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 through gastroscopy.
• Ages: 18-70 Years (concluding 18 and 70 Years)
• Life expectancy ≥3 months.
• Treatment-naive Stage IV (clinical staging, AJCC 8th) unresectable patients, no prior antitumor therapy (including radiation, chemotherapy, targeted therapy or immunotherapy, etc.).
• The Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0-1.
• Preoperative examinations using CT, MRI, PET-CT, etc., indicating only one unresectable factor OR peritoneal metastasis with another unresectable factor, such as:

• N3 lymph node metastasis, mainly referring to group 16 lymph node metastasis.
• Extensive or bulky lymph nodes (D2)
• Locally advanced T4b.
• Hepatic metastases (H1): ≤5 lesions with a total diameter ≤8cm.
• Peritoneal metastasis (CY1, P1).
• Ovarian metastasis (Krukenberg tumor).
• Physically fit for major abdominal surgery.
• Adequate organ and marrow function, defined as:

• Hematological status: Absolute neutrophil count (ANC) ≥1.5×10^9/L; Platelet count (PLT) ≥100×10^9/L; Hemoglobin (HGB) ≥9.0 g/dL.
• 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 patients with liver metastasis: TBIL ≤1.5×ULN; ALT and AST ≤5×ULN.
• Renal function: Creatinine clearance (Ccr) ≥50 mL/min (calculated using the Cockcroft/Gault formula).
• Adequate coagulation function, defined as International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times ULN.
• Voluntary participation and signed informed consent with expected good compliance and 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 inclusion criteria, 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 or difficulty 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%, uncontrolled hypertension, renal insufficiency, symptomatic peripheral neuropathy, and NCI classification >II)
• Has already on other medications prior to enrollment or could not be assured of compliance after enrollment.
• Allergy to any drugs in the regimen.
• Women who are pregnant or breastfeeding and have childbearing potential but are not taking 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 first dose.
• 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 first dose of study treatment.
• Has a diagnosis of autoimmune disease within the previous 2 years (Patients with vitiligo, psoriasis, alopecia areata, or Graves' disease who do not require systemic therapy within the last 2 years, hypothyroidism requiring only thyroid hormone replacement therapy, and type I diabetes mellitus requiring only insulin replacement therapy 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 an individual basis as determined by the physician with monitoring of viral copy number.
• Urinalysis indicating urine protein ≥2+ and 24-hour urine protein quantification >1.0g.