This is a prospective, single-arm, investigator-initiated phase II clinical study. The study evaluates the efficacy and safety of retlirafusp alfa (a PD-L1/TGF-βRII bifunctional fusion protein) combined with apatinib (a VEGFR-2 tyrosine kinase inhibitor) and nab-paclitaxel in patients with locally advanced unresectable, locally recurrent, or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma who have progressed after first-line immunotherapy-containing treatment.

Gastric cancer is one of the most common malignant tumors of the digestive system. For patients with advanced gastric cancer who have failed first-line immunotherapy plus chemotherapy, second-line treatment options remain limited. Retlirafusp alfa is a bifunctional fusion protein targeting PD-L1 and TGF-βRII. Apatinib is a small-molecule anti-angiogenic agent. Nab-paclitaxel is a chemotherapeutic agent recommended for second-line treatment of advanced gastric cancer. This prospective, single-arm study investigates the efficacy and safety of this triple combination regimen in immunotherapy-pretreated advanced second-line gastric or gastroesophageal junction adenocarcinoma, to provide a new therapeutic option for these patients.

Inclusion Criteria:

1. Able to provide written informed consent prior to any study-specific procedures
2. Age ≥ 18 years
3. ECOG performance status 0 or 1
4. Histologically or cytologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, locally advanced unresectable, locally recurrent, or metastatic
5. Human epidermal growth factor receptor 2 (HER2) negative
6. Failed first-line immunotherapy-containing systemic treatment
7. At least one measurable lesion per RECIST Version 1.1
8. Adequate organ function:

1)Hemoglobin ≥ 90 g/L 2)Absolute neutrophil count ≥ 1.5 × 10⁹/L 3)Platelet count ≥ 80 × 10⁹/L 4)Total bilirubin < 1.5 × upper limit of normal (ULN) 5)ALT/AST < 2.5 × ULN; < 5 × ULN in patients with liver metastasis 6)Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 60 mL/min 7)Urine protein < 2+ or 24-hour urine protein < 1 g 8)Left ventricular ejection fraction (LVEF) ≥ 50% 9)Coagulation function: INR ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN 8.Fertile male and female subjects must agree to use highly effective contraception during the study and for 6 months after the last dose of study treatment; female subjects must have a negative pregnancy test within 7 days before enrollment

Exclusion Criteria:

1. Known hypersensitivity to any component of the study drugs
2. Prior treatment with any VEGFR inhibitor (including apatinib, sorafenib, sunitinib)
3. Prior treatment with retlirafusp alf
4. Received any investigational drug within 4 weeks before first dose
5. Received systemic corticosteroid (> 10 mg prednisone equivalent daily) or other immunosuppressive agents within 2 weeks before first dose, except for allowed topical/inhaled use or physiological replacement
6. Active autoimmune disease or history of autoimmune disease (except controlled hypothyroidism, type 1 diabetes with stable insulin, vitiligo, resolved childhood asthma)
7. Known immunodeficiency (including HIV infection), organ transplantation, or allogeneic hematopoietic stem cell transplantation
8. Uncontrolled cardiac disease: NYHA Class ≥ II heart failure, unstable angina, myocardial infarction within 1 year, clinically significant arrhythmia requiring intervention
9. Severe infection (CTCAE Grade > 2) within 4 weeks before first dose; active pulmonary infection, interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis; active tuberculosis
10. Active hepatitis B (HBV DNA ≥ 2000 IU/mL) or active hepatitis C (HCV RNA positive)
11. History of other malignancy within 5 years before enrollment, except adequately treated basal cell carcinoma, squamous cell carcinoma of skin, or carcinoma in situ of cervix
12. Pregnant or lactating women
13. Unwilling or unable to comply with study procedures
14. Any other condition deemed inappropriate by the investigator