ctDNA-Guided Cetuximab or Bevacizumab Plus Trifluridine/Tipiracil in RAS/BRAF Wild-Type mCRC

Inclusion criteria

• Histologically confirmed colorectal adenocarcinoma
• Initial RAS/BRAF wild-type status
• Received first-line treatment with FOLFOX, FOLFIRI, or FOLFOXIRI combined with cetuximab, with documented clinical benefit (CR/PR/SD) and progression-free survival (PFS) ≥ 6 months
• Disease progression occurred during or within 3 months after cetuximab-based first-line therapy
• Experienced further tumor progression after receiving second-line or subsequent treatments
• At least 4 months have elapsed since the last administration of cetuximab
• At least one measurable lesion according to RECIST v1.1
• RAS/BRAF wild-type status confirmed by blood-based ctDNA testing
• Normal hematologic function (platelets \> 90 × 10⁹/L; white blood cells \> 3 × 10⁹/L; neutrophils \> 1.5 × 10⁹/L; hemoglobin \> 10.0 g/100 ml)
• Serum bilirubin ≤ 1.5 × upper limit of normal (ULN), transaminases ≤ 5 × ULN
• No ascites, normal coagulation function, serum albumin ≥ 35 g/L
• Child-Pugh class A liver function
• Serum creatinine below ULN or calculated creatinine clearance \> 50 ml/min (using the Cockcroft-Gault formula)
• ECOG performance status of 0-1
• Expected survival \> 3 months
• Signed written informed consent
• Willing and able to undergo follow-up until death, study completion, or study termination

Exclusion criteria

• Presence of RAS or BRAF gene mutations
• Severe arterial embolism or ascites
• Bleeding tendency or coagulation disorders
• Hypertensive crisis or hypertensive encephalopathy
• Severe and uncontrolled systemic complications such as infections or diabetes
• Clinically significant cardiovascular diseases, including cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medical therapy, unstable angina, congestive heart failure (NYHA class II-IV), or arrhythmias requiring medical treatment History of or physical examination indicating central nervous system diseases (e.g., primary brain tumor, epilepsy not controlled with standard therapy, any brain metastases, or history of stroke)
• History of other malignancies within the past 5 years (excluding adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, and/or thyroid cancer)
• Known allergy to any of the study drugs
• Pregnant or breastfeeding women
• Women of childbearing potential (within 2 years of last menstruation) or men with reproductive potential who are not using or refuse to use effective non-hormonal contraception (e.g., intrauterine device, barrier method with spermicidal gel, or sterilization)
• Inability or unwillingness to comply with the study protocol
• Any other disease, functional impairment caused by metastatic lesions, or suspicious findings on physical examination that may indicate contraindications to study treatment or place the patient at high risk of treatment-related complications