Establishment of Precision Targeted Therapy Strategies for Advanced Gastric Cancer Based on Novel Molecular Subtyping

Inclusion Criteria:

1. Age ≥18 years, regardless of gender;
2. Histologically or pathologically confirmed gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction;
3. Advanced or metastatic disease with no prior systemic therapy for advanced-stage disease (Patients who relapsed >6 months after completing neoadjuvant/adjuvant therapy are eligible, with prior neoadjuvant/adjuvant regimens not counted as prior lines of therapy);
4. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST v1.1);
5. Archival or fresh tumor tissue sample available for biomarker testing (HER2, CLDN18.2, and PD-L1 expression);
6. ECOG performance status: 0-1;
7. Life expectancy ≥12 weeks;

8. Adequate organ and bone marrow function meeting the following criteria:

   1. Hemoglobin ≥90 g/L (no blood transfusion within 14 days);
   2. Absolute neutrophil count (ANC) ≥1.5×10⁹/L;
   3. Platelet count ≥90×10⁹/L;
   4. Total bilirubin ≤1.5×upper limit of normal (ULN);
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (≤5×ULN if liver metastases are present);
   6. Serum creatinine ≤1.5×ULN;
   7. Left ventricular ejection fraction (LVEF) ≥50% by echocardiography; QTc interval <450 ms for males and <470 ms for females;
9. Coagulation parameters:
10. For patients not on anticoagulation therapy: INR ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5×ULN;
11. For patients receiving full-dose or parenteral anticoagulation: Stable anticoagulant dose for ≥2 weeks prior to enrollment, with coagulation tests within the therapeutic range;
12. Contraception requirements:
13. Women of childbearing potential must have a negative pregnancy test (serum or urine) within 14 days prior to enrollment and agree to use effective contraception during the study and for 3 months after the last dose;
14. Men must be surgically sterile or agree to use effective contraception during the study and for 3 months after the last dose;
15. Recovery from prior therapy-related toxicities to ≤Grade 1 (surgical wounds must be fully healed if applicable);
16. Voluntary participation with signed informed consent form and anticipated adherence to protocol requirements.

Exclusion Criteria:

1. History of gastrointestinal perforation and/or fistula within 6 months prior to treatment, or active gastrointestinal bleeding within 3 months;
2. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage;
3. Known history of hypersensitivity to any component of the investigational drug(s) or excipients;

4. Prior treatments meeting any of the following:

   1. Received any investigational drug within 4 weeks prior to the first dose of the study drug or within 5 half-lives of the last investigational agent (whichever is shorter);
   2. Concurrent enrollment in another interventional clinical study (observational or follow-up studies are permitted);
   3. Received antitumor therapy (including radiotherapy, chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologics, or tumor embolization) within 2 weeks prior to the first dose of the study drug;
5. History of leptomeningeal metastasis or current active brain metastases;
6. Severe infection (CTCAE v5.0 Grade >2) within 4 weeks prior to the first dose of the study drug (e.g., pneumonia requiring hospitalization, bacteremia, or septic complications); active pulmonary inflammation on baseline chest imaging, or signs/symptoms of infection requiring oral/IV antibiotics within 2 weeks prior to the first dose (prophylactic antibiotics excluded);
7. History of interstitial lung disease (except radiation pneumonitis without steroid treatment or non-infectious pneumonitis);
8. Active tuberculosis (TB) infection confirmed by medical history or CT scan, history of active TB within 1 year prior to enrollment, or untreated active TB diagnosed >1 year prior to enrollment;
9. Diagnosis of another malignancy within 5 years prior to the first dose of the study drug, except malignancies with low metastatic/lethal risk (5-year survival rate >90%), such as adequately treated basal cell carcinoma, squamous cell skin cancer, or carcinoma in situ of the cervix;
10. Pregnant or lactating women;
11. Other conditions deemed by the investigator to jeopardize subject safety or trial integrity, including severe comorbidities (e.g., psychiatric disorders), clinically significant laboratory abnormalities, or social/family factors that may compromise protocol adherence or data collection.