Overview

This is a prospective, pilot, two-arm, randomized, multicenter study exploring the efficacy and safety of osimertinib with or without savolitinib as first-line therapy in patients with de novo MET positive, EGFR-mutant advanced NSCLC.

Eligibility

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