Pembrolizumab Plus Ramucirumab in Metastatic Gastric Cancer

Inclusion Criteria:

• The patient is ≥18 years of age.
• The patient who has received an adequate information and provided informed consent forall the study-specific procedures in advance
• The patient has histologically or cytologically confirmed gastric carcinoma, includinggastric adenocarcinoma or GEJ adenocarcinoma. (Patients with adenocarcinoma of thedistal esophagus are eligible if the primary tumor involves the GEJ.) patient hasmetastatic disease or locally recurrent, unresectable disease.
• The patient's tumor tissue must have the pre-defined characteristics as follows ; EBV+or PDL1 CPS≥10
• The patient has measureable or evaluable disease as determined by standard computedtomography (CT) or magnetic resonance imaging (MRI) imaging. Examples of evaluable,nonmeasurable disease include gastric, peritoneal, or mesenteric thickening in areasof known disease, or peritoneal nodules that are too small to be considered measurableby Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
• The patient has experienced disease progression during first-line treatment orsecond-line therapy for metastatic disease
• Acceptable prior chemotherapy regimens for this protocol are combinationchemotherapy regimens that include platinum and/or fluoropyrimidine components (acceptable prior platinum agents are cisplatin, carboplatin, or oxaliplatin;acceptable prior fluoropyrimidine agents are 5-FU, capecitabine, or S-1).Regimens including a third agent, such as an anthracycline or a taxane, areacceptable provided a fluoropyrimidine and/or a platinum were used.
• Recurrence during or within 6 months of completion of adjuvant chemotherapy (capecitabine, 5-FU, or TS-1) will be considered as first-line chemotherapy.
• No prior exposure to anti-PD1 antibody or ramucirumab
• the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS)score of 0 or 1.
• Patients must have acceptable bone marrow, liver and renal function measured within 28days prior to administration of study treatment as defined below: Hemoglobin ≥9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥100 x 109/L Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) AST (SGOT)/ALT (SGPT) ≤ 3.0 x institutional upper limit of normal unless liver metastases are present inwhich case it must be ≤ 5x ULN Serum creatinine ≤1.5 x institutional ULN urinary protein is ≤1+ on dipstick or routine urinalysis (INR) ≤1.5 and (PTT) ≤5 seconds above the ULN (unlessreceiving anticoagulation therapy). Patients on anticoagulation therapy with unresectedprimary tumors or local tumor recurrence following resection are not eligible
• Female patients of childbearing potential must have a negative pregnancy test (urineor serum), must not be breastfeeding and using adequate contraceptive measures. Female patients must use a highly effective contraceptive measure from screening until 90days after the last dose of drug. All methods of contraception (except for totalabstinence) should be used in combination with the use of a condom by a male sexual partnerfor intercourse (see Restrictions below). (or vasectomy) Female patients must have evidence of non-childbearing potential by fulfilling one of thefollowing criteria at screening:

1. Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatment.
2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy, but not tubal ligation.
3. . For the duration of the study and for 1 week after the last study drugadministration, sexually active male patients must be willing to use barriercontraception i.e. condoms with all sexual partners. Where the sexual partner isa 'women of child-bearing potential' who is not using effective contraception,men must use a condom (with spermicide) during the study and for 6 months afterthe last dose of a study drug. (or vasectomy) -Biopsy during the screening window prior to dosing and at progression (ifclinically feasible)

Exclusion Criteria: -The patient has documented and/or symptomatic encephalitis, brain orleptomeningeal metastases. -The patient has experienced any Grade 3 to 4 GI bleeding within 3 months priorto enrollment. -The patient has experienced myocardial infarction, transient ischemic attack,cerebrovascular accident, or unstable angina, within 6 months prior toenrollment. -The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheterthrombosis or superficial venous thrombosis are not considered "significant")during the 3 months prior to first dose of protocol therapy. -The patient has an ongoing or active infection, symptomatic congestive heartfailure, unstable angina pectoris, symptomatic or poorly controlled cardiacarrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other seriousuncontrolled medical disorders in the opinion of the treating physician. -The patient has ongoing or active psychiatric illness or social situation thatwould limit compliance with treatment -The patient has uncontrolled or poorly controlled hypertension (>160 mmHgsystolic or >100 mmHg diastolic for >4 weeks) despite standard medicalmanagement. -The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28days prior to enrollment. -The patient has received chemotherapy, radiotherapy, immunotherapy, or targetedtherapy for gastric cancer within 2 weeks prior to enrollment. -The patient has received any investigational therapy within 30 days prior toenrollment. -The patient has undergone major surgery within 28 days prior to enrollment, orsubcutaneous venous access device placement within 7 days prior to enrollment. -The patient has received prior therapy with an agent that directly inhibits VEGF (including bevacizumab), or VEGF Receptor 2 activity, or any antiangiogenic agentand immunotherapy. -The patient is receiving chronic antiplatelet therapy, including aspirin,nonsteroidal anti- inflammatory drugs (NSAIDs; including ibuprofen, naproxen, andothers), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. -The patient has a known allergy to any of the treatment components. -Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior tostudy Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) fromadverse events due to agents administered more than 4 weeks earlier. -Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2antibodies). 19. Has known active Hepatitis B or Hepatitis C (e.g., HCV RNA [qualitative] is detected) and liver cirrhosis. Chronic HBV infection withanti-viral agent prophylaxis is allowed.

20. Has known liver cirrhosis at a level of Child-Pugh B (or worse) orcirrhosis (any degree) and a history of hepatic encephalopathy or clinicallymeaningful ascites resulting from cirrhosis. Clinically meaningful ascitesis defined as ascites from cirrhosis requiring diuretics or paracentesis.
21. The patient is pregnant or breastfeeding.