A Study of Radiation Therapy and Cemiplimab for People With Skin Cancer

Inclusion Criteria:

* Biopsy proven cutaneous squamous cell carcinoma which is locally advanced

  * Mixed histology tumors that are predominantly squamous cell carcinoma are eligible
  * Locally advanced primary tumor is T3-T4 and/or N+ by AJCC and/or UICC 8th edition clinical criteria
* T3-T4 primary tumor characteristics noted below:

  * Non-eyelid tumor \>4 cm in maximum dimension or with bone erosion or invasion, perineural invasion of nerve 0.1 mm or larger, or invasion beyond subcutaneous fat or \>6 mm from granular layer of adjacent normal epidermis
  * Eyelid tumor \>2 cm or invading adjacent ocular, orbital or facial structures
* ≥18 years old
* Unresectable or medically inoperable according to local multidisciplinary consensus for reasons such as:

  * Tumor or regional lymph node metastases that has recurred despite ≥2 prior surgical procedures, with another curative resection unlikely
  * Tumor or nodal disease with significant local invasion that precludes complete resection
  * Tumor or nodal disease in anatomically challenging area where surgery may result in significant disfigurement or dysfunction (amputation of nose, ear, eye, digit, limb, etc)
  * Medical contraindication to surgery
  * Patient refusal of surgery due to anticipate morbidity
* ECOG ≤2
* Adequate bone marrow and metabolic function (by blood tests)

  * Total bilirubin ≤1.5 x upper limit of normal
  * Aspirate aminotransferase (AST) ≤3 x upper limit of normal
  * Alanine aminotransferase (ALT) ≤3 x upper limit of normal
  * Alkaline phosphatase ≤2.5 x upper limit of normal
  * Serum creatinine ≤1.5 x upper limit of normal or estimated creatinine clearance \>30 mL/min according to Cockcroft-Gault formula
  * Hemoglobin \>9 g/dL
  * Absolute neutrophil count ≥1.5 x10\^9/L
  * Platelet count ≥75 x10\^9/L
* Able to provide informed consent
* Acceptable candidate for curative intent radiotherapy and Cemiplimab immunotherapy, in opinion of radiation and medical oncologist, respectively
* Life expectancy \>18 months

Exclusion Criteria:

* Primary tumor originating on the mucosal (non-hair bearing) lip or nose, anogenital (penis, scrotum, vulva, perianal) area
* Iatrogenic immunosuppression (\>prednisone 10 mg/day or equivalent within 14 days of initiation of treatment)
* Women of child bearing potential unwilling or unable to use effective contraception while receiving treatment with cemiplimab and for 4 months thereafter
* Distant metastases
* Clinically significant autoimmune disease that requires iatrogenic immunosuppression

  o For example, severe rheumatoid arthritis requiring disease modifying antirheumatic drugs, such as methotrexate
* Current or previous hematopoietic malignancy (leukemia, lymphoma)
* Prior allogeneic transplant of solid organ or bone marrow
* Concurrent malignancies with \>10% risk of metastasis or death within 2 years
* Prior aPD1 immunotherapy or PI3Kδ inhibitor use
* Prior radiotherapy for the cutaneous squamous cell carcinoma requiring treatment
* Other ongoing cancer therapy

  o Adjuvant endocrine therapy is permitted for patients with prostate or breast cancer
* Uncontrolled HIV or infectious hepatitis (viral load detectable in patient with known infection)
* Pregnancy or breastfeeding
* Comorbid or diagnostic abnormalities within the last year that would interfere with interpretation of study results