Immune Checkpoint Inhibitors for Organ Preservation in Non-metastatic dMMR/MSI-H Gastric or Colon Cancers

Inclusion Criteria:

• Subjects are able to comprehend the informed consent form, and voluntarily sign theinformed consent form.

• Subjects are ≥18 years old on the day of signing the informed consent form, with nogender restrictions.

• Histologically confirmed gastric cancer or colon cancer, without distant metastasisbased on CR or MR.

• ECOG performance status of 0-2.

• dMMR confirmed by immunohistochemistry or MSI-H confirmed by PCR and NGS. If MSIstatus and MMR status were not consistent, whether to enroll this patient should bedetermine by investigators. Patients with MMR heterogeneity in tumors could not beincluded.

• Patients who are about to receive or are receiving 24 weeks of PD1/PDL1 antibodymonothearpy and have not had the first efficacy assessment.

• Archived tumor tissue samples or freshly obtained tumor tissue samples areavailable.

• Female subjects of childbearing potential or male subjects with partners ofchildbearing potential agree to use highly effective contraception from 7 daysbefore the first dose until 120 days after the last dose. Female subjects ofchildbearing potential must have a negative serum pregnancy test within 7 daysbefore the first dose.

• Subjects have the ability and willingness to comply with the study protocol'svisits, treatment plan, laboratory tests, and other study-related procedures.

• For patients who are about to receive combination of Sintilimab, IBI310 andLenvatinib. subjects should have good organ function within the first 7 days ofinitial dosing: HGB ≥ 80g/L, NEU ≥ 1.010^9/L, PLT ≥ 7510^9/L, Cr≤1.5×ULN orCrCl≥50mL/min（Cockcroft-Gault method), TBiL ≤ 1.5×ULN, ALT and AST ≤3 ×ULN; urineprotein <2+; if urine protein ≥ 2+, 24 hour urinary protein quantity <2g; INR, APTT,PT ≤ 1.5 ×ULN

Exclusion Criteria:

• Distant metastasis;

• Previous treatment including CTLA4 blockade;

• Subjects with interstitial lung disease or a history of non-infectious pneumoniarequiring oral or intravenous corticosteroid treatment.

• Subjects with active autoimmune diseases requiring systemic treatment before thestart of the study or those considered at risk of recurrence or planned treatmentfor autoimmune diseases as judged by the investigator. Except for these conditions:a) skin diseases that do not require systemic treatment (e.g., vitiligo, alopecia,psoriasis, or eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiringstable doses of hormone replacement therapy; c) type 1 diabetes requiring stabledoses of insulin replacement therapy; d) childhood asthma fully resolved with noneed for intervention in adulthood; e) the investigator judges that the disease willnot relapse without external triggering factors.

• Subjects with a history of other malignant tumors within 5 years, excluding curedskin squamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma,localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, andprostate-specific antigen (PSA) ≤10 ng/mL (if measured) in patients who haveundergone curative treatment and have no biochemical recurrence of prostate-specificantigen (PSA)), in situ cervical/breast carcinoma, or Lynch syndrome.

• Subjects with uncontrolled comorbidities, including but not limited to: a) activeHBV or HCV infection; b) subjects who are HBsAg positive and/or HCV antibodypositive during screening must undergo HBV DNA and/or HCV RNA testing. Only subjectswith HBV DNA ≤500 IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can beenrolled; HBV DNA monitoring will be at the discretion of the investigator based onthe subject's condition during the trial; c) known HIV infection or AIDS history; d)active tuberculosis; e) uncontrolled hypertension (resting blood pressure ≥160/100mmHg), symptomatic congestive heart failure (NYHA II-IV), unstable angina ormyocardial infarction within 6 months, or the presence of QTc prolongation or therisk of arrhythmia (baseline QTc >470 msec ,refractory hypokalemia, long QT syndrome, atrial fibrillation with resting heartrate >100 bpm, or severe valvular heart disease); f) active bleeding that cannot becontrolled after medical treatment.

• History of allogeneic bone marrow or organ transplantation.

• Previous history of allergic reactions, hypersensitivity reactions, or intoleranceto antibody drugs (e.g., severe allergic reactions, immune-mediated hepatotoxicity,immune-mediated thrombocytopenia, or anemia).

• Pregnant and/or lactating females.

• For patients who are about to receive combination of Sintilimab, IBI310 andLenvatinib: a) Subjects with a history of gastrointestinal perforation or fistulawithin 6 months before the first dose. If the perforation or fistula has beentreated with resection or repair, and the disease is judged to be recovered orimproved by the investigator, then enrollment is allowed. b) Subjects who haveundergone major surgery within 28 days before the first dose (e.g., major abdominalor thoracic surgery; excluding drainage, diagnostic puncture, or peripheral vascularaccess replacement). c) Subjects who require systemic corticosteroids (≥10 mg/dayprednisone or equivalent) or immunosuppressive therapy for a continuous 7-day periodwithin 14 days before the first dose. Inhaled or locally applied steroids andphysiological replacement doses of steroids due to adrenal insufficiency areallowed. Short-term (≤7 days) corticosteroids for prophylaxis (e.g., contrast dyeallergy) or treatment of non-autoimmune diseases (e.g., delayed hypersensitivityreaction caused by exposure to allergens) are allowed. d) Toxicity from previousantitumor treatments has not recovered to Grade ≤2 (NCI-CTCAE v5.0) or baseline,except for alopecia, skin pigmentation (allowed at any level), and immune-relatedadverse reactions requiring physiological replacement (e.g., hypothyroidism,hypopituitarism, type 1 diabetes).