This is a multicenter, randomized, double-blind, controlled Phase 2/3 trial of zanzalintinib in combination with pembrolizumab versus zanzalintinib-matched placebo in combination with pembrolizumab in subjects with programmed death-ligand 1 (PD-L1) positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) incurable by local therapies who have not received prior systemic therapy for recurrent or metastatic disease.

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.