• Must be ≥ 18 years of age at the time of consent.

• Patient (or a legally authorized representative) must understand and voluntarily sign informed consent prior to any study-related assessments/procedures being conducted.

• Must be able and willing to comply to the study visit schedule and protocol requirements.

• Must have sufficient archived tumor tissue available for PD-L1 CPS determination. If not, patient must agree to a fresh tumor biopsy before starting the treatments. If patient only had a fine needle aspiration, a fresh biopsy with a core needle or punch biopsy is required.

• If the primary site is oropharynx, p16/HPV status must be determined. HPV status determined by cell free HPV DNA testing is also acceptable.

• Must have surgically resectable HNSCC including oral cavity, oropharynx, larynx, and hypopharynx. Patients with p16-positive or HPV-positive unknown primary of head and neck are eligible. Must be newly diagnosed HNSCC with T1-2 N1-3 or T3-4 N0-3 undergoing surgery as a standard of care. If the tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base or encases carotid artery, and/or prevertebral fascia involvement, it will be considered as unresectable and excluded.

• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Must meet the laboratory criteria outlined in the protocol.

• Patients of childbearing potential and patients whose sexual partners are of childbearing potential must be willing to practice an approved method of highly effective birth control with their partners starting at the time of informed consent and for 1 year after the completion of the study treatment regimen. Women of childbearing potential must have a negative pregnancy test within the 7 days prior to enrollment.