Inclusion Criteria:
* Newly diagnosed histologically or cytologically confirmed locally advanced, OPC HPV-negative head and neck squamous cell carcinoma (OPSCC) or HNSCC arising from oral cavity, larynx, or hypopharynx.
* Baseline resectable disease per the judgment of the treating surgical oncologist.
* Clinical stage III, IVA, or IVB disease as defined using the 8th (2017) edition of the tumor, node, metastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC):
* T1-2, N1-3 or
* T3, any N or
* T4, any N
* Documented tumor PD-L1 CPS ≥ 1 (by PD-L1 IHC pharmDx assay), determined locally.
* Willing to provide blood and newly obtained core or excisional biopsy of tumor lesion pre-treatment and at the time of surgery for pathologic and correlative analyses.
* Age 18 years or older at the time of informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ and marrow function as defined below:
* Absolute neutrophil count ≥ 1.5 K/cumm
* Platelets ≥ 100 K/cumm
* Hemoglobin ≥ 9 g/dL (without PRBC transfusion in the prior 7 days)
* Total serum bilirubin ≤ 1.5 x IULN (except for subjects with documented diagnosis of Gilbert syndrome). For subjects with a documented diagnosis of Gilbert's syndrome, total bilirubin must be ≤ 3.0 × ULN, provided that direct bilirubin is within normal limits
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* Creatinine clearance (measured or calculated via the Cockcroft-Gault equation or per institutional standards) ≥ 30 mL/min
* PT/INR or aPTT ≤ 1.5 x IULN (except for subjects receiving anticoagulant therapy)
* The effects of pembrolizumab and ficerafusp alfa on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 120 days (women) or 90 days (men) after completion of study treatment.
* Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Currently receiving any other investigational agents.
* Prior history of grade ≥ 2 intolerance or hypersensitivity reactions to other murine proteins, or the active substances of ficerafusp alfa, pembrolizumab, or any of their excipients.
* At higher risk of bleeding, including known bleeding diathesis or current active major bleeding, or recent major bleeding episode (within 4 weeks prior to enrollment).
* Any of the following within 6 months prior to starting study treatment: ST-elevation myocardial infarction, severe/unstable angina, uncontrolled cardiac ventricular arrhythmia, coronary/peripheral artery bypass graft or stent, cerebrovascular accident/stroke less than 6 months prior to enrollment, or congestive heart failure. Subjects with deep vein thrombosis who are hemodynamically stable can enroll if they are on a stable dose of anticoagulants for at least 3 months.
* Active autoimmune disease requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before first dose of study treatment.
* Chronic hepatitis B virus (HBV) infection with active disease meeting the criteria for anti-HBV therapy but not on a suppressive antiviral therapy prior to initiation of study treatment. HBV testing not required in the absence of known history of infection. Note: Subjects who are hepatitis B surface antigen positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. These subjects should remain on antiviral therapy throughout the study treatment period and follow local guidelines for HBV antiviral therapy post completion of study treatment.
* Known history of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible provided they completed curative antiviral therapy at least 4 weeks prior to initiation of study treatment. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
* Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) with viral load \>0 or CD4\<350. HIV testing is not required in the absence of known history of infection.
* Receipt of any organ transplantation, including autologous and allogeneic stem cell transplantation, except for transplants that do not require immunosuppression.
* Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and low-risk early stage prostate cancer defined as follows: Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen \< 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study entry. Other exceptions may be considered with the PI's consultation. The time requirement for no malignancy for 2 years does not apply to the cancer for which a subject is enrolled in the study.
* Any condition requiring systemic treatment with either corticosteroids (\>10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 7 days prior to the first dose of study treatment, except for topical, intranasal, intrabronchial, or ocular steroids. Corticosteroid use as premedication for allergic reactions (e.g., intravenous contrast), or as a prophylactic management of AEs related to the therapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the principle-Investigator.
* Use of a live or live attenuated vaccine within 4 weeks prior to Screening. Note: Administration of killed, recombinant, or inactivated vaccines is allowed.
* Pregnant or breastfeeding. People of childbearing potential must have a negative pregnancy test at screening and within 7 days of first dose of study treatment.
