A Single-arm, Multicenter Exploratory Clinical Trial of Anlotinib Combined With TQB2450 and the SOX Regimen as First-line Treatment for Advanced Gastric Cancer With Low PD-L1 Expression

A Single-arm, Multicenter Exploratory Clinical Trial of Anlotinib Combined With TQB2450 and the SOX Regimen as First-line Treatment for Advanced Gastric Cancer With Low PD-L1 Expression

To evaluate the efficacy and safety of anlotinib combined with TQB2450 and the SOX regimen as first-line treatment for advanced gastric cancer with low PD-L1 expression

Evaluation of the efficacy and safety of anlotinib in combination with TQB2450 and the SOX regimen as first-line treatment for advanced gastric cancer with low PD-L1 expression. Additionally, real-world data were collected from hospital-based patients receiving immune checkpoint inhibitor (ICI)-combined chemotherapy as first-line therapy for PD-L1-low advanced gastric cancer to establish an external control cohort. The efficacy outcomes between the two treatment strategies were then compared.

Inclusion Criteria:

• 1. Willing and able to provide written informed consent and comply with study procedures.
• 2. Histologically or cytologically confirmed HER2-negative (or HER2 status undetermined) unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (including signet ring cell carcinoma, mucinous adenocarcinoma, and hepatoid adenocarcinoma variants).
• 3. Disease recurrence >6 months after completion of (neo)adjuvant chemotherapy or radiotherapy.
• 4. At least one measurable or evaluable lesion according to RECIST v1.1 criteria. Measurable lesions must not have received prior local therapy (e.g., radiotherapy); however, lesions within previously irradiated fields may be designated as target lesions if documented progression is demonstrated per RECIST v1.1.
• 5. Age 18 and above.
• 6. ECOG performance status 0-1.
• 7. Life expectancy ≥3 months.
• 8. Organ Function Requirements and Laboratory Test Criteria During Screening (1) Complete Blood Count (CBC) Criteria： Hemoglobin (Hb): ≥ 90 g/L (no blood transfusion within 14 days) Absolute Neutrophil Count (ANC): ≥ 1.5 × 10⁹/L Platelet Count (PLT): ≥ 100 × 10⁹/L (no use of interleukin-11 [IL-11] or thrombopoietin [TPO] within 14 days) White Blood Cell Count (WBC): ≥ 4.0 × 10⁹/L (no granulocyte colony-stimulating factor [G-CSF] administration within 14 days) (2) Biochemical Panel Requirements: Total Bilirubin (TBIL): ≤ 1.5 × ULN (upper limit of normal),Alanine Aminotransferase (ALT) & Aspartate Aminotransferase (AST): ≤ 2.5 × ULN,Serum Creatinine (Cr): ≤ 1.5 × ULN or Creatinine Clearance (CrCl): ≥ 60 mL/min (calculated by Cockcroft-Gault formula),Serum Albumin: ≥ 25 g/L (2.5 g/dL) For Subjects with Hepatic Metastases:Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT): ≤ 5 × ULN，White Blood Cell Count (WBC): ≥ 4 × 10⁹/L，Platelet Count (PLT): ≥ 100 × 10⁹/L (without transfusion support)， Absolute Neutrophil Count (ANC): ≥ 1.5 × 10⁹/L (without granulocyte colony-stimulating factor [G-CSF] therapy) (3) Cardiac Function Assessment (Echocardiography)：Left Ventricular Ejection Fraction (LVEF): ≥ 50% (or above institutional lower limit of normal) (4) Coagulation Profile：International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN
• 9. Women of reproductive age must use effective contraception during the study period, after the last dose, and for at least 6 months following chemotherapy. It is recommended to start using contraception at least 3 months before the administration of the investigational drug; unsterilized males must also be required to use effective contraception for at least 6 months during the study period, after the last dose, and following chemotherapy. It is recommended to start using contraception at least 3 months before the administration of the investigational drug.
• 10. PD-L1 combined positive score ( CPS) <5

Exclusion Criteria:

• 1. Prior treatment with anlotinib hydrochloride or any immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies);
• 2. History of immunodeficiency disorders, including HIV infection, other acquired or congenital immunodeficiency diseases, or prior organ transplantation;
• 3. Active hepatitis B or C infection, or active pulmonary tuberculosis;
• 4. CT-confirmed ulcerative lesions or fecal occult blood positivity;
• 5. History of clinically significant bleeding (excluding epistaxis) within 1 month prior to enrollment;
• 6. Previous allogeneic bone marrow or solid organ transplantation;
• 7. Interstitial lung disease including idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or CT-confirmed active pneumonia;
• 8. Administration of live attenuated vaccines within 4 weeks before study initiation or anticipated during the study through 5 months post-treatment;
• 9. Systemic corticosteroids (>10 mg/day prednisone equivalent) or immunosuppressive therapy within 2 weeks prior to study initiation (inhaled or topical corticosteroids are permitted);
• 10. Known symptomatic CNS metastases or leptomeningeal carcinomatosis. Patients with previously treated CNS metastases may be eligible if neurologically stable for ≥4 weeks without steroids or anticonvulsants;
• 11. Conditions impairing oral drug absorption (e.g., dysphagia, chronic diarrhea, or intestinal obstruction);
• 12. Grade ≥2 peripheral neuropathy per NCI CTCAE v5.0;
• 13. Active infections requiring systemic antibiotics within 14 days prior to study entry;
• 14. Hepatic tumor burden exceeding 50% of total liver volume;
• 15. Bone metastases with impending spinal cord compression risk;
• 16. Uncontrolled comorbidities including:
• Poorly controlled hypertension (SBP ≥150 mmHg or DBP ≥100 mmHg despite antihypertensives)
• Grade ≥2 myocardial ischemia, myocardial infarction, or arrhythmias (QTc ≥480 ms)
• NYHA Class III-IV heart failure or LVEF <50% by echocardiography
• Uncontrolled active infections
• Decompensated liver cirrhosis or active hepatitis
• Uncontrolled diabetes (FBG >10 mmol/L)
• Proteinuria ≥++ on dipstick or confirmed 24-hour urinary protein >1.0 g
• 17. Non-healing wounds or fractures;
• 18. Coagulopathy (INR >1.5 or aPTT >1.5×ULN), bleeding diathesis, or requiring therapeutic anticoagulation:
• Known bleeding disorders (hemophilia, coagulopathies) or thrombocytopenia
• Hemoptysis (>2.5 mL/day) within 2 months
• Clinically significant bleeding within 3 months (GI bleeding, hemorrhagic ulcers, etc.)
• Chronic anticoagulation (warfarin/heparin) or antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day)
• 19. Major surgical procedures within 4 weeks prior to study or anticipated during treatment;
• 20. History within 6 months of:
• GI perforation/fistula
• Arterial/venous thromboembolism (excluding stable cerebral infarcts)
• 21. Clinically significant pleural/peritoneal effusions requiring intervention (asymptomatic minimal effusions not requiring treatment may be permitted);
• 22. Severe malnutrition;
• 23. Active substance abuse or psychiatric disorders impairing compliance;
• 24. Other active malignancies except:
• Curatively treated malignancies with >2 year disease-free interval
• Adequately treated non-melanoma skin cancer or lentigo maligna
• Carcinoma in situ with complete resection
• 25. Pregnancy or lactation;
• 26. Any condition deemed by investigators to compromise patient safety or study integrity;
• 27. Participation in other clinical trials within 30 days prior to enrollment or planned during study period.