Inclusion Criteria: 

• Patients must be ≥ 18 years of age (≥ 20 years of age in Japan).
• 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.
• All genders are permitted.
• Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity (including either exon 19 deletion and/or L858R) which is not amenable to curative therapy. 
• Documented radiologic disease progression on first line:
• MET amplification as determined by FISH (central) testing on tumour tissue collected following progression on 1L osimertinib treatment.
• Available tissue from a recent biopsy for MET analysis or willingness to collect additional tissue for central testing. 
• At least 1 lesion, not previously irradiated, not biopsied during the screening period, 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) which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour sample collection is performed.
• Prior lines of therapy in locally advanced/metastatic setting Only prior 1L osimertinib treatment in metastatic setting is permitted:
• Adequate haematological function defined as:
  • Absolute neutrophil count ≥1500/μL;
  • Haemoglobin ≥ 9 g/dL (no transfusion in the past 2 weeks);
  • Platelets ≥ 100,000/μL (no transfusion in the past 10 days).
• 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 ≤1.5 x ULN with ALT and AST ≤ ULN 12 Adequate renal function defined as a serum creatinine 1.5 times ULN.
• 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.
• Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin (LMWH) for ≥2 weeks.
• Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
• Ability to swallow and retain oral medications.
• Willingness and ability to comply with study and follow-up procedures.
• Females of childbearing potential must be using highly effective contraceptive measures should not be breast feeding, and must have a negative pregnancy test if 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 post-menopausal 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;
  • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 
  • 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: 

• Unresolved toxicities from any 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.
• 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).
• 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, chronic hypokalaemia not correctable with supplements, 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; e.g., complete left bundle branch block, third degree heart block, second degree heart block, P-R interval > 250 msec;
  • Acute coronary syndrome
• 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.
• Major surgical procedures ≤ 28 days of beginning study drug or minor surgical procedures ≤ 7 days. No waiting is required following port-a-cath placement.
• 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.
• 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.
• 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.
• 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.
• Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
• Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.
• Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
• Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study treatment with the exception of monotherapy osimertinib which may continue uninterrupted during screening.
• 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.
• Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment.
• Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class. Other exclusions.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Previous enrolment in the present study.
• Patients unable to provide the required number of samples for MET analysis. Exclusions from exploratory genetic research.
• Previous allogeneic bone marrow transplant.
• Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.