This multicentre, open-label, randomized phase II trial is ongoing in 30 centres in France. Main eligibility criteria include: histologically proven adenocarcinoma of the stomach, esophagus or gastroesophageal junction; locally advanced or metastatic disease; measurable disease (RECIST 1.1); no known HER2 overexpression; no prior palliative chemotherapy.

Patients are randomised to modified FOLFOX6 (oxaliplatin 85 mg/m2, FA 400 mg/m², FU 400 mg/m² bolus then 2400 mg/m² over 46 hr) alone or combined to either panitumumab (6 mg/kg) or AMG 102 (10 mg/kg), every two weeks until unacceptable toxicity or disease progression. Judgment criteria include 4-month progression-free survival (PFS) rate (primary endpoint), OS, objective response rate, and safety. Ancillary studies aim to identify candidate predictive and prognostic biomarkers among functional of molecular alterations of the EGFR/RAS/RAF and HGF/c-Met pathways, and to monitor circulating tumour cells and circulating immune cells (myeloid derived suppressor cells, NK cells) in sequential blood samples taken at baseline and through the study treatment. A total of 165 pts will be enrolled (Fleming's one-step design)

Inclusion Criteria:

• Histologically proven adenocarcinoma of the stomach, the esophagus or the cardia (with or without signet ring cells; intestinal, diffuse or mixed form).
• Locally advanced (non resectable) or metastatic disease.
• Measurable disease (at least one measurable tumor) according to the RECIST V1.1 criteria (the tumor should not be located in a previous field of radiation).
• Absence of previous palliative chemotherapy. Previous neo-adjuvant or adjuvant chemotherapies (alone or combinated with radiotherapy) are authorized, including biotherapy (except anti-EGFR or anti-c-Met / HGF), if it has been stopped at least 12 months before inclusion.
• Previous radiotherapy authorized if stopped at least 14 days before randomization and if at least one measurable target outside the radiation area is present.
• No major surgery ≤ 28 days, or minor surgery ≤ 14 days, prior to randomization
• Sites of disease evaluated within 28 days prior to randomization with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest X-ray).
• Age ≥ 18 years.
• Patient general status : ECOG 0-1.
• Life expectancy ≥ 3 months.
• Hemoglobin > or = 9 g/L - (transfusion authorized if necessary), PNN ≥ 1,5.109/l, platelets ≥ 100.109/l.
• Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of hepatic metastases), alkaline phosphatase ≤ 2.5 ULN (≤ 5 ULN in case of hepatic metastases), total bilirubinemia ≤ 1.5 ULN)
• Creatinine clearance (calculated or measured) ≥ 50 ml / min, serum creatinine > 1.5 ULN
• Prothrombin time (PT) ≥ 60 %, INR < 1,5 (except if anticoagulant therapy)
• Magnesemia and calcemia ≥ Lower Limit of Normal (LLN)
• Negative Pregnancy test for women of child-bearing age.
• Information given to the patient and signed informed consent.
• Public Health insurance coverage.
• Sample of tumour (primitive or metastatic) available.

Exclusion Criteria:

• Known brain or leptomeningeal metastases.
• Positive HER2 Status (IHC 3+ or IHC2+/FISH or CISH+) .
• contraindication, allergy or hypersensitivity to ANY OF the study treatments.
• Prior Treatment with EGFR inhibitor or HGF / c-Met inhibitor.
• Patient already included in another clinical trial testing an experimental drug.
• Peripheral edema > grade 2.
• Proteinuria > 1 g/24h
• Clinically significant cardiovascular disease (such as unstable angina pectoris, severe congestive heart failure, uncontrolled severe cardiac arrhythmia) within 12 months prior to randomization.
• Thrombosis or ischemic vascular event during the last 12 months (deep venous thrombosis, pulmonary embolism, STROKE or established cerebral infarction, myocardial infarction).
• Medical history or signs of interstitial pneumopathy or pulmonary fibrosis.
• Peripheral neuropathy > grade 1.
• Clinically significant hemorrhage of the upper gastrointestinal tract (requiring blood transfusion or hemostatic interventional procedure.
• Actively evolutive inflammatory bowel disease or any other intestinal disease causing chronic diarrhea (≥ grade 2).
• Any uncontrolled concomitant disease (e.g., uncontrolled diabetes) or medical history (e.g., organ transplantation) which, according to the opinion of the investigator, may interfere with the interpretation of the study results.
• Any comorbidity or situation which, according to the opinion of the investigator, could increase the risk of toxicity (e.g., Dihydropyrimidine dehydrogenase deficiency).
• Chronic or active HIV, HBV or HCV infections.
• Severe and\or not healed wound.
• Any active infection requiring systemic treatment, or any uncontrolled infection within 14 days before randomization.
• Other concomitant malignancy or history of cancer (except carcinoma in situ of the cervix, or non melanoma skin cancer, with curative intent treatment), except when considered in complete remission for at least 5 years before randomization.
• Pregnant women or women who might become pregnant during the study (or who plan to become pregnant within 6 months after the last administration of a study drug) or lactating women.
• Men or women who have the age of procreation and who do not abide with the use of a highly efficient contraceptive means (according to the current institutional standards) or, alternatively, the use of abstinence during the study treatment and until 6 months after last administration of the study drugs.
• Patient unwilling to comply with the medical follow-up required by the trial because of geographic social or psychological reasons.