Durvalumab vs Placebo With Stereotactic Body Radiation Therapy in Early Stage Unresected Non-small Cell Lung Cancer (NSCLC) Patients / Osimertinib Following SBRT in Patients With Early Stage Unresected NSCLC Harboring an EGFR Mutation

Main Cohort Key Inclusion Criteria:

1. Age ≥18 years
2. Planned SoC SBRT as definitive treatment
3. WHO/ECOG PS of 0, 1 or 2
4. Life expectancy of at least 12 weeks
5. Body weight >30 kg
6. Submission of tumor tissue sample if available
7. Adequate organ and marrow function required
8. Patients with central or peripheral lesions are eligible
9. Staging studies must be done during screening (PET-CT within 10 weeks)
10. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions

Osimertinib Cohort Key Inclusion Criteria

1. Age ≥18 years
2. Planned SoC SBRT as definitive treatment
3. World Health Organization (WHO)/ECOG PS of 0, 1, or 2
4. Patients with central or peripheral lesions are eligible
5. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions
6. Staging studies must be done during screening (PET-CT within 10 weeks)
7. Submission of available tumor tissue sample
8. Confirmation by local laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R)
9. Adequate bone marrow reserve or organ function required
10. Female patients should be using highly effective contraceptive measures
11. Male patients should be asked to use barrier contraceptives (ie, condoms) during sex with all partners during the trial and avoid procreation

Main Cohort Key Exclusion Criteria:

1. Mixed small cell and non-small cell cancer
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. Epidermal growth factor receptor local testing is strongly recommended prior to enrollment. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort
6. Prior exposure to immune-mediated therapy with exceptions

Osimertinib Cohort Key Exclusion Criteria

1. Mixed small cell and non-small cell cancer
2. Patients currently receiving potent inducers of CYP3A4
3. Patients with known or increased risk factor for QTc prolongation
4. Treatment with any of the following:

1. Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation
2. Prior treatment with neoadjuvant or adjuvant EGFR TKI
3. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4
4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib
5. Any of the following cardiac criteria

1. Mean resting corrected QT interval >470 msec, obtained from 3 ECGs
2. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval
4. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD