Watch-and-Wait Approach With Dostarlimab in Localized dMMR/MSI-H Gastric Cancer: GERCOR Phase II Study

Inclusion Criteria:

1. Capable of giving signed and dated informed consent,
2. An ECOG PS of 0-1,
3. ≥18 and ≤75 years old, The patient over 75 years of age is eligible only if all the following conditions aremet:

• The patient's G8 questionnaire score is above 14 AND
• The patient is eligible for surgery and has no contraindications to repeated UGIendoscopy with biopsies,

4. Histologically proven non-metastatic gastric or OGJ adenocarcinoma cT2 to T4, Nx, M0after computed tomography thorax-abdomen-pelvis (TAP-CT) and echo-endoscopy (EUS)according to the 7th Edition of the International Union Against Cancer; NB:Echo-endoscopy will be performed only if the tumor is not obstructive at UGI endoscopy ± a new UGI endoscopy with 10 biopsies, photos (if not done at the first UGI endoscopydone for diagnosis) and if possible (not mandatory) tumor tattooing/inking. Ifobstructive, the tumor will be classified as cT3 or cT4 (in the situation when thetumor was obstructive and prevented EUS, it was classified T3N+, if it did not invadethe adjacent organs on CT scan, because obstructing tumours represented locallyadvanced disease in the vast majority of cases in previous studies). In this case anew UGI endoscopy must be done with 10 biopsies, photos (if not done at the first GGIendoscopy done for diagnosis) and if possible (not mandatory) tumor tattooing/inkingto follow the location of the tumor.
5. No peritoneal carcinomatosis (optional coelioscopy; recommended in case of doubt/suspicious on CT/ imaging),
6. No prior therapy (chemotherapy, radiotherapy, or immunotherapy) for localized gastricor OGJ adenocarcinoma,
7. Tumor status confirmed to be dMMR/MSI-H as follows:

• MMR protein expression status will be evaluated by immunohistochemistry (IHC) withfour antibodies (anti-hMLH1, anti-hMSH2, anti-hMSH6, anti-hPMS2) according to thelocal procedures. dMMR will be defined as loss of MLSH1 and PMS2, loss of MSH2 andMSH6, or loss of only one protein with presence of MSI-H. MSI analysis will be performed by polymerase chain reaction [PCR] using a pentaplexpanel (BAT-25, BAT-26, NR-21, NR-24, and NR-27; PROMEGA). MSI-H is defined asinstability in two or more of the five studied markers. For the purpose of this studysamples with 2 unstable markers will also undergo MMR analysis by IHC. Agreement ofSponsor (GERCOR) on a dMMR/MSI status is mandatory to include the patient (thepatient's file [an anonymized mail] has to be send to Sponsor). Approval/refusal emailfor inclusion of the patient will be send by the Sponsor within 24 hours of receipt ofthe Investigator email. In case of discrepancy between IHC and PCR, the final decisionabout the dMMR/MSI status will be taken by GERCOR or coordinating investigator,

8. Hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥9 g/dL,
9. Adequate renal function: serum creatinine level ≤150 μM and clearance ≥50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),
10. Adequate liver function: ≤1.5 x upper limit of normal (ULN) of direct bilirubin ≤ ULNfor participants with total bilirubin levels >1.5 x ULN (inclusion possible if knownGilbert syndrome), alkaline phosphatase <5 x ULN, alanine aminotransferase (ALT), andaspartate aminotransferase (AST) ≤2.5 x ULN,
11. International normalized ratio (INR), prothrombin time (PT), and activated partialthromboplastin time (aPTT) ≤1.5 x ULN, except for the patient on anticoagulant therapywho must have PT-INR-aPTT within therapeutic range is deemed appropriate by theInvestigator,
12. Radiological tumor assessment at screening performed within 28 days before inclusionaccording to RECIST version 1.1 by chest, abdomen, and pelvis CT, showing the absenceof metastatic or non-surgical disease,
13. A female participant is eligible to participate if she is not pregnant orbreastfeeding, and one of the following conditions applies:

• Is a woman of non-childbearing potential as defined: i/ ≥ 45 years of age and hasnot had menses for >1 year, ii/ Amenorrheic for <2 years without a hysterectomyand oophorectomy and have a follicle stimulating hormone (FSH) value in thepostmenopausal range upon pre-study (screening) evaluation, iii/post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation documentedhysterectomy or oophorectomy must be confirmed with medical records of the actualprocedure or confirmed by an ultrasound, magnetic resonance imaging (MRI), or CTscan. Tubal ligation must be confirmed with medical records of the actualprocedure, otherwise the patient must fulfill the criteria in Inclusion criteria

15. Information must be captured appropriately within the site's sourcedocuments,

• Negative pregnancy blood test within 72 hours before the first dose ofdostarlimab, AND
• If woman of childbearing potential (WOCBP), female patient must be willing to usea highly effective form of contraception from screening throughout the studytreatment and 4 months after the last dose of dostarlimab,

14. Male participants are eligible to participate if they agree to the following duringthe study treatment and for 4 months after the last dose of dostarlimab:

• Refrain from donating sperm,
• Must use contraception/barrier as follows:
• Agree to use a male condom when having sexual intercourse with a WOCBP whois not currently pregnant.
• Agree to use a male condom when engaging in any activity that allows forpassage of ejaculate to another person,

15. Providing primary tumor tissue samples (processed as formalin-fixed, paraffin-embedded [FFPE] blocks or freshly frozen) acquired during UGI endoscopy together with images (mandatory), NB: The patient's agreement will be specifically requested for endoscopicimages in the patient information note and informed consent for their use as clinicaldata that may be analyzed and presented in publications. These data will be used inthe same manner as other personal data. The confidentiality of these data will bemaintained,
16. Willingness and capablility to comply with scheduled visits, treatment schedule,laboratory tests, tumor biopsies, and other requirements of the study,
17. Registration in a National Health Care System (PUMa - Protection Universelle Maladieincluded).

Exclusion Criteria:

1. Prior concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targetedtherapy, immunotherapy),
2. Treatment with any investigational medicinal product within 28 days prior to studyentry,
3. Treatment anticoagulant or hemostasis disorder contraindicating - biopsies duringendoscopy,
4. Major surgical procedure within 28 days (4 weeks) prior to the first dose of studytreatment,
5. Other serious and uncontrolled non-malignant disease (including active infection) oris considered a poor medical risk due to a serious, uncontrolled medical disorder,nonmalignant systemic disease or active infection requiring systemic therapy. Specificexamples include, but are not limited to, active, non-infectious pneumonitis;uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction;uncontrolled major seizure disorder; unstable spinal cord compression; superior venacava syndrome; or any psychiatric or substance abuse disorders that would interferewith cooperation with the requirements of the study,
6. Other concomitant or previous malignancy other than the disease under study, except asnoted below: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamouscell carcinoma of the skin, iii/ cancer from which the patients was in completeremission for ≥3 years,
7. Metastases (M stage disease) whatever the location,
8. Pregnancy or breastfeeding,
9. Human immunodeficiency virus (HIV),
10. Active hepatitis B virus (HBV, defined as having a positive hepatitis B surfaceantigen [HBsAg] test) or hepatitis C virus (HCV) prior to inclusion, Note: Patientswith past HBV infection or resolved HBV infection (defined as having a negative HBsAgtest and a positive antibody to hepatitis B core antigen antibody test) are eligible. Note: Patients positive for HCV antibody are eligible only if PCR testing is negativefor HCV RNA.
11. Patient under a legal protection regime (guardianship, curatorship, judicialsafeguard) or administrative decision or incapable of giving his/her consent,
12. Impossibility of submitting to the medical follow-up of the study for geographical,social, or psychiatric illness. Non-eligible to immunotherapy:
13. Pyloric tumor, NB: tumors of the pylorus will be excluded because of the risk of highocclusion in case of pseudo progression and associated surgery,
14. Any history of autoimmune disease including, but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis, Note: History ofautoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone maybe eligible. Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
15. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest imaging,
16. Any live, attenuated vaccine within 14 days prior to the firs dose of study treatmentor such administration is anticipated during the study,
17. Prior therapy with any immune-checkpoint inhibitors, including antibodies or drugstargeting CD137, CTLA-4, PD-1, or PD-L1 or other checkpoint pathways,
18. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
19. Treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone, cyclophosphamide,azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to the first dose of adjuvant treatment or is required to receivesystemic immunosuppressive medications during the study. Inhaled or topical steroidsand adrenal replacement doses >10 mg daily prednisone equivalents are permitted in theabsence of active autoimmune disease. Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled into the study afterapproval of the Medical Contact. Note: Subjects are permitted the use of topical, ocular,intra-articular, intranasal, and inhalational corticosteroids (with minimal systemicabsorption). Adrenal replacement steroid doses including doses >10 mg daily prednisone ispermitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g.,contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-typehypersensitivity reaction caused by a contact allergen) is permitted.