The Selective Personalized Radio-Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer Trial 2

Inclusion Criteria: 1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Patient 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. 3. Age \> 18 years at time of study entry 4. Body weight ≥35 kg 5. Life expectancy of at least 12 weeks 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Previously untreated, pathologically proven NSCLC and one of the following stages: 1. American Joint Committee on Cancer (AJCC) version 8 Stage II disease, medically or technically unresectable 2. AJCC version 8 Stage III disease 3. Recurrent disease after curative-intent treatment for early-stage NSCLC, with current disease burden that would qualify as AJCC version 8 stage II-III 8. PD-L1 testing performed using an FDA-approved immunohistochemical assay and demonstrating tumor proportion score (TPS) of at least 50%. 9. Whole body PET/CT within 42 days prior to study entry demonstrating at least one hypermetabolic pulmonary lesion or thoracic lymph node. 10. MRI of the brain or head CT with contrast within 42 days prior to study entry. 11. PFTs within 42 days of study entry are recommended but not required. 12. Adequate normal organ and marrow function as defined below: Hemoglobin ≥9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L Platelet count ≥75 × 109/L Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with Gilbert's syndrome. Serum albumin ≥ 3.0 g/dL AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal Measured creatinine clearance \>40 mL/min or Calculated creatinine clearance \>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. * Males: (Weight in kg) x (140 - Age) ÷ (72 x serum creatinine in mg/dL) * Females: (Weight in kg) x (140 - Age) x 0.85 ÷ (72 x serum creatinine in mg/dL) Exclusion Criteria: 1. Participation in another clinical study with an investigational product during the last 3 months 2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study 3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy, with these exceptions: 1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. 2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment on this study may be included after consultation with the Study Physician. 4. Any concurrent chemotherapy, Intraperitoneal (IP) chemotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 5. 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 IP 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 6. History of leptomeningeal carcinomatosis 7. Prior radiotherapy that would preclude safe delivery of radiotherapy as specified in this study. 8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first planned dose of IP. 9. History of allogenic organ transplantation. 10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: 1. Patients with vitiligo or alopecia 2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 3. Any chronic skin condition that does not require systemic therapy 4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician 5. Patients with celiac disease controlled by diet alone 11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 12. History of grade 3 or greater edema (e.g., peripheral, pulmonary) 13. History of venous thrombosis within the past 3 months prior to the planned first dose of study treatment. Note: Subjects with thrombosis due to mechanical obstruction by the tumor that is found incidentally and is asymptomatic and does not require therapy may be enrolled at the investigator's discretion and should be closely monitored. 14. Cardiac or peripheral vascular disease meeting any of the following criteria: 1. History of myocardial infarction in the prior 12 months 2. History of stroke or transient ischemic attack requiring medical therapy 15. Congestive heart failure ≥ Class 3 based on New York Heart Association Functional Classification 16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 17. History of active primary immunodeficiency 18. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. 1. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. 2. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 19. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). 20. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion: 1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent 3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP. 22. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. 23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 24. Patients who have received prior anti-PD-1 or anti PD-L1 therapy: 1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy 2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. 3. Must not have experienced a ≥Grade 3 immune related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. 4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day.