Astra Zeneca (Immuno Stereotactic Ablative Body Radiotherapy) ISABR Study: Randomized Phase I/II Study of Stereotactic Body Radiotherapy

Inclusion Criteria: For inclusion in the study subjects must fulfill all of the following criteria: 1. Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluation. 2. Newly diagnosed, untreated, biopsy proven non-small cell lung cancer. 3. Medically inoperable or patient refusal to surgery as defined by any single of the following criteria: a. Determined unfit for surgery by thoracic surgeon or radiation oncologist as documented in the medical record b. Pulmonary function test (PFTS) showing Forced Expiratory Volume in the first second (FEV1) ≤ 1.2 L or diffusing Lung Capacity (DLC) \<60%, c. Poor exercise tolerance or failed pre-operative cardiac work-up, d. Patient refusal to undergo definitive surgery as documented in clinical note by a surgeon, pulmonologist, medical oncologist, or radiation oncologist. 4. Clinically stage I disease by American Joint Committee on Cancer (AJCC) 7th edition. (N0, M0, T stages T1-T2a) or patients with stage T2bN0M0 (clinical stage IIA) disease who are medically unfit for standard of care chemotherapy as documented by a medical oncologist or radiation oncologist, or who refuse standard of care chemotherapy as documented by a medical oncologist or radiation oncologist. 5. Age \> 18 years at time of study entry. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. 7. Adequate normal organ and marrow function as defined below: * Haemoglobin ≥ 9.0 g/dL. * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3). * Platelet count ≥ 100 x 109/L (\>100,000 per mm3). * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.\>\> * aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/ alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN. * Serum creatinine creatinine clearance (CL) \>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) 8. Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. 9. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: 1. ECOG Performance status \>1. 2. Patients with metastatic or node positive NSCLC. 3. Patients with prior radiation therapy to the same bronchopulmonary segment. 4. History of automimmune disease including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematous, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, or glomerulonephritis. a. However, patients with type 1 diabetes mellitus, vitiligo, alopecia, hypothyroidism requiring hormone replacement, Graves disease, or skin disorders not requiring systemic treatment are permitted to enroll. 5. Patients with history of idiopathic pulmonary fibrosis, idiopathic pneumonitis, drug induced pneumonitis, or evidence of active pneumonitis on screening chest CT scan. 6. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 7. Participation in another clinical study with an investigational product during the last 6 months. 8. Any previous treatment with a Programmed Death-1 (PD1) or Programmed Death-Ligand 1(PD-L1) inhibitor, including durvalumab, and therapeutic anticancer vaccine. 9. History of another primary malignancy except for: 1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ. 10. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction. 11. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 12. Any unresolved ≥ Grade 2 pulmonary toxicity from previous anti-cancer therapy. 13. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1. 14. History of primary immunodeficiency. 15. History of allogeneic organ transplant. 16. History of hypersensitivity to durvalumab or any excipient. 17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. 18. Known history of previous clinical diagnosis of tuberculosis. 19. History of leptomeningeal carcinomatosis. 20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. 21. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control. 22. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 23. Subjects with uncontrolled seizures. -