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 bylocal therapy.

• Subjects should not have had prior systemic therapy administered in therecurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization if given as part of multimodal treatment forlocally 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.

• Subjects with oropharyngeal cancer must have 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 isunavailable, 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/orstable on supportive therapy.

• Age 18 years (or the legal age of consent in your country, if higher than 18) orolder 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, oranti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitoryT-cell receptor (eg, CTLA-4, OX-40, CD137).

• Life expectancy < 3 months.

• Had progressive disease within 6 months of completion of curatively intendedsystemic treatment for locoregionally advanced HNSCC.

• Radiation therapy for bone metastases within 2 weeks, any other radiation therapywithin 4 weeks prior to randomization.

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior 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 weeksprior to randomization. Complete wound healing from major or minor surgery must haveoccurred at least prior to randomization.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms perelectrocardiogram (ECG) within 28 days before randomization.

• Pregnant or lactating females.

• Administration of a live, attenuated vaccine within 30 days before randomization.