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 areeligible

• Locally advanced primary tumor is T3-T4 and/or N+ by AJCC and/or UICC 8thedition 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 subcutaneousfat 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 consensusfor reasons such as:

• Tumor or regional lymph node metastases that has recurred despite ≥2 priorsurgical procedures, with another curative resection unlikely

• Tumor or nodal disease with significant local invasion that precludes completeresection

• Tumor or nodal disease in anatomically challenging area where surgery mayresult 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 ofinitiation of treatment)

• Women of child bearing potential unwilling or unable to use effective contraceptionwhile 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 antirheumaticdrugs, 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 breastcancer

• Uncontrolled HIV or infectious hepatitis (viral load detectable in patient withknown infection)

• Pregnancy or breastfeeding

• Comorbid or diagnostic abnormalities within the last year that would interfere withinterpretation of study results