Trifluridine/Tipiracil Plus Fruquintinib vs. Trifluridine/Tipiracil Plus Bevacizumab in Refractory Metastatic Colorectal Cancer: A Randomized, Controlled, Open-Label, Non-Inferiority Trial

Other illness

• 1.Prior treatment with trifluridine/tipiracil, fruquintinib, or any other VEGF-receptor tyrosine-kinase inhibitor (e.g., apatinib, regorafenib, anlotinib).
  • 2.Pregnant or lactating women, or women who may become pregnant during the study.
  • 3.Anti-cancer therapy given ≤ 4 weeks before randomization (or not yet completed).
  • 4.Clinically relevant non-haematological CTCAE grade ≥ 3 toxicity from prior anti-cancer therapy that has not resolved to ≤ grade 1 (except alopecia and skin pigmentation).
  • 5.Symptomatic central-nervous-system metastases, unstable neurological status, or requirement for an increased steroid dose to control CNS disease.
  • 6.Severe or uncontrolled acute or chronic active infection. 7.History of active or interstitial lung disease, pneumonitis, or pulmonary arterial hypertension.
  • 8.Clinically significant active hepatitis of any cause, including but not limited to hepatitis B or C.
  • 9.Known HIV-positive status. 10.Uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg), uncontrolled arrhythmia, or symptomatic arrhythmia.
  • 11.Arterial thrombo-embolic event ≤ 6 months before randomization, including cerebrovascular accident or myocardial infarction.
  • 12.Major surgery ≤ 4 weeks before randomization (surgical incision must be fully healed before study drug administration), not yet recovered from previous surgery, or major surgery anticipated during the study.
  • 13.Radiotherapy ≤ 2 weeks before randomization, except short-course palliative radiotherapy for symptom relief.
  • 14.Any other clinically significant medical condition that, in the investigator's opinion, would compromise patient safety or study integrity.
  • 15.Concurrent or previous malignancy within 5 years, except adequately treated basal-cell or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix.

• All study participants must sign the informed consent form before any study-related procedures are initiated.
• Aged 18-75 years, both males and females.
• Histologically confirmed unresectable colorectal cancer.
• RAS status known (mutant or wild-type).
• Progression or intolerance after at least two prior systemic regimens that must have contained fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy plus anti-VEGF therapy and/or anti-EGFR therapy.
• At least one measurable lesion per RECIST v1.1.
• Able to swallow oral tablets or capsules.
• Estimated life expectancy ≥ 12 weeks.
• ECOG performance status 0-1.
• Adequate major organ function (within 7 days before randomization):
  • Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelet count ≥ 75 × 10⁹/L Hemoglobin ≥ 90 g/L (no transfusion within 7 days) Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present) Urinalysis showing proteinuria ≤ 1+ or 24-h urine protein \< 1 g INR or PT ≤ 1.5 × ULN (acceptable if on anticoagulation and PT within intended therapeutic range)
• Women of child-bearing potential must have a negative serum pregnancy test within 7 days before randomization; all participants and their partners must agree to use highly effective contraception from screening through at least 6 months after the last dose of study medication.