Overview
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
Description
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.
Eligibility
Inclusion Criteria:
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- Willing and able to provide written informed consent and comply with study procedures.
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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).
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3. Disease recurrence >6 months after completion of (neo)adjuvant chemotherapy or
radiotherapy.
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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.
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5. Age 18-75 years.
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6. ECOG performance status 0-1.
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7. Life expectancy ≥3 months.
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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
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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.
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10. PD-L1 combined positive score ( CPS) <5
Exclusion Criteria:
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- Prior treatment with anlotinib hydrochloride or any immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies);
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2. History of immunodeficiency disorders, including HIV infection, other acquired
or congenital immunodeficiency diseases, or prior organ transplantation;
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3. Active hepatitis B or C infection, or active pulmonary tuberculosis;
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4. CT-confirmed ulcerative lesions or fecal occult blood positivity;
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5. History of clinically significant bleeding (excluding epistaxis) within 1 month
prior to enrollment;
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6. Previous allogeneic bone marrow or solid organ transplantation;
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7. Interstitial lung disease including idiopathic pulmonary fibrosis, drug-induced
pneumonitis, organizing pneumonia, or CT-confirmed active pneumonia;
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8. Administration of live attenuated vaccines within 4 weeks before study
initiation or anticipated during the study through 5 months post-treatment;
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9. Systemic corticosteroids (>10 mg/day prednisone equivalent) or
immunosuppressive therapy within 2 weeks prior to study initiation (inhaled or
topical corticosteroids are permitted);
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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;
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11. Conditions impairing oral drug absorption (e.g., dysphagia, chronic diarrhea,
or intestinal obstruction);
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12. Grade ≥2 peripheral neuropathy per NCI CTCAE v5.0;
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13. Active infections requiring systemic antibiotics within 14 days prior to study
entry;
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14. Hepatic tumor burden exceeding 50% of total liver volume;
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15. Bone metastases with impending spinal cord compression risk;
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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
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17. Non-healing wounds or fractures;
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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)
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19. Major surgical procedures within 4 weeks prior to study or anticipated during
treatment;
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20. History within 6 months of:
- GI perforation/fistula
- Arterial/venous thromboembolism (excluding stable cerebral infarcts)
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21. Clinically significant pleural/peritoneal effusions requiring intervention
(asymptomatic minimal effusions not requiring treatment may be permitted);
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22. Severe malnutrition;
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23. Active substance abuse or psychiatric disorders impairing compliance;
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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
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25. Pregnancy or lactation;
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26. Any condition deemed by investigators to compromise patient safety or study
integrity;
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27. Participation in other clinical trials within 30 days prior to enrollment or
planned during study period.