UCDCC#270: Avelumab and Stereotactic Ablative Radiotherapy in Non-responding and Progressing NSCLC Patients

Inclusion Criteria: 1. Signed informed consent. 2. Ability to comply with the protocol. 3. Adults \>18 years of age with histologically proven stage IV non-small cell lung cancer. 4. At least two sites of measurable disease as defined by RECIST 1.1; one of which must be amenable to treatment with SAR and accessible for a mandatory pre-treatment biopsy and a post- treatment biopsy at physician discretion. If a pulmonary nodule is being considered for SAR it must range in size from 1-5 cm. 5. Have provided written consent for protocol directed biopsies. 6. Patients with treated supratentorial metastases are allowed if stable, the patient is off steroids or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) and no evidence of intracranial hemorrhage. 7. Archival tumor sample available. A minimum of 10 unstained slides. No fine needle aspiration (FNAs) allowed or tumor tissue from bone. 8. ECOG performance status score of 0 or 1 (Appendix 1). 9. Life expectancy ≥ 3 months. 10. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days of the first study treatment: 1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused) 2. Liver function tests meeting the following criteria: total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 × ULN (for subjects with documented metastatic disease to the liver). 3. INR and aPTT \<1.5 × ULN (for patients on anticoagulation they must be receiving a stable dose for at least 1 week prior to randomization) 4. Creatinine clearance \>30 mL/min by Cockcroft-Gault formula (or local institutional standard method). 11. No history of severe hypersensitivity reactions to other mAbs. 12. No other active malignancy. 13. No active autoimmune disease or a history of known or suspected autoimmune disease except as detailed in the exclusion criteria below. 14. No chemotherapy or radiotherapy within the past 28 days. 15. Any number of prior treatments is allowed. Must have failed at least one treatment regimen for metastatic disease and must have failed platinum-based chemotherapy (including as treatment for localized disease) or be deemed ineligible for platinum-based therapy by the treating medical oncologist. 16. Most recent prior regimen was a PD-1 inhibitor (nivolumab or pembrolizumab) with progression. Last dose must have been delivered within 90 days of enrollment. 17. Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1% per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 60 days after avelumab treatment. 18. Negative serum pregnancy test at screening for women of childbearing potential. Exclusion Criteria: 1. Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement. 2. All subjects with brain metastases, except those meeting the following criteria: 1. Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment 2. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) 3. Subjects must be either off steroids or on a stable or decreasing dose of \<10mg daily prednisone (or equivalent) 3. Leptomeningeal disease. 4. Uncontrolled pleural or pericardial effusion or ascites that would require recurrent drainage. 5. Uncontrolled tumor related pain. 6. Uncontrolled hypercalcemia. 7. Pregnant and lactating women. 8. Uncontrolled concomitant disease. 9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication 10. Significant acute or chronic infections including, among others: 1. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 2. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive) 11. Oral or IV antibiotics within 2 weeks prior to enrollment. 12. Active tuberculosis 13. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma). 14. Known hypersensitivity or allergy to any component of the avelumab formulation. 15. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: 1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible 2. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day 3. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 16. Patients with a prior allogeneic bone marrow transplantation or prior solid organ transplantation. 17. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. A history of radiation pneumonitis in the radiation field (fibrosis) is permitted.