Study of Zanzalintinib (XL092) + Pembrolizumab vs Pembrolizumab in Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Inclusion Criteria: * Histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapy. * Should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization if given as part of multimodal treatment for locally advanced disease is allowed. * The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, and larynx. * PD-L1 expression level Combined Positive Score (CPS) ≥ 1. * Participants with oropharyngeal cancer must have human papillomavirus (HPV) status from tumor tissue. * Measurable disease according to RECIST 1.1 as determined by the Investigator. * Tumor samples (archival or fresh tumor biopsy) are required. If archival tissue is unavailable, must provide fresh tumor tissue biopsy prior to randomization. * Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs) related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. * Age 18 years (or the legal age of consent in your country, if higher than 18) or older on the day of consent. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Adequate organ and marrow function. Exclusion Criteria: * Nasopharynx, salivary gland or occult primary site (regardless of p16 status). * Has disease that is suitable for local therapy administered with curative intent. * Has received prior therapy with zanzalintinib, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (for example, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137). * Life expectancy \< 3 months. * Had progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC. * Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to randomization. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to randomization. * Positive hepatitis B surface antigen (HBsAg) test. * Positive hepatitis C virus (HCV) antibody test. * Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to randomization. Complete wound healing from major or minor surgery must have occurred at least prior to randomization. * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms per electrocardiogram (ECG) within 28 days before randomization. * Pregnant or lactating females. * Administration of a live, attenuated vaccine within 30 days before randomization.