Study of Avelumab and/or Radiation Therapy in People With Advanced Merkel Cell Carcinoma

Inclusion Criteria:

* Biopsy proven Merkel cell carcinoma which is unresectable or metastatic, stage III or IV
* Prior first-line treatment with aPD1 monotherapy (defined as at least one dose of pembrolizumab, avelumab, nivolumab, etc.) with evidence of progression of disease ≥10 weeks after starting therapy, in the absence of significant clinical deterioration

  * Patients with clinical deterioration during aPD1 monotherapy are eligible ≥6 weeks after starting aPD1 therapy
  * Criteria for clinical deterioration to be determined and agreed upon by treating physician and Principal Investigator
* All detectable sites of MCC are amenable to comprehensive ablative radiation therapy in opinion of treating radiation oncologist and principal investigator
* ≥18 years of age
* Performance status ≤2 on the Eastern Cooperative Oncology Group Performance Scale
* Able to provide valid written informed consent
* Normal organ and marrow function

  * Hematologic: Neutrophil count ≥1500/mm\^3, platelet count ≥100,000/mm\^3, hemoglobin ≥9 g/dL
  * Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal, unless Gilbert's syndrome; aspartate transaminase and alanine transaminase ≤ 2.5 times the upper limit of normal (in the absence of hepatobiliary metastases); ≤ 3.0 times the upper limit of normal (in the presence of hepatobiliary metastases)
  * Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula.

Exclusion Criteria:

* Prior systemic therapy for MCC other than first-line aPD1 monotherapy (ie, chemotherapy)
* Pregnancy or breastfeeding
* Adverse events due to prior cancer therapy which are grade 3 or higher and have not resolved

  °Patients with prior grade 3 or higher immune related adverse events are not eligible, even if they have resolved
* Prior severe hypersensitivity reaction (CTCAE version 5.0 grade ≥3) to avelumab
* Prior radiotherapy which precludes the ability to safely deliver comprehensive ablative radiation therapy in the opinion of the treating radiation oncologist and principal investigator

  °Institutional guidelines for reirradiation will be used when making this determination
* Known central nervous system metastases
* Known clinically significant cardiovascular disease, defined as:

  * Stroke or myocardial infarction within 6 months of first dose of avelumab
  * Symptomatic congestive heart failure (New York Heart Association Class 2 or higher)
  * Serious arrhythmia requiring anti-arrhythmic agents
* Known Human Immunodeficiency Virus infection
* Known Hepatitis B or C infection requiring ongoing treatment
* Vaccination within 4 weeks of first dose of avelumab

  °Inactivated vaccines are permissible
* Iatrogenic immunosuppression with daily systemic corticosteroid equivalent of \>10 mg of prednisone
* Active autoimmune disease that may cause clinical deterioration during immunotherapy

  °Including, but not limited to:
* Inflammatory bowel disease or immune colitis
* Immune mediated pneumonitis or pulmonary fibrosis
* History of solid organ or hematopoietic transplant
* Active infection requiring systemic therapy
* Active suicidal ideation or behavior
* Comorbid or diagnostic abnormalities which would interfere with interpretation of study results
* Known hematopoietic cancer or dysfunction (i.e., leukemia, lymphoma)
* Known non-MCC solid tumor with known metastasis or estimated risk of metastasis \>20% within 3 months