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.
None
Is capable of giving signed and dated informed consent,
Has an ECOG PS of 0-1,
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.
Single group
Dostarlimab
DrugPost-Inclusion: Dostarlimab 500mg IV q3wx4 cycles (Cs). Week 12 (W12) * cCR (both cohorts): Dostarlimab 1,000mg q6w×2 cycles. * Downstaging (Stage 2-3), no PD/mets: Dostarlimab 500mg q3w×4Cs. * Main cohort: SD/PD, Stage 1, positive(+), no cCR→Surgery. Post-surgery: Becker-TRG 1a/1b/2→Dostarlimab 1,000mg q6w×6Cs; Becker-TRG 3→Stop Trt. * Additional unfit cohort: SD/PD, Stage 1, biopsy(+) ± mets→Stop dostarlimab, withdraw from Trt, investigator-directed care, remain in FU. W24 * cCR at W12\&W24: Dostarlimab 1,000mg q6w×4Cs. * cCR at W12 but not W24: * Main cohort: Stop dostarlimab; surgery/adjuvant Trt per investigator. * Additional unfit cohort: Stop dostarlimab; withdraw from Trt; FU only. * Downstaging at W12 + cCR at W24: Dostarlimab 1,000mg q6w×4Cs. * Downstaging at W12 but no cCR at W24: * Main cohort: Surgery; if Becker-TRG 1a/1b/2, dostarlimab 1,000mg q6w×4Cs. * Additional unfit cohort: Stop dostarlimab, withdraw from Trt, investigator-directed care, remain in FU.
Clinical complete response (cCR)
Main initial cohort: To evaluate clinical complete response (cCR) at 1 year defined as the rate of patients who at 1 year from the start of therapy with dostarlimab are alive, were not operated for tumor resection, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging stage 3 or 4 (endoscopic grade). Additional unfit cohort: To evaluate cCR at 1 year defined as the rate of patients who at 1 year from the start of therapy with dostarlimab are alive, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging stage 3 or 4 (endoscopic grade).
Pathological complete response (pCR)
Pathological complete response is defined as 100% fibrosis or fibro-inflammation or necrosis or granulomatous reaction within an entire gross lesion without microscopic evidence of carcinoma, and no positive lymph nodes, after examination of the complete macroscopic surgical specimen equivalent to a Becker TRG Grade 1a (complete regression).
Loco/loco-regional and distant recurrence
Loco/loco-regional recurrence is defined as cancer recurrence within the regional resection area or local anastomotic site. Distant recurrence is defined as peritoneal recurrence, liver metastasis or metastasis at other extra-abdominal sites as well as nodal metastasis beyond the regional nodes
Event-free survival (EFS)
Event-free survival is defined as time from first dose of treatment to surgery for tumoral resection, first progression of disease local or distant recurrence, or death due to any cause. Alive patients without event will be censored at the last follow-up.
Time to treatment failure (TTF)
Time to treatment failure is defined as the interval between initiating therapy (first dose of dostarlimab) and the earliest of clinical progression, depending on whether the patient had surgery for tumoral resection or not, or death. Measured in both cohorts.
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