The objective of this randomized controlled clinical trial is to evaluate the efficacy of ctDNA-guided rechallenge with cetuximab plus trifluridine/tipiracil compared with bevacizumab plus trifluridine/tipiracil in patients with treatment-refractory, RAS/BRAF wild-type metastatic colorectal cancer.

Colorectal cancer (CRC) remains a major public health challenge in China, where its incidence and mortality continue to rise. Although surgical resection is the cornerstone of curative treatment, metastatic disease develops in 30-40% of patients. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies such as cetuximab and panitumumab are pivotal therapeutic agents for patients with RAS wild-type metastatic colorectal cancer (mCRC), exerting antitumor effects through inhibition of the EGFR pathway and activation of antibody-dependent cell-mediated cytotoxicity.

Recent evidence from phase II trials and retrospective analyses has suggested that rechallenge with anti-EGFR monoclonal antibodies in later-line settings may confer clinical benefit in selected patients who previously responded to first-line anti-EGFR-based therapy. Studies such as CRICKET and CHRONOS have highlighted the feasibility of this approach, with emerging data supporting the utility of circulating tumor DNA (ctDNA) to guide patient selection based on RAS, BRAF, and EGFR extracellular domain mutation status. Notably, the VELO study demonstrated improved progression-free survival (PFS) with third line panitumumab plus trifluridine/tipiracil compared to trifluridine/tipiracil alone, particularly in patients with ctDNA-confirmed RAS/BRAF wild-type status. Similarly, the ongoing PARERE and recently reported CITRIC studies have further emphasized the value of molecular stratification using liquid biopsy to refine anti-EGFR rechallenge strategies and optimize treatment sequencing.

The current study builds upon these findings and aims to evaluate and compare the efficacy and safety of cetuximab plus trifluridine/tipiracil versus bevacizumab plus trifluridine/tipiracil as later-line treatments in Chinese patients with RAS/BRAF wild-type mCRC, with treatment selection informed by ctDNA profiling. By integrating real-world clinical data and contemporary molecular diagnostics, this study seeks to assess the potential benefit of cetuximab-based rechallenge therapy in a population with limited therapeutic options and to contribute further evidence supporting the implementation of personalized, biomarker-guided strategies in later-line mCRC management.

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

Data and materials used in this study can be made available following study completion upon reasonable request to the corresponding author, subject to ethical and legal considerations and applicable data-sharing agreements.