Combination of Immune Checkpoint in Locally Advanced or Metastatic MSI/dMMR Esogastric Adenocarcinomas

Inclusion Criteria:

• Male or female patient ≥18 years of age at time of informed consent form signature.

• Patient with MSI-H/dMMR, HER2 negativeadvanced or metastatic gastric,gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours expressPD-L1 with a combined positive score (CPS) ≥ 5.

• Patient to be treated with a first line therapy for locally advanced/metastaticdisease.

• No prior treatment with chemotherapy for locally advanced/metastatic disease. o Note - adjuvant or neoadjuvant chemotherapy is allowed providing that 6 monthshave relapsed between completion of adjuvant chemotherapy and recurrence.

• Measurable disease (outside any previous irradiated field within the past 6 months)defined as at least one unidimensional lesion that can be accurately measured as ≥ 10 mm with CT scan according to RECIST V1.1 (Appendix 01).

• Note: Lesions intended to be biopsied should not be defined as target lesions.

• Note: previously irradiated lesions can be selected as target lesion only ifrecurrence/PD is documented after RT.

• Patient with PS ECOG 0 or 1 (Appendix 02).

• Adequate hematologic and end-organ function, defined by the following laboratorytest results:

Absolute neutrophil count ≥ 1.5 109/L (without growth factor support within 14 d) Platelets ≥ 100 109/L (without transfusion for platelets within 7 d) Hemoglobin ≥ 9 g/dL (without transfusion within 7 d) Creatinine clearance according to CKD-EPI ≥ 30 mL/min/1.73 m2 Serum total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 x ULN is acceptable) ASAT and ALAT ≤ 3 x ULN (or up to 5 x ULN in case of liver metastasis or hepatic infiltration)

• Availability of a representative formalin-fixed paraffin-embedded (FFPE) sample ofthe primary or metastatic tumor tissue (resection or biopsy) with an associatedpathology report must be available. This tumor sample must meet the followingquality/quantity control criteria: ≥30 % of tumor cells and a tumor surface area ≥ 5mm2 or biopsiable disease (see next inclusion criteria).

• Tumor lesion visible by medical imaging and accessible to repeatable percutaneous orendoscopic sampling that permits core needle biopsy without unacceptable risk of asignificant procedural complications, and suitable for retrieval of a minimum of 4cores with a needle minimum diameter :16-gauge.

• Note 1: Fine needle aspirates, bone biopsies do not satisfy the requirement fortumor tissue.

• Note 2: Tumor lesions used for biopsy should not be lesions used as RECIST 1.1target lesions unless there are no other lesions suitable for biopsy. If aRECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm in longestdiameter.

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test atthe Screening Visit (within 72 hours of first dose of study drugs) and must agree touse highly effective contraceptive measures starting with the Screening Visitthrough

• 9 months after the end of the treatment with oxaliplatin

• 6 months after the end of the treatment with fluorouracil

• 5 months after the end of the treatment with nivolumab or botensilimab orBalstilimab

• 6 months for capecitabine

• Highly effective contraception is defined in Appendix 03.

Note Non-childbearing potential is defined as:

1. ≥ 50 years of age and has not had menses for greater than 1 year.

2. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and afollicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.

3. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.

• Male patients with a female partner(s) of childbearing potential must agree touse highly effective contraceptive measures throughout the study starting withthe screening visit through 6 months after the end of the treatment withoxaliplatine or 3 months after the last dose for other study treatments isreceived. Males with pregnant partners must agree to use a condom; noadditional method of contraception is required for the pregnant partner.

• Patient should understand, sign, and date the written voluntary informedconsent form prior to any protocol-specific procedures performed and should beable and willing to comply with study visits and procedures as per protocol.

• Patients must be covered by a medical insurance.

Exclusion Criteria:

• Oesogastric cancer eligible to treatment with curative intent

• Patients previously treated by anti-PD-1, anti-PD-L1, or anti-CTLA-4 or any otherimmunotherapy

• Patients with surgery or radiotherapy within less than 4 weeks before C1D1

• Patients with persistent AE Grade >1 related to previous anti-cancer treatment,except alopecia (all grades), laboratory value according to criteria I7.

• Patients with: hypokalemia, hypomagnesemia, hypocalcemia less than normal

• Patients with known prolongation QT/QTc interval i.e. QT/QTc interval longer than 450 msec for men and longer than 470 msec for women according to the inclusion ECG.

• Symptomatic, untreated, or actively progressing central nervous system (CNS)metastases.

Note: Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:

• Measurable disease, per RECIST v1.1, must be present outside the CNS.

• The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

• Metastases are limited to the cerebellum or the supratentorial region (i.e., nometastases to the midbrain, pons, medulla, or spinal cord).

• There is no evidence of interim progression between completion of CNS-directedtherapy and initiation of study treatment.

• The patient has not undergone stereotactic radiotherapy within 7 days prior toinitiation of study treatment, whole-brain radiotherapy within 14 days prior toinitiation of study treatment, neurosurgical resection within 21 days prior toinitiation of study treatment.

• The patient has no ongoing requirement for corticosteroids as therapy for CNSdisease. Anticonvulsant therapy at a stable dose is permitted. A minimal wash-outperiod of 10days for corticosteroids is required.

• Patients with other malignancy unless this malignancy is not expected tointerfere with the evaluation of study endpoints (basal or squamous cellcarcinoma of the skin, in-situ carcinoma of the cervix, localized prostatecancer), or with no evidence of disease for ≥ 2 years.

• Known allergy or hypersensitivity to any of the study drugs or any of the studydrug excipients.

• of ILD or non-infectious pneumonitis requiring glucocorticoids.

• History of allogeneic organ transplant.

• Psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the study.

• Patient with peripheral sensory neuropathy with functional impairment.

• Patients with clinically significant active heart disease or myocardialinfarction within 6 months, history of uncontrolled or symptomatic cardiacdisease.

• Patient with recent (within 7d before C1D1) or concomitant treatment withbrivudine.

• Patient with complete absence of dihydropyrimidine dehydrogenase (DPD) activity (blood uracil level ≥ 150 ng/mL) or partial deficit in DPD (i.e. blood uracillevel between ≥ 16 ng/ml and < 150 ng/mL)

• Patients with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalent) within 14 days or anotherimmunosuppressive medication within 30 days of the first dose of studytreatment. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent) are permitted in the absence of activeautoimmune disease.

• Patient with Live vaccines injection within 4 weeks before C1D1. Examples oflive vaccines include, but are not limited to, the following: measles, mumps,rubella, chicken pox, yellow fever and BCG. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; howeverintranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines,and are not allowed.

• Active autoimmune disease or history of autoimmune disease that requiredsystemic treatment within 2 years of the start of study treatment (i.e., withuse of disease-modifying agents or immunosuppressive drugs).

• History or current evidence of any condition, co-morbidity, therapy, any activeinfections, or laboratory abnormality that might confound the results of thestudy, interfere with the patient's participation for the full duration of thestudy, or is not in the best interest of the patient to participate, in theopinion of the treating Investigator.

• Patients with documented:

• Active hepatitis B (chronic or acute; defined as having a positive hepatitis Bsurface antigen [HBsAg] test at screening) unless their HBV is stably controlled onnucleoside analogs (eg entecavir or tenofovir) which will be continued for theduration of the study. Note: Patients with past hepatitis B virus (HBV) infection orresolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed inthese patients prior to C1D1.

• Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody areeligible only if PCR is negative for HCV RNA, or

• HIV infection

• Prior organ or bone marrow transplant.

• Pregnant or lactating women.