Normal liver and kidney function. * Capable of understanding and complying with the protocol requirements and must have signed the informed consent document. * Contraception: Sexually active fertile subjects must agree to use a highly effective method of contraception during the study and for 2 months after the last dose of cetuximab and 4 months after the last dose of pembrolizumab. Exclusion Criteria: * Prior treatment with Zanzalintinib or other vascular endothelial growth factor receptor (VEGFR)-targeted therapies, -Cetuximab, or other epidermal growth factor receptor (EGFR) inhibitors. * More than two prior lines of systemic therapy in the recurrent/metastatic setting. * Relapsed disease within 3 months of definitive therapy. * Prior treatment with small molecule kinase inhibitors, chemotherapy, biologic, or other anticancer therapies within certain time frames (2-4 weeks before the first dose of study treatment). * Brain metastases or cranial epidural disease unless stable after treatment for at least 4 weeks. * Concomitant anticoagulation with oral anticoagulants or platelet inhibitors, unless on stable doses of acceptable anticoagulants. * Active infection requiring systemic treatment or significant cardiovascular, gastrointestinal, or other serious health issues that may affect study participation. * Known or suspected autoimmune disease, except for specific conditions like type I diabetes or controlled skin disorders. * Pregnancy or breastfeeding: Women must not be pregnant or breastfeeding at screening. * Other malignancies within the past 2 years (except for certain low-grade cancers like localized skin cancers).