Ph2 Study of Savolitinib and Durvalumab (MEDI4736) Combination in Advanced MET Amplified Gastric Cancer(VIKTORY-2)

Inclusion Criteria:

1. Provision of fully informed consent prior to any study specific procedures.

2. Patients must be ≥ 19 years of age

3. Body weight >30 kg

4. MET amplification by local NGS (The NGS result of the implementation agency isdefined as copy number 4 or higher, which is the standard for amplification)

5. Patients with gastric cancer (GC) who are in progressive stages and have progressedduring or after 1st or 2nd chemotherapy treatment, regardless of whether they are IOcontactless (naïve) or IO

6. There shall be at least one measurable lesion according to the modified RECIST 1.1criteria.

7. Patients are willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations.

8. ECOG performance status 0-1 with no deterioration between screening and the firstdose of study treatment

9. Patients must have a life expectancy ≥ 3 months from proposed first dose date.

10. Patients must have had a washout period of 2 weeks for any prior therapy prior tothe start ot study drug. The following intervals between the end of the priortreatment and first dose of study drug must be observed: ≥ 4 weeks for radiotherapy (patients who receive palliative radiation for nontarget lesions need not have a 4week washout period and can be enrolled if at least >=7 days); patients may receivea stable dose of bisphosphonates or denusomab as long as these were started at least 4 weeks prior to treatment; ≥ 4 weeks for major surgery; ≥ 7 days for minor surgicalprocedures; ≥ 14 days (or 5 half lives whoever is longest) for any investigationalproduct.

11. Patients must have acceptable bone marrow, liver and renal function measured within 28 days prior to administration of study treatment as defined below:

• Haemoglobin ≥9.0 g/dL (within 2 weeks of registration transfusion permitted)

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

• Platelet count ≥100 x 109/L (within 2 weeks of registration transfusionpermitted)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x theupper limit of normal (ULN) with TBL≤ 1x ULN OR TBL >1ULN-≤1.5x ULN with ALTand AST ≤ 1x ULN

• Serum creatinine ≤1.5 x institutional ULN

• Glomerular filtration rate < 45 mL/min as assessed by standard methodology atthe investigating centre

12. Female patients must be using highly effective contraception during clinical trialsand for three months after permanent discontinuation of drug administration, andthere should be evidence that they are not breastfeeding, that they are negative inpregnancy tests, or that they meet one of the following criteria in screening:

13. Male test subjects with a likely female spouse should be asked to use blockedcontraception during the clinical trial and for six months after permanent cessationof administration of the test drug. The test subjects should avoid sperm donationfrom the start of the test treatment to the 6th month after permanentdiscontinuation.

14. optionally biopsy during the screening window prior to dosing and at progression (fresh frozen will be optionally if clinically feasible)

Exclusion Criteria:

1. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

2. Any previous treatment with MET inhibitors (prior exposure to anti-PD1/PDL1allowed)<<if the study allows prior anti PD-1, PD-L1 and CTLA-4>> Patients who havereceived prior anti-PD-1, anti PD-L1 or anti CTLA-4:

3. Any gastrointestinal condition that would preclude adequate absorption ofsavolitinib including but not limited to inability to swallow oral medication,refractory nausea and vomiting, chronic gastrointestinal diseases or previoussignificant bowel resection, intestinal obstruction or CTCAE grade 3 or grade 4upper GI bleeding within 4 weeks before the enrollment.

4. Active or prior documented autoimmune or inflammatory disorders (including IBD[e.g.Chohn's disease, ulcerative colitis or diverticulitis], SLE, sarcoidosis syndrome,tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, history of primary immunodeficiency.

5. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice).

6. Active hepatitis B (positive HBV surface antigen (HBsAg) result) or hepatitis C (HCV). Patients with a past or resolved HBV infection are eligible if:

• Negative for HBsAg and positive for hepatitis B core antibody [anti-HBcAb]. or:

• Positive for HBsAg, but for > 6 months have had normal transaminases and HBVDNA levels <2000 IU/ml (ie, are in an inactive carrier state).

• Subjects with HBV infection, characterised by positive HBsAg and/or anti-HBcAbwith undetectable HBV DNA (< 10 IU/ml or under the limit of detection per locallab standard) do not require antiviral therapy prior to randomisation.

• Patients with HBV infection, characterised by positive HBsAg and/oranti-HBcAb with detectable HBV DNA (≥ 10 IU/ml or above the limit ofdetection per local laboratory standard), must be treated with antiviraltherapy for 2-4 weeks prior to the start of study treatment, with thechoice of antivirals as per institutional practice. Following antiviraltherapy initiation, subjects must show adequate viral suppression (ie, HBVDNA ≤ 2000 IU/mL) prior to randomisation. Participants will remain onantiviral therapy for the study duration and for at least 6 months afterthe last dose of IP Patients with positive HCV antibody are eligible onlyif the polymerase chain reaction is negative for HCV RNA.

7. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease,or cord compression. Note: Subjects previously treated for CNS metastases that areasymptomatic, radiographically and neurologically stable for at least 4 weeks and donot require corticosteroids (of any dose) for symptomatic management for at least 4weeks prior to the first dose of treatment are not excluded.

8. Patients with second primary cancer, except: adequately treated non-melanoma skincancer, curatively treated in-situ cancer of the cervix, or other solid tumourscuratively treated with no evidence of disease for ≤3 years.

9. Current or prior use of immunosuppressive medication within 4 weeks prior to thefirst dose of durvalumab, with the exceptions of intranasal, topical, and inhaledcorticosteroids; systemic corticosteroids at physiologic doses not to exceed a dose > 10 mg prednisone / day or equivalent)

10. Patient was in receipt of any live attenuated vaccination within 30 days prior tostudy entry or within 30 days of receving study therapy.

11. Patients currently receiving (or unable to stop use at least 2 weeks) prior toreceiving the first dose of savolitinib, medications known to be potent inhibitorsof CYP1A2 or strong inducers of CYP3A4 with a narrow therapeutic range

12. Patient with any of the following cardiac criteria:

-Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3electrograms (ECGs) using Friderecia's correction . etc

13. Within 6months of treatment Any evidence of severe or uncontrolled systemic disease,including active infection (requiring antibiotics, antifungals or antivirals),diabetes type I and II, uncontrolled seizures, bleeding diatheses, severe COPD,severe Parkinson's disease.

14. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, Major surgical procedure (as defined by theInvestigator) within 28 days prior to the first dose of IP. Note: Local surgery ofisolated lesions for palliative intent is acceptable. For a unresolved toxicity,

15. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent

16. Male or female patients who are familiar with pregnancy and contraception and haveno intention of contraception.

17. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

18. History of allogenic organ transplantation.

19. Past history of PD-L1 or epileptic lung disease (ILD) or evidence of clinicallyactive epileptic lung disease

20. History of liver cirrhosis of any origin and clinical stage; or history of otherserious liver disease or chronic disease with relevant liver involvement, with orwithout normal LFTs*, such as Hemochromatosis,Alpha-1 Antitrypsin deficiency ,Autoimmune hepatitis (AIH), Primary sclerosing cholangitis (PSC), Primary biliarycirrhosis (PBC), Biopsy-confirmed Non-Alcoholic Steatohepatitis (NASH) with advancedfibrosis, Biopsy- confirmed Alcoholic Steatohepatitis with advanced fibrosis,Wilson's disease, Hepatocellular carcinoma