To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations

Inclusion Criteria:

1. Patients must be 18 or the legal age of consent in the jurisdiction in which thestudy is taking place, at the time of signing the informed consent form.

2. Patients with histologically documented NSCLC of predominantly non-squamous,squamous, and adenosquamous pathology who present with locally advanced,unresectable (Stage III) disease (according to Version 8 of the IASLC Staging Manualin Thoracic Oncology). It is recommended but not required that except for overt cT4disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchialultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have beenconfirmed with whole body 18FDG PET plus contrast-enhanced CT in addition to or incombination with PET.

3. Patient who are eligible for and - planning to undergo CCRT or SCRT treatment.

4. Patients who had recurred from Stage I/II/III after complete surgery or had grossincomplete resections can be included if they didn't receive treatment with anychemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigationalagents.

5. Patients with HBV are only eligible for inclusion if they meet all the followingcriteria:

• Demonstrate absence of HCV co-infection or history of HCV co-infection

• Demonstrate absence of HIV co-infection

• Patients with active HBV infection are eligible if they are:

• Receiving anti-viral treatment for at least 6 weeks prior to studytreatment, HBV DNA is suppressed to <100 IU/mL and transaminase levels arebelow ULN. Participants with a resolved or chronic HBV infection are eligible if they are:

• Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG ortotal anti-HBc Ab]. In addition, patients must be receiving anti-viralprophylaxis for 2-4 weeks prior to study treatment or

• Positive for HBsAg, but for > 6 months have had transaminases levels below ULNand HBV DNA levels below <100 IU/mL (i.e., are in an inactive carrier state).In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeksprior to study treatment.

6. Patients with HIV are only eligible for inclusion if they meet all the followingcriteria:

• Demonstrate absence of HBV/ HCV co-infection

• Undetectable viral RNA load for 6 months

• CD4+ count of >350 cells/μL

• No history of AIDS-defining opportunistic infection within the past 12 months

• Stable for at least 4 weeks on the same anti-HIV medications

7. Availability of the EGFRm test results confirming that the tumour harbours one ofthe two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations includingde novo T790M

8. WHO performance status of 0 or 1 with no deterioration over the previous 2 weeksprior to baseline at screening and prior to first dose.

9. Minimum life expectancy of > 12 weeks at Day 1.

10. At least one lesion that can be accurately measured at baseline as ≥ 10 mm in thelongest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT orMRI and is suitable for accurate repeated measurements.

11. Male and/or female. Contraceptive use by males or females should be consistent withlocal regulations regarding the methods of contraception for those participating inclinical studies and/or SoC CRT

12. Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the ICF and in this CSP.

13. Provision of signed and dated written Optional Genomics Initiative ResearchInformation and Consent Form prior to collection of samples for optional genomicsinitiative research that supports the Genomic Initiative.

Note: If a patient declines to participate in optional genetic research, there will be no penalty or loss of benefit to the patient, and he/she will not be excluded from other aspects of the study.

Exclusion Criteria:

1. Any presence of small cell and mixed small-cell and non-small cell histology.

2. Past medical history of ILD/pneumonitis, drug-induced ILD, radiation pneumonitisthat required steroid treatment, or any evidence of clinically activeILD/pneumonitis.

3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the timeof starting study treatment with the exception of alopecia and Grade 2 priorplatinum-therapy related neuropathy. Patients with irreversible toxicity that is notreasonably expected to be exacerbated by study intervention in the opinion of theinvestigator may be included after consultation with the AstraZeneca medical monitor (eg, hearing loss).

4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses, which in the investigator's opinionmakes it undesirable for the patient to participate in the trial or which wouldjeopardise compliance with the protocol, or active infection (eg, patients receivingtreatment for infection, including HCV, HIV, and tuberculosis) or activeuncontrolled HBV infection.

5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product or previous significant bowel resection that wouldpreclude adequate absorption of osimertinib.

6. History of another primary malignancy except for malignancy treated with curativeintent with no known active disease ≥ 2 years before the first dose of studyintervention and of low potential risk for recurrence. Exceptions include adequatelyresected non-melanoma skin cancer and curatively treated in situ disease. Patientswho have received RT with overlapping fields (eg, cured breast cancer) should beexcluded.

7. Patient meets any of the following cardiac criteria:

8. Mean resting QTc > 470 msec, obtained from 3 ECGs, using the screening clinicECG machine-derived QTc value.

9. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG eg, complete left bundle branch block, third degree heart block andsecond-degree heart block. Patients with atrial fibrillation controlled bymedication or arrhythmias controlled by pacemakers may be permitted based onthe investigator judgement with cardiologist consultation recommended.

10. History of QT prolongation associated with other medications that requireddiscontinuation of that medication.

11. Congenital long QT syndrome, family history of long QT syndrome, unexplained suddendeath under 40 years of age in first-degree relatives or patients with any factorsthat increase the risk of QTc prolongation/arrhythmic events such as electrolyteabnormalities, heart failure or any concomitant medication known to prolong the QTinterval and cause TdP.

12. Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing laboratory values:

• Absolute neutrophil count <1.5 × 10^9/L

• Platelet count <100 × 10^9/L

• Haemoglobin <90 g/L

• Alanine transferase >2.5 times the upper limit of normal (ULN)

• Aspartate transferase >2.5 times ULN

• Total bilirubin >1.5 times ULN or >3 times ULN in the presence of documentedGilbert's Syndrome (unconjugated hyperbilirubinaemia)

• Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault formula); confirmation ofcreatinine clearance is only required when creatinine is >1.5 times ULN.

10. Patients currently receiving (or unable to stop use prior to receiving the firstdose of study treatment) medications or herbal supplements known to be stronginducers of CYP3A4 (at least 3-week prior to dosing). All patients must try to avoidconcomitant use of any medications, herbal supplements and/or ingestion of foodswith known inducer effects on CYP3A4.

11. Prior treatment with any chemotherapy, radiation therapy, immunotherapy orinvestigational agents for locally advanced, unresectable Stage III NSCLC. Priorsurgical resection (ie, Stage I, II, or III) with no systemic treatment withresidual disease or a recurrence is permitted.

12. Prior exposure to EGFR-TKI therapy

13. Major surgical procedure (excluding placement of vascular access) or significanttraumatic injury within 4 weeks of the first dose of study intervention or ananticipated need for major surgery during the study.

14. Participation in another clinical study with a study intervention or investigationalmedicinal device administered in the last 4 weeks (unless the safety profile isknown prior to first dose of study intervention), or concurrent enrolment in anotherclinical study (unless the study is observational [noninterventional], or thepatient is in the followup period of an interventional study).

15. History of hypersensitivity to active or inactive excipients of osimertinib or drugswith a similar chemical structure or class to osimertinib.

16. History of hypersensitivity to active or inactive excipients of the chemotherapyregimen of choice (pemetrexed or paclitaxel; cisplatin or carboplatin) or RT ordrugs with a similar chemical structure or class to the chemotherapy.

17. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site).

18. Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions, andrequirements.

19. Previous enrolment in the present study. Rescreening of individuals who were screenfailures is allowed.

20. For females only: Currently pregnant (confirmed with positive pregnancy test) orbreastfeeding.

21. Patients should refrain from breastfeeding from enrolment throughout the study anduntil 6 weeks after last dose of study intervention.

22. In addition, the following are considered criteria for exclusion from theexploratory genetic research:

• Prior allogeneic bone marrow transplant.

• Non-leukocyte depleted whole blood transfusion within 120 days of geneticsample collection.