establishment of precision targeted therapy strategies for advanced gastric cancer based on novel molecular subtyping

Conditions: Gastric Cancer; HER2 + Gastric Cancer; CLDN18.2-positive Adenocarcinoma of the Gastroesophageal Junction; PD-L1 Positive

Summary: this study is a prospective, umbrella-design, phase ii clinical trial. eligible participants with advanced or metastatic gastric cancer who are treatment-naïve for advanced-stage systemic therapy will undergo biomarker profiling (her2, cldn18.2, and pd-l1) via next-generation sequencing (ngs) or immunohistochemistry (ihc). participants will be stratified into distinct molecular subtypes and assigned subtype-specific therapeutic regimens. the primary objectives are to assess treatment efficacy (e.g., objective response rate) and safety profiles across molecularly defined cohorts.


Eligibility criteria:
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.

Keywords: gastric cancer her2 cldn18.2 pd-l1