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.