Inclusion Criteria:

• Age ≥ 18 years old.

• Histological confirmation of locally advanced or radiation-naïve recurrent oral cavity (HPV/p16-unrelated) squamous cell carcinoma requiring complex upfront surgical resection, including metastatic patients deemed potentially curable on multidisciplinary review.

• Measurable disease

• Non-measurable disease

• ECOG Performance Status (PS) ≤ 2

• Negative serum or urine pregnancy test done ≤ 10 days prior to (registration or radiotherapy), for persons of childbearing potential only.

• Ability to complete questionnaire(s) by themselves or with assistance.

• Provide signed written informed consent in accordance with ethical, regulatory, and institutional requirements.

• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

• Willing to provide tissue and blood samples for correlative research purposes.

• T3-T4, any N, M0, or M1 with low volume distant metastatic disease recommended for aggressive locoregional treatment on multidisciplinary review.

• Recurrent or platinum refractory disease acceptable if no prior radiotherapy

• Surgically resectable or borderline resectable

• Adequate bone marrow, hepatic, and renal function based on screening lab values within 35 days prior to beginning immunotherapy:

  • WBC ≥ 2 K/microliter

  • Neutrophils ≥ 1.5 K/microliter 

  • Platelets ≥ 100 K/microliter

  • Hemoglobin ≥ 9.0 g/deciliter 

  • Serum Creatinine ≤ 1.5 x ULN or creatinine clearance > 40ml/min using the Cockcroft-Gault formula.

  • Female CrCl = (140 – age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

  • Male CrCl = (140 – age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL 

  • AST/ALT ≤ 3 x ULN

  • Total bilirubin <1.5 x ULN (except subjects with Gilbert Syndrome who can have total bilirubin <3.0 mg/deciliter).

• Women of childbearing potential must have a negative serum or urine pregnancy test within 10 days prior to beginning immunotherapy.

• Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception from time of enrollment for the duration of treatment with nivolumab and for 6 months after discontinuation of nivolumab. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 6 months after the last dose of nivolumab.

Exclusion Criteria:

• Participation in another clinical study with an investigational product during the last 3 months 

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study during the follow-up period of the study 

• Any of the following: 

  • Pregnant women

  • Nursing women 

  • Men or women of childbearing potential who are unwilling to employ adequate contraception 

• Histologies other than squamous cell carcinoma, adenosquamous, or sarcomatoid squamous cell carcinoma. 

• Unresectable disease 

• Head and neck tumors not originating from the oral cavity, or HPV/p16- positive disease 

• Active or prior documented autoimmune or inflammatory diseases (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis, systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis]). The following are exceptions to this criterion: 

  • Patients with diverticulosis

  • Patients with vitiligo or alopecia 

  • Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement 

  • Any chronic skin condition that does not require systemic therapy

  • Patients without active disease in the last 5 years may be included after consultation with the study physician 

  • Patients with celiac disease controlled by diet alone 

• Patients with active ILD/pneumonitis or with a history of ILD/pneumonitis requiring steroids 

• Chronic steroid use >= equivalent of prednisone 10 mg/day 

• Prior radiation therapy to the head and neck 

• Prior treatment with immunotherapy including PD1 or PD-L1 inhibitor, anti-PD-L2, anti-CD137, anti-CTLA4 or any drug specifically targeting T cell co-stimulation pathways 

• Patients with QTc interval > 470 msec during screening 

• History of allogeneic organ or bone marrow transplant 

• Receipt of live attenuated vaccine within 30 days prior to the first dose pembrolizumab 

• Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with HIV on long-term antiretrovirals with undetectable viral load are eligible. 

• History of active primary immunodeficiency. 

• Patients with metastatic SCC neck disease of unknown primary site. 

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/10/2024. Questions regarding updates should be directed to the study team contact.