Neoadjuvant Immunoradiotherapy in Head & Neck Cancer (NIRT 2-HNC)

Inclusion Criteria: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent. 2. Histologically confirmed diagnosis of stage III-IVA HPV-negative HNSCC who are planned for surgical resection and in the opinion of the investigator are able to safely undergo neoadjuvant anti-PD-1 and radiation will be enrolled in this study. Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention these tumor locations are assumed to be HPV-negative Male participants: 3. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 75 days, corresponding to time needed to eliminate any study treatment) plus an additional 120 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period. Female participants: 4. A female participant is eligible to participate if she is not pregnant (see Appendix 3),or breastfeeding and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR 2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 75 days (corresponding to time needed to eliminate any study treatment) plus 30 days (a menstruation cycle) after the last dose of study treatment. 5. The participant must provide (or legally acceptable representative if applicable) written informed consent for the trial. 6. Have provided archival tumor tissue sample collected within the last 6 months or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained slides, slides should be submitted to the testing laboratory within 14 days from the date slides are cut. For archival tissue samples collected \>6 months from screening, PI approval is required. 7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 10 days prior to the date of enrollment 8. Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study treatment. Exclusion Criteria: 1. A WOCBP who has a positive serum or urine pregnancy test within 72 hours prior to first dose of pembrolizumab (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks \[could consider shorter interval for kinase inhibitors or other short half-life drugs\] prior to enrollment Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. 4. Has received prior radiotherapy to the head and neck region. 5. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed. 6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 8. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) or other solid tumor or hematologic malignancy that have undergone potentially curative therapy outside of the head and neck are not excluded. 9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 13. Has an active infection requiring systemic therapy. 14. Has a known history of Human Immunodeficiency Virus (HIV) testing is not required unless mandated by local health authority 15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 16. Has a known history of active TB (Bacillus Tuberculosis). testing is not required unless mandated by local health authority 17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. 20. Patients with T1,T2 and T3 larynx cancer are excluded. 21. Patients with prior history of solid organ and/or allo-transplantation. 22. Patients with pre-existing neuropathy of grade 2 or higher peripheral neuropathy.