The purpose of this study is to measure efficacy and safety of osimertinib as induction therapy prior to curative intent RT and maintenance osimertinib in chemotherapy ineligible or refusal adult patients with Stage III, unresectable NSCLC with common EGFR mutations (exon 19 deletion or L858R).

Study details include:

• The study duration will be approximately 13 months for recruitment and 2 years of follow up from the last patient's initiation into the study.
• The induction treatment with osimertinib will be up to12 weeks, followed by 6 weeks of RT treatment and osimertinib maintenance treatment until disease progression or death.
• The visit frequency will be once after 12 weeks during the induction treatment period, every 3 weeks during the RT period (daily visits for RT), and every 12 weeks during the osimertinib maintenance treatment period.

Inclusion Criteria:

1. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form.
2. Participants with histologically documented NSCLC of predominantly nonsquamous, squamous, and adenosquamous pathology who present with locally advanced, unresectable (Stage III, according to Version 8 of the IASLC Staging Manual in Thoracic Oncology) disease. It is recommended but not required that except for overt cT4 disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchial ultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have been confirmed with whole body contrast-enhanced CT.
3. Participants who had recurred from Stage I/II/III after complete surgery or had gross incomplete resections can be included if they didn't receive treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents.
4. Participants with availability of the EGFRm test results confirming that the tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo T790M
5. WHO performance status of 0, 1 or 2 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to first dose.
6. Participants who are eligible for and planning to undergo RT treatment per physician assessment.
7. Participant refusal or ineligible for chemotherapy per physician assessment.
8. Minimum life expectancy of > 12 weeks at Day 1.
9. At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
10. Capable of giving signed informed consent as described which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria

1. Any presence of small cell and mixed small-cell and non-small cell histology.
2. Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD.
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the participant to participate in the trial or which would jeopardize compliance with the protocol, or active infection.
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. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Patients who have received RT with overlapping fields (eg, cured breast cancer) should be excluded.
6. Patient meets any of the following cardiac criteria: Mean resting QTc > 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
7. Inadequate bone marrow reserve or organ function.
8. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy. Prior treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents for locally advanced, unresectable Stage III NSCLC. Prior surgical resection (ie, Stage I, II, or III) with no systemic treatment with residual disease or a recurrence is permitted.

11 Prior exposure to EGFR-TKI therapy. 12 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.

13 Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks.

14 History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.

15 History of hypersensitivity to active or inactive excipients of RT. 16 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

17 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

18 Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.

19 For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.

20 Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trails via the request portal.

All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrails.pharmacm.com/ST/Submission/Disclosure.

Indicates that AZ accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrails.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in approved sponsored tool. Signed Data Sharing Agreement(non-negotiable contract for data accessors)must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MES to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrails.pharmacm.com/ST/Submission/Disclosure.