Osimertinib With or Without Savolitinib as 1L in de Novo MET+, EGFR+ NSCLC

Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Informed consent 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. 2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses. Age 3. Participant must be ≥18 years at the time of signing the ICF. All genders are permitted. Type of Participant and Disease Characteristics 4. Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity. 5. Has not received any systemic treatment of advanced NSCLC. * Prior adjuvant/neo-adjuvant therapy completed \> 6 months before screening is allowed. 6. MET amplification/high expression as determined by FISH, IHC or NGS testing on tumor tissue collected before any systemic treatment in first line. * MET high expression by IHC, 3+ in ≥75% of tumor cells * increased MET gene copy number by FISH, MET gene copy ≥5 or MET / CEP7 ratio ≥2; or by tissue NGS, ≥20% tumour cells, ≥200x sequencing depth of coverage and CN ≥5. * Local IHC, FISH and pre-existing local NGS results are acceptable, central FISH and central NGS confirmation is highly suggested if tissue sample available. 7. WHO or Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing and a minimum life expectancy of 12 weeks. 8. At least 1 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 computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements. 9. Adequate haematological function defined as: * Haemoglobin≥8.5 g/dL (no transfusion in the past 2 weeks). * Absolute neutrophil count ≥1.5×109/L. * Platelet count ≥100,000/μL (no transfusion in the past 10 days) 10. Adequate liver function defined as: * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the upper limit of normal (ULN) with total bilirubin (TBL) ≤ ULN * OR TBL \>ULN to ≤1.5x ULN with ALT and AST ≤ ULN 11. Adequate renal function defined as a creatinine \<1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min, as assessed using the standard methodology at the investigating centre (eg, Cockcroft-Gault, Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration formulae, ethylenediaminetetraacetic acid clearance or 24-hour urine collection). Confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN. 12. Adequate coagulation parameters, defined as: * International Normalisation Ratio (INR) \<1.5 x ULN and activated partial thromboplastin time \<1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects these parameters. 13. Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin (LMWH) for ≥2 weeks. 14. Ability to swallow and retain oral medications. 15. Willingness and ability to comply with study and follow-up procedures. Reproduction 16. Females must be using highly effective contraceptive measures (see Section 5.3.2), and have a negative pregnancy test (serum) for women of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening: * Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. * Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution. * Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. * Further information is available in Appendix F (Contraception Requirements). 17. Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection). 2. Any of the following cardiac diseases currently or within the last 6 months: * Unstable angina pectoris * Congestive heart failure (New York Heart Association \[NYHA\] ≥Grade 2) * Acute myocardial infarction * Stroke or transient ischemic attack * Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy). * Mean resting correct QT interval (QTcF) \>470 msec for women and \>450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value. * Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium \< LLN; Serum/plasma magnesium \< LLN; Serum/plasma calcium \< LLN), congenital or familial long QT syndrome, family history of 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. * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval \>250 msec. * Acute coronary syndrome 3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy. 4. Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement. 5. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol. 6. Active hepatitis B (HBV) (positive HBV surface antigen \[HBsAg\] result) or hepatitis C (HCV). Viral testing is not required for assessment of eligibility for the study. Patients with a past or resolved HBV or HCV infection are eligible if: * Negative for HBsAg and positive for hepatitis B core antibody \[anti-HBc\] or * Positive for HBsAg, but for \>6 months have had normal transaminases and HBV DNA levels between 0 to 2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study. * HBV DNA levels \>2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study. * Patients with positive HCV antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid. 7. Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer. 8. Unresolved toxicities from any prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment/randomization with the exception of alopecia 9. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 2 weeks prior to start of study intervention. Subjects with leptomeningeal metastases are ineligible. 10. Past medical history of ILD/pneumonitis, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 11. Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies). Testing is not required for assessment of eligibility for the study.. 12. Known history of liver fibrosis/cirrhosis. 13. Known contraindications to osimertinib administration. 14. Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class. Prior/Concomitant Therapy 15. Prior exposure to HGF/MET inhibitors, e.g., foretinib, crizotinib, cabozantinib, merestinib, onartuzumab, capmatinib, tepotinib, etc.. 16. Prior exposure to EGFR TKI. 17. Patients 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 CYP3A4, strong inhibitors of CYP1A2, within 2 weeks of the first dose of study treatment (3 weeks for St John's Wort) will be excluded. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 during the study and for 3 months later the last dose intake. Prior/Concurrent Clinical Study Experience 18. Participation in another clinical study with a study interventional medication administered within five half-lives of the compound or 3 months, whichever is greater or investigational medicinal device administered in the last 30 days prior to randomisation/first dose of study intervention or 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. Other Exclusions 19. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 20. 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. 21. For women only-Currently breastfeeding. 22. Previous enrolment in the present study. 23. Without civil capacity or with restricted civil capacity. 24. Any other reasons judged by the leading investigator to prevent the subject from participating in this study