Based on the current status and progress in the treatment of gastric cancer, our center prospectively designed a first-line comprehensive treatment plan for unresectable or postoperative recurrent advanced gastric/gastroesophageal conjoint adenocarcinoma, fruquintinib + sintilimab + oxaliplatin + Capecitabine (CAPEOX), which utilizes the tumor immunomodulation and vascular normalization effects of fruquintinib. While improving the effective perfusion of intravenous chemotherapy with CAPEOX regimen, further combining with PD-1 monoclonal antibody to regulate the immunosuppressive microenvironment and reactivate the anti-tumor immune response of the body. An exploratory dose-climbing trial was designed to evaluate the clinical efficacy and safety of fruquintinib in combination with Sintilimab and CAPEOX in clinical practice. At the same time, changes in genome, pathology and immune microenvironment of tumor-related tissues before and after treatment were observed, and molecular markers related to curative effect were screened to explore the molecular mechanism affecting the curative effect of combination therapy, and further enrichment of therapeutic advantage groups to improve the surgical conversion rate laid the foundation for future large-scale clinical studies

Inclusion Criteria:

1. Subjects aged 18-75 years (including 18 and 75 years);

2. Understand the research procedure and content, and voluntarily sign a written informed consent;

3. Incurable advanced/recurrent gastric or gastroesophageal junction adenocarcinoma with histopathological and/or cytological confirmation of HER2-negative or HER2 status unknown;

4. There is at least one measurable lesion according to RECIST 1.1 criteria;

5. No previous treatment with VEGFR-targeting drugs or PD-1/PD-L1 monoclonal antibody. Patients who had received platinum or paclitaxel or fluorouracil adjuvant chemotherapy after surgery and recurred more than 6 months after the end of chemotherapy without grade 2 toxicity or higher could be enrolled.

6. Physical condition score (ECOG PS score) : 0-1 score;

7. Expected survival ≥3 months;

8. The main organs function well;That is, the relevant check indicators within 14 days before randomization meet the following requirements:

   Hemoglobin ≥ 90 g/L (no transfusion within 14 days); Neutrophil count > 1.5×109/L; Platelet count ≥ 100×109/L; Total bilirubin ≤ 1.5×ULN (upper limit of normal); Serum glutamic pyruvic aminotransferase (ALT) or serum glutamic oxalacetic aminotransferase (AST) ≤ 2.5×ULN; If there is liver metastasis, ALT or AST ≤ 5×ULN; Endogenous creatinine clearance ≥ 60 ml/min (Cockcroft-Gault formula); Cardiac Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%; Thyroid function index: thyroid stimulating hormone (TSH), free thyroxine (FT3/FT4) in the normal range;

9. Weight of more than 40 kg (including 40 kg), or BMI > 18.5

10. Women who are fertile must have a negative urine or serum pregnancy test within 7 days prior to randomization and must consent to use highly effective contraception during the study period and for at least 120 days after the last administration of fruquintinib and sintilimab and for at least 180 days after the last administration of chemotherapy (Appendix 9);

11. Men who are not sterilized must consent to use highly effective contraception during the study period and for at least 120 days after the last administration of fruquintinib and sintilimab and for at least 180 days after the last administration of chemotherapy (Appendix 9).

Exclusion Criteria:

1. Patients with other malignant tumors in the past or at the same time, but have been cured of early tumors, including skin basal cell carcinoma, cervical carcinoma in situ, stage I lung cancer, stage I colorectal cancer and other tumors that researchers judge will not affect the patient's life in the short term can be excluded;
2. Participated in other drug clinical trials within four weeks;
3. have multiple factors that affect oral medication (such as inability to swallow, chronic diarrhea, and intestinal obstruction);
4. Have a history of bleeding, any bleeding event with a severity rating of CTCAE5.0 or higher occurring within 4 weeks prior to screening;
5. Patients with known central nervous system metastasis or history of central nervous system metastasis before screening. For patients with clinically suspected CNS metastasis, CT or MRI examination must be performed within 28 days before enrollment to rule out CNS metastasis.
6. Patients with hypertension who are not well controlled by single antihypertensive medication (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90mmHg); Patients with history of unstable angina pectoris; Patients with newly diagnosed angina pectoris or myocardial infarction within 3 months prior to screening; Arrhythmias (including QTcF: ≥450 ms in men and ≥470 ms in women) requiring long-term use of antiarrhythmic drugs and New York Heart Association grade ≥II cardiac insufficiency;
7. long-term unhealed wounds or incomplete healing fractures;
8. Imaging shows that the tumor has invaded important blood vessels, or the investigator determines that the patient's tumor is highly likely to invade important blood vessels during treatment and cause fatal massive bleeding;
9. Patients with abnormal coagulation function and bleeding tendency (14 days before randomization must meet: INR in the normal range without the use of anticoagulants, or no clinically significant abnormalities); Patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin, or their analogs; Low doses of warfarin (1 mg orally, once daily) or low doses of aspirin (up to 100 mg daily) are permitted for prophylactic purposes if INR ≤ 1.5;
10. Occurrence of arteriovenous thrombosis events within 6 months prior to screening, such as cerebrovascular accident (including temporary ischemic attack), deep vein thrombosis (except venous thrombosis caused by intravenous catheterization in previous chemotherapy and cured by investigators), pulmonary embolism, etc.;
11. Urine routine indicated urinary protein ≥++ and confirmed 24-hour urinary protein quantity > 1.0g;
12. Have used immunotargeted therapy drugs;
13. Have a history of immunodeficiency, or other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation;
14. Patients with infectious pneumonia, non-infectious pneumonia, interstitial pneumonia and other patients requiring corticosteroids;
15. A history of serious chronic autoimmune diseases, such as systemic lupus erythematosus; History of ulcerative enteritis, Crohn's disease and other inflammatory bowel diseases, irritable bowel syndrome and other chronic diarrheal diseases; A history of sarcoidosis or tuberculosis; History of active hepatitis B, hepatitis C and HIV infection; Well controlled non-severe immune diseases such as dermatitis, arthritis, psoriasis, etc. can be included. Hepatitis B virus drops <1000copy/ml could be included in the group.
16. Patients with hypersensitivity to human or murine monoclonal antibodies;
17. Those who have a history of psychotropic drug abuse and cannot quit or have mental disorders;
18. pleural effusion or abdominal effusion with clinical symptoms requiring clinical intervention;
19. Patients who do not follow medical advice, do not use drugs according to regulations, or have incomplete data that can affect the evaluation of efficacy or safety;
20. In the judgment of the investigator, there is a serious concomitant disease that endangers the patient's safety or interferes with the patient's completion of the study.

Deidentified individual participant data will be shared for secondary analysis under controlled access.

Clinical study report will be available within 6 months after article publication on Vivli.

Proposals require approval by an independent review committee and a signed data use agreement. Access criteria: (1) Meta-analysis of outcomes; (2) Validation of novel biomarkers.