Neoadjuvant SHR-A1811 ± Adebrelimab in GC/GEJ

Prior treatment

• Presence of contraindications to esophageal or gastric surgical resection.
• History of another primary malignancy, except for: basal cell carcinoma of the skin, superficial bladder cancer (Ta, non-invasive), squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; or malignancies that have received curative treatment and remained recurrence-free for ≥5 years.
• Significant clinically meaningful bleeding or definite bleeding tendency within 1 month before informed consent, such as gastrointestinal bleeding or fecal occult blood ≥2+ (positive); or endoscopically, radiologically, or highly suspected esophageal fistula or gastric perforation.
• Serious cardiovascular or cerebrovascular disease, including but not limited to: NYHA class II or greater heart failure; myocardial infarction or cerebrovascular accident (cerebral ischemia, symptomatic cerebral infarction, etc.) within 3 months before the first dose; grade ≥2 persistent arrhythmia (per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ); atrial fibrillation of any grade; unstable arrhythmia or unstable angina within 1 month before the first dose in patients with coronary artery disease; congestive heart failure not meeting the above criteria; or symptomatic superior vena cava syndrome.
• History of primary immunodeficiency or active autoimmune disease; or current use of immunosuppressants or systemic corticosteroids (≥10 mg/day prednisone or equivalent) that continued within 2 weeks before enrollment.
  • Note: Patients with type 1 diabetes mellitus, stable hypothyroidism on hormone replacement therapy (including hypothyroidism due to autoimmune thyroid disease), psoriasis not requiring systemic treatment, or vitiligo are eligible.
• Breastfeeding women unwilling to use adequate contraception during the study and for 6 months after the last dose of study drug.

Other illness

• Any serious or uncontrolled systemic disease at the discretion of the investigator, including uncontrolled hypertension (systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg), uncontrolled diabetes mellitus, or signs of active bleeding.
• Evidence of active infection, including hepatitis B (HBsAg positive with HBV DNA ≥2000 IU/mL, after excluding drug-induced or other causes of hepatitis), hepatitis C (anti-HCV antibody positive with HCV RNA above the lower limit of detection), or human immunodeficiency virus (HIV) infection; or uncontrolled active bacterial, viral, fungal, rickettsial, or parasitic infection unless treated and resolved before study drug administration.
• History of hypersensitivity to any component of the study drugs, or history of grade ≥3 hypersensitivity to macromolecular protein preparations or monoclonal antibodies.
• History of interstitial pneumonia, radiation pneumonitis, severe chronic obstructive pulmonary disease, severe pulmonary dysfunction, or symptomatic bronchospasm.
• Any other condition that, in the opinion of the investigator, makes the participant unsuitable for enrollment in this clinical trial.

Other

• Pathological diagnosis of HER2-negative esophageal or gastric adenocarcinoma, defined as HER2 IHC 0 or 1+.
• Presence of non-regional lymph node or distant organ metastasis. For suspected peritoneal carcinomatosis or ascites on imaging, histological or cytological confirmation via laparoscopy or other procedures is required.

• Voluntary signed informed consent and willingness to comply with protocol requirements.
• Age ≥18 years at the time of informed consent signing; both sexes eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 within 7 days before study drug administration.
• Resectable locally advanced esophageal or gastric adenocarcinoma, as determined by the investigator, staged as cT1b-2 N+ M0 or cT3-4 Nany M0 (AJCC 8th edition).
  • Note: Bone scan is required if bone lesions are suspected; diagnostic laparoscopy is required if peritoneal metastasis is suspected or for Lauren diffuse-type tumors.
  • 5\. HER2 intermediate-to-high expression by immunohistochemistry (IHC) 2+ or 3+. 6. No prior antitumor therapy for esophageal or gastric adenocarcinoma. 7. Availability of tumor tissue (primary tumor or metastatic lymph node) for pathological testing, including paraffin block, paraffin-embedded sections, or fresh tissue sections; archival tissue is preferred. If unavailable, a new baseline biopsy is required.
  • 8\. No severe cardiac dysfunction; left ventricular ejection fraction (left ventricular ejection fraction, LVEF) ≥55% within 28 days before study drug administration.
  • 9\. Adequate organ function within 7 days before study drug administration, defined as:
• Hematologic function:
  • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L Platelet count ≥100 × 10⁹/L Hemoglobin ≥90 g/L No blood or component transfusion within 14 days before the first dose, and no treatment with hematopoietic growth factors (e.g., granulocyte colony-stimulating factor (G-CSF) , erythropoietin) within 7 days before the first dose.
• Hepatic function:
  • Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
• Renal function:
  • Serum creatinine (Cr) ≤1.5 × ULN, or creatinine clearance (CrCl) ≥50 mL/min (calculated by the Cockcroft-Gault formula).
• Coagulation function:
  • International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (APTT) ≤1.5 × ULN (except for patients receiving therapeutic anticoagulation).
• Urinalysis:
  • Urine protein \<2+; if urine protein ≥2+, 24-hour urine protein must be ≤1 g. 10. Male participants and women of childbearing potential (including premenopausal women and women within 2 years after menopause) must agree to use effective contraception from the time of informed consent signing until 6 months after the last dose of study drug. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose of study drug.