This is a multicenter, single arm Phase 2B study in subjects with locally advanced oral cavity squamous cell carcinoma (OCSCC) with surgically resectable disease. The study will assess the combination of neoadjuvant XL092 and pembrolizumab for safety and improvement of pathologic response rates compared to historical standard of care with perioperative pembrolizumab. The primary objective is to estimate the pathologic response rate defined as either pathological complete response (pCR), which is the absence of residual viable tumor, or major pathologic response (MPR), which is <10% of residual tumor following the completion of neoadjuvant therapy and surgery. The study will be conducted in two stages. Per Simon's Stage 1, 11 patients will be enrolled. Simon Stage 2 will be gated on multiple factors. If ≥2 pathologic response is observed (pCR or MPR), the trial will proceed with cohort expansion and enroll an additional 15 patients for a total of 26 patients.

Inclusion Criteria:

• Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.
• Age ≥ 18 years at the time of consent.
• Tumors must have PD-L1 Combined Positive Score (CPS) ≥ 1.
• ECOG or Karnofsky Performance Status of 0-1
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) within 30 days prior to treatment .

Exclusion Criteria:

• Known HPV-positive cancer
• Active infection requiring systemic therapy.
• Prior treatment with XL-092
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).