Retlirafusp Alfa Combined With Zeprumetostat, Apatinib, and Chemotherapy as First-Line Treatment for Metastatic GC/GEJC

1. Have a thorough understanding of this study and have voluntarily signed the informed consent form;
2. Age between 18 and 65 years old, male or female;
3. Patients with unresectable locally advanced or metastatic gastric/esophageal gastroesophageal junction adenocarcinoma confirmed by pathological or histological examination;
4. ECOG physical condition score of 0-1;
5. Expected survival of ≥ 3 months;
6. Have not received any anti-tumor treatment (including chemotherapy, targeted therapy, immunotherapy, etc.) for unresectable locally advanced or metastatic gastric cancer before (including any adjuvant treatment after gastric cancer radical surgery, provided that the time from the end of the last adjuvant chemotherapy to the discovery of metastatic disease is greater than 6 months);
7. Have at least one measurable lesion (meets RECIST v1.1 criteria);

8. The functions of important organs meet the following requirements (do not use any blood components, and cell growth factors within 14 days before enrollment):

   • Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; platelets ≥ 100 × 10\^9/L; hemoglobin ≥ 90 g/L;
   • Total bilirubin ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 5.0 × ULN; albumin ≥ 30 g/L
   • Serum creatinine ≤ 1.5 × ULN and creatinine clearance rate (calculated using the Cockcroft-Gault formula) ≥ 60 ml/min;
   • Good coagulation function, and need to meet the following conditions: international normalized ratio (INR) ≤ 1.5 (for those not receiving anticoagulation treatment); prothrombin time (PT) ≤ 1.5 × ULN; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
   • Normal thyroid function, defined as thyroid stimulating hormone (TSH) within the normal range. (If the baseline TSH is outside the normal range, and total T3 (or FT3) and FT4 are within the normal range, and there are no clinical symptoms, they can also be enrolled);
   • No active bleeding, such as hematemesis, hematochezia, gingival bleeding, epistaxis, and hemorrhage from hemorrhoids, and fecal occult blood ≤ +; gastroscopy shows no high bleeding risk of the primary lesion (such as exposed blood vessels at the ulcer base);
9. Patients with potential fertility need to use a medically approved contraceptive method (such as intrauterine device, contraceptive pills, or condoms) during the study treatment and within 1 month after the end of the study treatment; and the serum or urine HCG test must be negative within 72 hours before enrollment, and must be non-lactating.

Exclusion Criteria:

1. Patients with a known HER-2 status as positive (immunohistochemistry 3+, or, immunohistochemistry 2+ and FISH positive);
2. Those who had other malignant tumors within 5 years before enrollment, including skin basal cell or squamous cell carcinoma after radical surgery, or cervical carcinoma in situ, excluding;
3. Those who had received allogeneic bone marrow transplantation or organ transplantation in the past;
4. Those who had severe cardiovascular diseases within 6 months before enrollment, including unstable angina pectoris or myocardial infarction;
5. Subjects who were allergic to the study drug or any of its auxiliary preparations;
6. Those who had uncontrolled hypertension before enrollment, defined as: systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 90 mmHg;
7. Those who had any disease or condition that affected drug absorption before enrollment, or who could not take the drug orally;
8. Those who had active peptic ulcers in the stomach and duodenum, ulcerative colitis, or active bleeding from any unresected tumor, or conditions that the investigator judged might cause gastrointestinal bleeding or perforation;
9. Those who had clear evidence or history of significant bleeding within 3 months before enrollment (3-month bleeding > 30 mL, accompanied by hematemesis, melena, or bloody stool), hemoptysis (fresh blood > 5 mL within 4 weeks), or a thromboembolic event within 12 months (including stroke events and/or transient ischemic attacks);
10. Those with significant clinical cardiovascular diseases, including but not limited to acute myocardial infarction within 6 months before enrollment, severe/ unstable angina pectoris or coronary artery bypass surgery; congestive heart failure with NYHA classification > 2; drug-induced ventricular arrhythmias; LVEF (left ventricular ejection fraction) \< 50%;
11. Active or uncontrolled severe infections (≥ CTCAE v5.0 grade 2 infection);
12. Known human immunodeficiency virus (HIV) infection. Those with a clinically significant history of liver disease, including viral hepatitis [for those known to be HBV carriers, active HBV infection must be excluded, i.e., HBV DNA positive (> 1×104 copies/mL or > 2000 IU/ml); known hepatitis C infection (HCV) and HCV RNA positive (> 1×103 copies/mL)];
13. Patients with any active autoimmune disease or a history of autoimmune disease (as listed below, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitaryitis, vasculitis, nephritis, hyperthyroidism; patients with vitiligo; those who had complete remission of childhood asthma and no intervention required after adulthood can be included; patients with bronchial asthma requiring medical intervention cannot be included); alternative treatments are not considered systemic treatments; the following patients can be included: those with autoimmune-related hypothyroidism who received thyroid hormone replacement therapy; those with type 1 diabetes that can be controlled with insulin therapy;
14. Those who used immunosuppressants or systemic hormone therapy to achieve immunosuppression purposes within 7 days before enrollment (dose > 10mg/day prednisone or other equivalent efficacy hormones);
15. Those who currently have interstitial lung disease or pneumonia, pulmonary fibrosis, acute pulmonary diseases, radiation pneumonia;
16. Pregnant (positive pregnancy test before medication) or lactating women;
17. Any other diseases, clinically significant metabolic abnormalities, physical examination abnormalities or laboratory test abnormalities, as judged by the investigator, suggesting that the patient has a certain disease or condition that is not suitable for using the study drug (such as having epilepsy and requiring treatment), or will affect the interpretation of the study results, or place the patient at a high risk;
18. Urinalysis indicates that urine protein is ≥ 2+, and the 24-hour urine protein volume is > 1.0g;
19. Other acute or chronic diseases, mental disorders, or abnormal laboratory test results that may lead to the following outcomes: increase the risk of participating in the study or receiving the study drug, or interfere with the interpretation of the study results, and according to the researcher's judgment, patients classified as not eligible to participate in this study are considered unsuitable for inclusion by the researcher;
20. Participating in another interventional clinical study at the same time, unless participating in an observational (non-interventional) clinical study or in the follow-up stage of an interventional study; patients considered not suitable for inclusion in this study by the researcher.