Safety and Efficacy of Fruquintinib Plus Nab-Paclitaxel and Iparomlimab and Tuvonralimab Injection in the Second-Line Treatment for Immunotherapy-experienced Advanced Gastric Cancer

Prior treatment

• History of gastrointestinal perforation and/or fistula within 6 months prior to the first dose of study medication.
• Receipt of any of the following treatments:
  • Severe adverse reactions to prior immunotherapy.
  • Prior treatment with CTLA4 inhibitors.
  • Any study medication within 4 weeks prior to the first dose of study medication.
  • Concurrent enrollment in another clinical study (excluding observational studies or survival follow-ups of interventional studies).
  • Last dose of anti-cancer therapy ≤ 3 weeks prior to the first study medication, or fixed-field palliative radiotherapy ≤ 2 weeks prior to study intervention.
  • Corticosteroid use (\>10 mg prednisone equivalent/day) within 2 weeks prior to study medication; the investigator may decide on eligibility in special cases. Inhaled/topical steroids and adrenal replacement at \>10 mg/day prednisone equivalent are permitted in the absence of active autoimmune diseases.
  • Anti-tumor vaccines or live vaccines within 4 weeks prior to study medication.
  • Major surgery or severe trauma within 4 weeks prior to study medication.
• Previous anti-tumor treatment toxicities not recovered to ≤ CTCAE Grade 1 (excluding alopecia) or the specified inclusion/exclusion criteria levels.
• Severe infection (CTCAE \>Grade 2) within 4 weeks prior to study medication (e.g., severe pneumonia, bacteremia, infectious complications requiring hospitalization); baseline chest imaging showing active pulmonary inflammation, or infection symptoms/signs requiring oral/IV antibiotics within 2 weeks prior to study medication (excluding prophylactic antibiotics).
• History of interstitial lung disease (excluding radiation pneumonitis or non-infectious pneumonitis not treated with steroids).
• Active tuberculosis (confirmed by history/CT) or history of active tuberculosis within 1 year prior to enrollment, or untreated active tuberculosis more than 1 year prior to enrollment.
• History of any other malignant tumor within 5 years prior to study medication (excluding low-risk tumors with \>90% 5-year survival rate, e.g., adequately treated basal cell/squamous cell skin cancer or cervical intraepithelial neoplasia).

Other illness

• History of active autoimmune diseases (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism) or a history of such diseases (excluding vitiligo, or childhood asthma/allergies cured and requiring no intervention in adulthood; autoimmune hypothyroidism on stable thyroid replacement; type 1 diabetes on stable insulin).
• Immunodeficiency history (including HIV-positive status, acquired/congenital immunodeficiency, organ transplantation, or allogeneic bone marrow transplantation).
• Inadequately controlled cardiovascular symptoms/diseases, including: (1) NYHA Class II or higher heart failure; (2) Unstable angina; (3) Myocardial infarction within 1 year; (4) Clinically significant supraventricular/ventricular arrhythmias (uncontrolled with clinical intervention).
• Significant clinical bleeding or definite bleeding tendency within 3 months (e.g., gastrointestinal bleeding, hemorrhagic gastric ulcer, vasculitis). If baseline occult blood in stool is positive, re-testing is allowed; endoscopy may be performed based on clinical judgment if positive after re-testing.
• Hypertension inadequately controlled by anti-hypertensive medication (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg).

Lab values

• Hypersensitivity to any component of monoclonal antibodies, fruquintinib, or albumin-bound paclitaxel.
• Abnormal coagulation (INR \>1.5×ULN or PT \>ULN+4s), with bleeding tendency or thrombolytic/anticoagulant therapy (small-dose low-molecular-weight heparin or oral aspirin for prophylaxis permitted during the trial).
• Other factors (e.g., concurrent severe diseases including mental illness, severely abnormal lab values, family/social factors) that may lead to forced withdrawal from the study, as determined by the investigator.

Other

• Uncontrolled pleural, pericardial, or peritoneal effusions requiring repeated drainage.
• Central nervous system metastases.
• Urinalysis showing urine protein ≥++ and confirmed 24-hour urine protein \>1.0 g.
• Active ulcers, unhealed wounds, or fractures.
• Pregnant or breastfeeding women.

• ≥ 18 years
• Pathologically or cytologically confirmed diagnosis of gastric cancer (GC) or gastroesophageal junction (GEJ) cancer.
• Failure of first-line treatment with PD-1/PD-L1 inhibitors
• With measurable lesions according to RECIST 1.1 criteria.
• ECOG performance status of 0-1
• Expected survival ≥3 months;
• Major organ functions meet the following requirements :
  • Absolute neutrophil count (ANC) ≥ 1,500/mm³ (1.5 × 10⁹/L) (no growth factors used within 14 days).
  • Platelet count (PLT) ≥ 100,000/mm³ (100 × 10⁹/L) (no correction therapy used within 7 days).
  • Hemoglobin (Hb) ≥ 9 g/dL (90 g/L) (no correction therapy used within 7 days).
  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN).
  • Total bilirubin (BIL) ≤ 1.5 × upper limit of normal (ULN).
  • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) levels ≤ 2.5 × upper limit of normal (ULN); ≤ 5 × upper limit of normal (ULN) for patients with liver metastases.
  • Urinalysis is normal, or urine protein \< (++), or 24-hour urine protein level \< 1.0 g.
• Normal coagulation function, with no history of active bleeding or thrombotic diseases:
  • International normalized ratio (INR) ≤ 1.5 × ULN.
  • Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.
  • Prothrombin time (PT) ≤ 1.5 × ULN.
• For patients with potential fertility, the following requirements must be met:
  • Adopt a medically acceptable contraceptive method (e.g., intrauterine device, oral contraceptives, or condoms) during the study treatment period and for 3 months after the completion of study treatment.
  • Serum human chorionic gonadotropin (β-HCG) test must be negative within 72 hours prior to study enrollment.
  • Must not be breastfeeding.
• Patients must have provided written informed consent, and be willing and able to comply with the scheduled visits, study treatment plan, laboratory tests, and other trial procedures.