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

Inclusion Criteria:

• 1. Willing and able to provide written informed consent and comply with studyprocedures.
• 2. Histologically or cytologically confirmed HER2-negative (or HER2 statusundetermined) unresectable locally advanced or metastatic gastric/gastroesophagealjunction adenocarcinoma (including signet ring cell carcinoma, mucinousadenocarcinoma, and hepatoid adenocarcinoma variants).
• 3. Disease recurrence >6 months after completion of (neo)adjuvant chemotherapy orradiotherapy.
• 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 targetlesions 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 transfusionwithin 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 14days) White Blood Cell Count (WBC): ≥ 4.0 × 10⁹/L (no granulocyte colony-stimulatingfactor [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-Gaultformula),Serum Albumin: ≥ 25 g/L (2.5 g/dL) For Subjects with HepaticMetastases: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 FunctionAssessment (Echocardiography)：Left Ventricular Ejection Fraction (LVEF): ≥ 50% (orabove institutional lower limit of normal) (4) Coagulation Profile：InternationalNormalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN
• 9. Women of reproductive age must use effective contraception during the studyperiod, after the last dose, and for at least 6 months following chemotherapy. It isrecommended to start using contraception at least 3 months before the administrationof the investigational drug; unsterilized males must also be required to useeffective contraception for at least 6 months during the study period, after thelast dose, and following chemotherapy. It is recommended to start usingcontraception at least 3 months before the administration of the investigationaldrug.
• 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 orcongenital 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 monthprior to enrollment;
• 6. Previous allogeneic bone marrow or solid organ transplantation;
• 7. Interstitial lung disease including idiopathic pulmonary fibrosis, drug-inducedpneumonitis, organizing pneumonia, or CT-confirmed active pneumonia;
• 8. Administration of live attenuated vaccines within 4 weeks before study initiationor anticipated during the study through 5 months post-treatment;
• 9. Systemic corticosteroids (>10 mg/day prednisone equivalent) or immunosuppressivetherapy within 2 weeks prior to study initiation (inhaled or topical corticosteroidsare permitted);
• 10. Known symptomatic CNS metastases or leptomeningeal carcinomatosis. Patients withpreviously treated CNS metastases may be eligible if neurologically stable for ≥4weeks without steroids or anticonvulsants;
• 11. Conditions impairing oral drug absorption (e.g., dysphagia, chronic diarrhea, orintestinal obstruction);
• 12. Grade ≥2 peripheral neuropathy per NCI CTCAE v5.0;
• 13. Active infections requiring systemic antibiotics within 14 days prior to studyentry;
• 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 despiteantihypertensives)

• 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 requiringtherapeutic 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 ≥300mg/day or clopidogrel ≥75 mg/day)

• 19. Major surgical procedures within 4 weeks prior to study or anticipated duringtreatment;
• 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 studyintegrity;
• 27. Participation in other clinical trials within 30 days prior to enrollment orplanned during study period.