DEWI: Watch-and-Wait With Dostarlimab in Localized dMMR/MSI-H Gastric/GEJ Adenocarcinoma Phase II Study

Watch-and-wait Strategy to Initiate Dostarlimab-based Immunotherapy in Localized Deficient Mismatch Repair (dMMR) and/or Microsatellite Instability High (MSI-H) oEso-gastric Junction and Gastric Adenocarcinoma: An Open-label GERCOR Phase II Study

This phase II study evaluates dostarlimab followed by a watch-and-wait strategy in patients with localized dMMR/MSI-H gastric or gastroesophageal junction (GEJ) adenocarcinoma. The study aims to determine whether surgery can be safely avoided in patients achieving a complete response, defined by negative endoscopy and tumor-free biopsies after treatment.

Patients with localized, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma are currently treated with radical surgery, the only curative option, typically combined with perioperative chemotherapy. However, surgery is associated with substantial morbidity and a significant impact on quality of life. Given the high efficacy of immune checkpoint inhibitors in localized dMMR/MSI-H tumors, surgery omission may be a potential strategy for selected patients.

This national, multicenter, open-label phase II study will evaluate dostarlimab in patients with localized dMMR/MSI-H gastric or GEJ adenocarcinoma. The primary objective is to determine whether a watch-and-wait approach can safely replace surgery in patients achieving a complete response after treatment, defined by negative endoscopy and tumor-free biopsies.

Study aims Main cohort: To evaluate dostarlimab followed by a watch-and-wait approach in patients with localized dMMR/MSI-H gastric or GEJ adenocarcinoma.

Additional unfit cohort (patients unfit for surgery): To evaluate the efficacy of dostarlimab in patients aged >70 years with localized dMMR/MSI-H gastric or GEJ adenocarcinoma who are deemed unfit for surgical resection.

Sample size Main initial cohort study (phase II): A total of 89 patients will be included (59 patients in the original protocol conducted in France and Italy, and an additional 30 patients to be enrolled exclusively in France).

Additional unfit cohort: A total of 39 patients will be included (20 patients in the original protocol conducted in France and Italy, and an additional 19 patients to be enrolled exclusively in France).

Inclusion and exclusion criteria are identical in both cohorts, except for inclusion criteria 3 and 4.

Inclusion criteria

The patient is eligible to be included in the study only if all the following criteria apply:

1. Is capable of giving signed and dated informed consent,

2. Has an ECOG PS of 0-1,

3. Age ≥18 years old:

   • A patient over 70 years of age is eligible to participate in the main initial cohort if the patient respects all the criteria and has a score G8 of ≥14.
   • A patient over 70 years with a score G8 <14 should have a consultation with an onco-geriatrician to determine the best treatment or therapeutic strategy based on age and co-morbidity. After this consultation, the patient is eligible for main initial cohort if "fits for surgery" with no contraindications to repeated UGI endoscopy with biopsies (no change to the initial protocol) and can follow the study plan and procedures outlined in the study.
   • If a patient is over 70-year-old, has a G8 score <14, and is unfit for surgery (as determined by onco-geriatric advice and multidisciplinary team [MDT] conclusion), the patient cannot be included in the phase II study (main initial cohort). This patient can be included in the unfit supplemental cohort, with the available Geriatric Core Dataset (G-CODE) test result being mandatory for inclusion (No switching between cohorts is allowed).

4. Has histologically proven non-metastatic gastric or OGJ adenocarcinoma cT2 to T4, Nx, M0 after computed tomography thorax-abdomen-pelvis (TAP-CT) and echo-endoscopy (EUS), performed within 6 weeks before inclusion, according to the 7th Edition of the International Union Against Cancer; NB1: 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 endoscopy done for diagnosis). If obstructive, the tumor will be classified as cT3 or cT4 (in the situation when the tumor was obstructive and prevented EUS, it was classified T3N+, if it did not invade the adjacent organs on CT scan, because obstructing tumors represented locally advanced disease in the vast majority of cases in previous studies). In this case a new UGI endoscopy must be done with 10 biopsies, photos (if not done at the first GGI endoscopy done for diagnosis).

   NB2: Echo endoscopy is not mandatory/performed for patient included in additional unfit cohort. TNM stage will be determine by CT scanner.

5. Has no peritoneal carcinomatosis (optional coelioscopy; recommended in case of doubt/ suspicious on CT/ imaging),

6. Has not received prior therapy (chemotherapy, radiotherapy, or immunotherapy) for localized gastric or OGJ adenocarcinoma,

7. Tumor status confirmed to be dMMR/MSI-H as follows:

   - MMR protein expression status will be evaluated by immunohistochemistry (IHC) with four antibodies (anti-hMLH1, anti-hMSH2, anti-hMSH6, anti-hPMS2) according to the local procedures. dMMR will be defined as loss of MLSH1 and PMS2, loss of MSH2 and MSH6, or loss of only one protein with presence of MSI-H.

   MSI analysis will be performed by polymerase chain reaction [PCR] using a pentaplex panel (BAT-25, BAT-26, NR-21, NR-24, and NR-27; PROMEGA). MSI-H is defined as instability in two or more of the five studied markers. For this study, samples with 2 unstable markers will also undergo MMR analysis by IHC. Agreement of Sponsor (GERCOR) on a dMMR/MSI status is mandatory to include the patient (the patient's file [an anonymized mail] must be sent to Sponsor). Approval/refusal email for inclusion of the patient will be sent by the Sponsor within 24 hours of receipt of the Investigator email. In case of discrepancy between IHC and PCR, the final decision about the dMMR/MSI status will be taken by GERCOR or coordinating investigator,

8. Has hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥9 g/dL,

9. Has adequate renal function: serum creatinine level ≤150 µM and clearance ≥30 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),

10. Has adequate liver function: ≤1.5 x upper limit of normal (ULN) of direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 x ULN (inclusion possible if known Gilbert syndrome), alkaline phosphatase <5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 x ULN,

11. Has international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 x ULN, except for the patient on anticoagulant therapy who must have PT-INR-aPTT within therapeutic range is deemed appropriate by the Investigator,

12. Has radiological tumor assessment at screening performed within 6 weeks before inclusion according to RECIST version 1.1 by chest, abdomen, and pelvis CT, showing the absence of metastatic or non-surgical disease,

13. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

    • Is a woman of non-childbearing potential as defined: i/ ≥ 45 years of age and has not had menses for >1 year, ii/ Amenorrheic for <2 years without a hysterectomy and oophorectomy and have a follicle stimulating hormone (FSH) value in the postmenopausal range upon pre-study (screening) evaluation, iii/ post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, magnetic resonance imaging (MRI), or CT scan. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must fulfill the criteria in Inclusion criteria 15. Information must be captured appropriately within the site's source documents,
    • Has negative pregnancy blood test within 72 hours before the first dose of dostarlimab, AND
    • If woman of childbearing potential (WOCBP), female patient must be willing to use a highly effective form of contraception from screening throughout the study treatment and 4 months after the last dose of dostarlimab,

14. Male participants are eligible to participate if they agree to the following during the 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 who is not currently pregnant.
      • Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person,

15. Provides 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 endoscopic images in the patient information note and informed consent for their use as clinical data that may be analyzed and presented in publications. These data will be used in the same manner as other personal data. The confidentiality of these data will be maintained,

16. Is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study,

17. Is registered in the National Health Care System (PUMa - Protection Universelle Maladie included).

Exclusion criteria

The patient is ineligible for the study if any of the following criteria apply:

1. Has received prior concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targeted therapy, immunotherapy),

2. Has received treatment with any investigational medicinal product within 28 days prior to study entry,

3. Has a treatment anticoagulant or hemostasis disorder contraindicating - biopsies during endoscopy,

4. Has had major surgical procedure within 28 days (4 weeks) prior to the first dose of study treatment,

5. Has other serious and uncontrolled non-malignant disease (including active infection) or is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection requiring systemic therapy. Specific examples 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 vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,

6. Has other concomitant or previous malignancy other than the disease under study, except as noted below:

   i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer from which the patients was in complete remission for ≥3 years,

7. Has metastases (M stage disease) whatever the location,

8. Is pregnant or breastfeeding,

9. Has human immunodeficiency virus (HIV),

10. Has a documented hepatitis B surface antigen (HBsAg) positive result wither at the pre-inclusion visit or within 3 months prior to the first dose of the study intervention, along with and known active hepatitis, including acute or chronic hepatitis B virus (HBV).

    Exception: For patients who are HBsAg positive but do not have hepatitis (neither acute nor chronic HBV), antiviral treatment is recommended prior to treatment with dostarlimab:

    • if the HBV DNA level is ≥ 500 IU/mL or 2,500 copies/mL: antiviral treatment is recommended before starting dostarlimab and should be initiated within 3 weeks of starting immunotherapy or, at the latest, concomitantly. This treatment should continue for up to 12 months after the end of treatment with dostarlimab or any other immunosuppressive therapy.
    • if the HBV DNA level is < 500 IU/mL or 2,500 copies/mL: antiviral treatment is recommended before starting dostarlimab and should be initiated concurrently at the latest. This treatment should be continued for up to 12 months after the end of treatment with dostarlimab or any other immunosuppressive therapy.

11. Has hepatitis C virus (HCV) prior to inclusion, Note: Patients positive for HCV antibody are eligible only if PCR testing is negative for HCV RNA.

12. Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent,

13. Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness.

    Non-eligible to immunotherapy:

14. Has pyloric tumor, Note: tumors of the pylorus will be excluded because of the risk of high occlusion in case of pseudo progression and associated surgery,

15. Has 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 antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.

    Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.

16. Has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest imaging,

17. Has received any live, attenuated vaccine within 14 days prior to the firs dose of study treatment or such administration is anticipated during the study,

18. Has received prior therapy with any immune-checkpoint inhibitors, including antibodies or drugs targeting CD137, CTLA-4, PD-1, or PD-L1 or other checkpoint pathways,

19. Has had prior allogeneic bone marrow transplantation or prior solid organ transplantation,

20. Has received treatment with systemic corticosteroids or other systemic immunosuppressive medications (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 receive systemic immunosuppressive medications during the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence 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 after approval of Medical Contact. Note: Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses including doses >10 mg daily prednisone is permitted. 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-type hypersensitivity reaction caused by a contact allergen) is permitted.