A Study of Osimertinib-based Adaptive Treatment Guided by ctDNA EGFRm+ Monitoring in NSCLC

Inclusion Criteria: 1. Provision of signed and dated, written informed consent form (ICF) prior to any study specific procedures. 2. Male or female participants aged 18 years old and above. 3. ECOG PS of 0-1. 4. Life expectancy of at least 3 months at recruitment. 5. Participants able to collect plasma samples at baseline. 6. Newly diagnosed, and histologically documented locally advanced or metastatic non-squamous NSCLC with sensitizing EGFR mutations positive (either Exon 19 deletion or 21 L858R, confirmed by histology or cytology), and classified as stage IIIB, IIIC, IV or recurrent NSCLC which are not amenable to curative surgery or radiotherapy (per Version 8 of the International Association for the Study of Lung Cancer \[IASLC\] Staging Manual in Thoracic Oncology). 7. Detectable EGFRm (Ex19del or L858R) in plasma ctDNA by central Super ARMS PCR testing at the time of screening. 8. Participants must have untreated advanced NSCLC and intend to receive osimertinib plus chemotherapy as first-line treatment. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapy, investigational agents, are permitted as long as treatment was completed at least 12 months prior to receiving the first dose of study treatment. 9. Participants with asymptomatic and stable central nervous system (CNS) metastases for at least 2 weeks (for those who received definitive therapy and steroids, a stable neurological status for at least 2 weeks after completion of the treatment is required) will be allowed, including leptomeningeal metastases. 10. At least 1 lesion, not previously irradiated that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis of ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days of the baseline tumour assessment scans. 11. Patients with hepatitis B virus (HBV) are only eligible for inclusion if they meet all the following criteria: * Demonstrated absence of hepatitis C virus (HCV) co-infection or history of HCV co-infection * Demonstrated absence of human immunodeficiency virus (HIV) infection * Participants with active HBV infection are eligible if they are: * Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to \<100 IU/mL and transaminase levels are below upper limit of normal (ULN). * Participants with a resolved or chronic HBV infection are eligible if they are: * Negative for hepatitis B surface antigen (HBsAg) and positive for hepatitis B core antibody \[anti-HBc IgG or total anti-HBc Ab\]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment. or * Positive for HBsAg, but for \> 6 months have had transaminases levels below ULN and HBV DNA levels below \<100 IU/mL or below the detectable limit of locally available test kit (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment. 12. Patients with HIV are only eligible for inclusion if they meet all the following criteria: * Demonstrated 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 13. Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: * Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. * Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution. * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 14. Male participants must be willing to use barrier contraception. Exclusion Criteria: 1. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 2. 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 (e.g. participants receiving treatment for infection) including hepatitis C and HIV, or active uncontrolled HBV infection. Screening for chronic conditions is not required. 3. Any of the following cardiac criteria: * Mean resting corrected QTc \>470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value. * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block and second degree heart block. * Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including: * Serum/plasma magnesium\* \< LLN * Serum/plasma calcium\* \< LLN * Hypokalaemia\* ≥ CTCAE Grade 2 heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. * Correction of electrolyte abnormalities should be documented prior to first dose 4. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: * Absolute neutrophil count (ANC) \<1.5 × 109/L * Platelet count \<100 × 109/L * Hemoglobin \<90 g/L * Alanine aminotransferase (ALT) \>2.5 times the ULN if no demonstrable liver metastases or \>5 times ULN in the presence of liver metastases. * Aspartate aminotransferase (AST) \>2.5 times ULN if no demonstrable liver metastases or \>5 times ULN in the presence of liver metastases. * Total bilirubin \>1.5 times ULN if no liver metastases or \>3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases. * Serum Creatinine \>1.5 times ULN concurrent with creatinine clearance \<50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN. 5. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of investigational product (IP). 6. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 prior platinum-therapy related neuropathy. 7. 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. 8. Prior treatment with any systemic anti-cancer therapy for advanced NSCLC not amenable to curative surgery or radiation including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapies, investigational agents are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease. 9. Prior treatment with an EGFR-TKI. 10. Major surgery within 4 weeks of the first dose of IP. Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery (VATS) are permitted. 11. Palliative radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. 12. Participants currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4 (at least 3-week prior). All participants must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4. 13. Participation in another clinical study with an investigational product within 5 half-lives of the compound or 3 months whichever is greater prior to Day 1. 14. History of hypersensitivity to active or inactive excipients of Osimertinib or drugs with a similar chemical structure or class to Osimertinib. 15. Contraindication for pemetrexed and cisplatin/carboplatin according to local approved label. 16. Women who are breast-feeding. 17. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site). 18. 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.