This study will test the use of comprehensive ablative radiation therapy (CART), with the immunotherapy drug avelumab, in people with Merkel cell carcinoma (MCC) that has progressed after treatment and cannot be removed with surgery. The study researchers want to find out if CART works well when combined with avelumab.

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

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.