Neoadjuvant Ficerafusp Alfa With Pembrolizumab in Resectable SCC

Inclusion Criteria: * Participants must have histologically or cytologically confirmed, untreated and newly diagnosed, locoregionally advanced head and neck squamous cell carcinoma (HNSCC) arising from oral cavity, oropharynx (with documented HPV-negative disease if presenting with oropharyngeal SCC), larynx, or hypopharynx. * Participants should have resectable disease at baseline per the discretion of the treating surgical oncologist. * Participants must have clinical stage disease as defined below 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: III * T3, any N: III, IVA, IVB * T4, any N: IVA, IVB * Tumor must be PD-L1 positive with a CPS score equal to 1 or greater (by any approved assay or scoring method). * Participants must be willing to provide blood and tissue pre-treatment and at the time of surgery for pathologic and correlative analyses. Specifically, willingness to provide a newly obtained core or excisional biopsy of a tumor lesion from the primary tumor site. * Age 18 years or older at the time of informed consent. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Participants must have adequate organ and marrow function as defined below: * absolute neutrophil count ≥1500/mcL * platelets ≥100 x 109/L * total serum bilirubin ≤1.5X upper limit of normal (ULN) (except for subjects with documented Gilbert syndrome) and AST (SGOT) and ALT (SGPT) ≤2.5X ULN * AST(SGOT) / ALT (SGPT) ≤3X ULN * Creatinine ≤institutional ULN or GFR of ≥30 mL/min/1.73 m2 * Coagulation PT/INR or activated partial thromboplastin time (aPTT) ≤1.5X ULN unless subject is receiving anticoagulant therapy * Female participants of childbearing potential should have a negative urine or serum pregnancy test within 7 days of study registration. Female subjects of childbearing potential should have a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the first dose of study medication. * Female participants of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 120 days after the last dose of study drugs. * Unsterilized male patient having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until day 60 after the last dose of study drugs. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Recurrent or metastatic (M1 or IVC disease by AJCC 2017 8th edition staging) HNSCC or very early-stage HNSCC (stage I or II by AJCC 2017 8th edition staging); or head and neck cancer arising at other primary subsites such as the skin, paranasal sinuses, nasal cavity, or salivary glands. * HPV-associated oropharyngeal cancer (as determined by p16 positivity by immunohistochemistry and/or confirmatory HPV RNA ISH or PCR testing, or by plasma HPV DNA testing results). * Inoperable or surgically unresectable at baseline per the treating investigator(s). * ECOG performance status of 2 or greater. * Prior exposure to anti-EGFR antibody or anti-PD-1 immunotherapy. * Significant bleeding risk peri-operatively at the judgment of the treating investigator(s); such as those with a known bleeding diathesis or experiencing a major bleeding episode within 4 weeks of enrolling to the study. * 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. * Known psychiatric, behavioral, or substance abuse disorders that would interfere with cooperation of the study requirements. * Subjects with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti-HBV therapy and are not on a suppressive antiviral therapy prior to initiation of study treatment. 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. Note: Subjects should remain on antiviral therapy throughout the study treatment period and follow local guidelines for HBV antiviral therapy post completion of study treatment. * Subjects with a known history of hepatitis C virus (HCV) who have not completed curative antiviral treatment or have an HCV viral load above the limit of quantification at Screening. Note: subjects must have completed curative antiviral therapy at least 4 weeks prior to treatment. * Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). HIV testing is not required unless mandated by local health authority. * 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 registration 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. Other exceptions may be considered with the input of the Sponsor-Investigator. * 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 Sponsor-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. * Active pregnancy or breastfeeding. * Unwilling to provide tumor or blood samples for research.