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