Conversion Therapy of Sintilimab in Combination With Fruquintinib and Chemotherapy Versus Sintilimab and Chemotherpay in Stage IV Gastric Cancer

Inclusion Criteria:

• Histologically confirmed gastric/gastroesophageal junction adenocarcinoma throughgastroscopy.

• Ages: 18-70 Years (concluding 18 and 70 Years)

• Life expectancy ≥3 months.

• Treatment-naive Stage IV (clinical staging, AJCC 8th) unresectable patients, noprior antitumor therapy (including radiation, chemotherapy, targeted therapy orimmunotherapy, etc.).

• The Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0-1.

• Preoperative examinations using CT, MRI, PET-CT, etc., indicating only oneunresectable factor OR peritoneal metastasis with another unresectable factor, suchas:

1. N3 lymph node metastasis, mainly referring to group 16 lymph node metastasis.

2. Extensive or bulky lymph nodes (D2)

3. Locally advanced T4b.

4. Hepatic metastases (H1): ≤5 lesions with a total diameter ≤8cm.

5. Peritoneal metastasis (CY1, P1).

6. Ovarian metastasis (Krukenberg tumor).

• Physically fit for major abdominal surgery.

• Adequate organ and marrow function, defined as:

1. Hematological status: Absolute neutrophil count (ANC) ≥1.5×10^9/L; Plateletcount (PLT) ≥100×10^9/L; Hemoglobin (HGB) ≥9.0 g/dL.

2. Liver function: For patients without liver metastasis, serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); ALT and AST ≤2.5×ULN. For patientswith liver metastasis: TBIL ≤1.5×ULN; ALT and AST ≤5×ULN.

3. Renal function: Creatinine clearance (Ccr) ≥50 mL/min (calculated using theCockcroft/Gault formula).

• Adequate coagulation function, defined as International Normalized Ratio (INR) orProthrombin Time (PT) ≤1.5 times ULN.

• Voluntary participation and signed informed consent with expected good complianceand follow-up.

• Not involved in other clinical trials.

• Willing to provide blood and histological samples.

• No serious conditions affecting anesthesia, or surgery.

• No hematologic disorders affecting postoperative hemoglobin levels.

Exclusion Criteria:

• Has distal metastases other than oligometastases as defined in the inclusioncriteria, such as pulmonary metastases, brain metastases, bone metastases, etc.

• HER-2 positive patients or willing to receive Trastuzumab.

• Endoscopic signs of active bleeding from the lesion.

• Patients with moderate/large volume of ascites.

• Near-obstruction at the cardia or pylorus affecting feeding and gastric emptying ordifficulty swallowing tablets.

• Concurrently suffering from other serious illnesses that are difficult to control (Severe uncontrolled recurrent infections, atrial fibrillation, angina pectoris,cardiac insufficiency, ejection fraction measurement under 50%, uncontrolledhypertension, renal insufficiency, symptomatic peripheral neuropathy, and NCIclassification >II)

• Has already on other medications prior to enrollment or could not be assured ofcompliance after enrollment.

• Allergy to any drugs in the regimen.

• Women who are pregnant or breastfeeding and have childbearing potential but are nottaking adequate contraceptive measures.

• Organ transplant recipients requiring immunosuppression.

• Patients without decision-making capacity or with psychiatric disorders.

• Systemic treatment with Chinese herbal anti-tumor or immunomodulatory drugs (including thymosin, interferons, interleukins) within 2 weeks before the firstdose.

• Use of immunosuppressive drugs within 4 weeks before the first study treatment,excluding local steroids or physiological doses of systemic steroids.

• Has received a live or live-attenuated vaccine within 30 days prior to the firstdose of study treatment.

• Has a diagnosis of autoimmune disease within the previous 2 years (Patients withvitiligo, psoriasis, alopecia areata, or Graves' disease who do not require systemictherapy within the last 2 years, hypothyroidism requiring only thyroid hormonereplacement therapy, and type I diabetes mellitus requiring only insulin replacementtherapy are eligible for enrollment).

• Known history of primary immunodeficiency.

• Known to have active tuberculosis.

• Has history of human immunodeficiency virus (HIV) infection (i.e., HIV antibody .positive); untreated acute or chronic active hepatitis B or hepatitis C infection.Patients receiving antiretroviral therapy are eligible for enrollment on anindividual basis as determined by the physician with monitoring of viral copynumber.

• Urinalysis indicating urine protein ≥2+ and 24-hour urine protein quantification >1.0g.