Trastuzumab Combined With Retlirafusp Alfa in Treating HER2（Human Epidermal Growth Factor Receptor 2） 2+/3+ Gastric/Gastroesophageal Junction Adenocarcinoma After First-line Systemic Therapy Failure

Inclusion Criteria:

• Fully understand this study and voluntarily sign the informed consent form, with good compliance and cooperation with follow-up;
• Age ≥18 years;
• Eastern Cooperative Oncology Group（ECOG） score 0-1;
• Histologically or cytologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, locally advanced and unresectable, with local recurrence or distant metastasis;
• Immunohistochemistry (IHC) testing for Her2 expression: IHC3+ or IHC2+;
• First-line standard treatment failure in gastric adenocarcinoma or gastroesophageal junction adenocarcinoma: (1) postoperative recurrence or metastasis patients progressing during concurrent chemoradiotherapy; (2) for neoadjuvant/adjuvant therapy containing immunotherapy, if patients progress during treatment or within 6 months after treatment, it is also considered first-line treatment failure;
• Patients must have at least one measurable lesion (according to RECIST 1.1 criteria);
• Major organ functions are normal, meeting the following criteria:(1) Blood routine test standards must meet (no blood transfusion or blood products, and no use of G-CSF or other hematopoietic stimulating factors within 14 days to correct): A. Hemoglobin (Hb) ≥90 g/L; B. Absolute neutrophil count (ANC) ≥1.5 ×10^9/L; C. Platelet count (PLT) ≥80×10^9/L; (2) Biochemical tests must meet the following standards: A. Total bilirubin (TBIL) <1.5 × upper limit of normal (ULN);B. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 ULN, or <5 ULN for patients with liver metastasis; C. Serum creatinine (Cr) ≤1.5 ULN or estimated creatinine clearance >60 ml/min (Cockcroft-Gault formula); D. Urinalysis results: urine protein (UPRO) <2 or 24-hour urine protein <1 g; (3) Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥ lower limit of normal (50%); (4) Coagulation: international normalized ratio (INR) ≤1.5×ULN and activated partial thromboplastin time ≤1.5×ULN;(5) Pulmonary function: forced expiratory volume in 1 second (FEV1) ≥1.2 L, FEV1% ≥70%, carbon monoxide diffusing capacity (DLCO) ≥50%; (6) Cardiac chocardiography: left ventricular ejection fraction (LVEF) ≥50%;(7) Electrocardiogram Fridericia-corrected QT interval (QTcF): women <470 ms, men <450 ms; (8) Others: lipase ≤1.5×ULN (if lipase >1.5×ULN without clinical or imaging evidence of pancreatitis, enrollment is allowed); amylase ≤1.5×ULN (if amylase >1.5×ULN without clinical or imaging evidence of pancreatitis, enrollment is allowed); alkaline phosphatase (ALP) ≤2.5×ULN.
• Women of childbearing potential must agree to use effective contraception during the study and for 6 months after the study; must have a negative serum or urine pregnancy test within 7 days before enrollment, and must not be breastfeeding; men must agree to use contraception during the study and for 6 months after the study.

Exclusion Criteria:

• Known allergy to any investigational drug or its excipients, or allergy to humanized monoclonal antibody products (such as trastuzumab, pertuzumab, etc.).
• (1) Received any investigational drug within 4 weeks before the first use of the study drug; (2) subjects who require systemic treatment with corticosteroids (daily dose >10 mg prednisone equivalent) or other immunosuppressants within 2 weeks before the first use of the study drug, except for using corticosteroids for local esophageal inflammation, allergy prevention, or nausea and vomiting; (3) other special situations need to be discussed with the sponsor. In the absence of active autoimmune disease, inhaled or local steroids and adrenal corticosteroid replacement at doses >10 mg/day prednisone equivalent are allowed; (4) subjects who have received anti-cancer vaccines or live vaccines within 4 weeks before the first administration of the study drug.
• Having any active autoimmune disease or a history of autoimmune disease (such as interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism), except for vitiligo or childhood asthma/allergies that have resolved and require no intervention in adulthood; autoimmune-mediated hypothyroidism treated with a stable dose of thyroid replacement hormone and type 1 diabetes patients using a stable dose of insulin can be included.
• History of immunodeficiency, including positive HIV test, or having other acquired or congenital immunodeficiency diseases, or a history of organ transplant or allogeneic bone marrow transplantation.
• Uncontrolled clinical symptoms or diseases of the heart, such as (1) NYHA II or higher heart failure, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias requiring medical intervention.
• Severe infection (CTCAE > Grade 2) within 4 weeks before first use of the study drug, such as severe pneumonia requiring hospitalization, bacteremia, or infections with complications; baseline chest imaging indicating active lung inflammation; symptoms or signs of infection within 2 weeks before first use of the study drug requiring oral or intravenous antibiotics, except for prophylactic antibiotic use; history of interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis, or other uncontrolled acute lung diseases; active pulmonary tuberculosis found by history or CT, or a history of active pulmonary tuberculosis within 1 year before enrollment, or a history of active pulmonary tuberculosis over 1 year ago but not properly treated; subjects with active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL) or hepatitis C (HCV antibody positive and HCV-RNA above the detection limit of the assay).
• Before using the study drug for the first time, diagnosed with any other malignant tumor is excluded, except for those with low risk of metastasis and death (5-year survival rate >90%), such as fully treated basal cell or squamous cell skin cancer or cervical carcinoma in situ.
• Pregnant or breastfeeding women; subjects of reproductive potential who are unwilling or unable to use effective contraception.
• Patients who, in the investigator's judgment, are considered not suitable to enroll.