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.

1. Subjects 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.
2. The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, and larynx.
3. PD-L1 expression level Combined Positive Score (CPS) ≥ 1.
4. Subjects with oropharyngeal cancer must have HPV status from tumor tissue.
5. Measurable disease according to RECIST 1.1 as determined by the Investigator.
6. Tumor samples (archival or fresh tumor biopsy) are required. If archival tissue is unavailable, must provide fresh tumor tissue biopsy prior to randomization.
7. 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.
8. Age 18 years (or the legal age of consent in your country, if higher than 18) or older on the day of consent.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
10. Adequate organ and marrow function.

Exclusion Criteria:

1. Nasopharynx, salivary gland or occult primary site (regardless of p16 status).
2. Has disease that is suitable for local therapy administered with curative intent.
3. 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 (eg, CTLA-4, OX-40, CD137).
4. Life expectancy < 3 months.
5. Had progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
6. Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to randomization.
7. 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.
8. Positive hepatitis B surface antigen (HBsAg) test.
9. Positive hepatitis C virus (HCV) antibody test.
10. 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.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 28 days before randomization.
12. Pregnant or lactating females.
13. Administration of a live, attenuated vaccine within 30 days before randomization.