This study is a single-center, prospective, single-arm exploratory study aimed at evaluating the efficacy and safety of trifluridine/tipiracil in combination with cetuximab in the treatment of third-line and above RAS/BRAF wild-type metastatic colorectal cancer.

Inclusion Criteria:

1. Patient able and willing to provide written informed consent and to comply with the study protocol and follow-up inspection.

2. Histologically or cytologically confirmed metastatic adenocarcinoma of the colon; excluding appendiceal and anal canal cancers.

3. Previously received at least second-line treatment, including two standard treatment regimens (such as fluoropyrimidine, capecitabine, irinotecan, oxaliplatin with or without anti-VEGF or anti-EGFR agents), if previously received first-line anti-EGFR therapy, achieving at least a partial response (PR) or above, with a discontinuation interval of at least one year.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

5. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) (based on RECIST 1.1 criteria, with the longest diameter of tumor lesions on CT/MRI scan ≥10mm, and the shortest diameter of lymph node lesions on CT/MRI scan ≥15mm).

6. Wild-type RAS/BRAF gene detected.

7. Able to take oral medication.

8. Normal organ function, meeting the following criteria within 14 days before treatment initiation:

   • Neutrophil count ≥1.5×10^9/L;
   • Platelet count ≥75×10^9/L;
   • Hemoglobin ≥9.0g/dL;
   • Aspartate aminotransferase (AST) ≤2.5×upper limit of normal (ULN) (or ≤5×ULN if liver metastases);
   • Alanine aminotransferase (ALT) ≤2.5×ULN (or ≤5×ULN if liver metastases);
   • Total bilirubin ≤1.5×ULN;
   • Creatinine clearance (calculated by Cockcroft and Gault formula) >60mL/min or serum creatinine ≤1.5×ULN;

9. Expected survival time >3 months (90 days).

10. Women of childbearing potential must have used reliable contraception for 7 days prior to enrollment, have had a negative pregnancy test, and agree to use appropriate contraception methods during the trial and for 6 months after the last dose of investigational drug. Men must agree to use appropriate contraception methods or have undergone surgical sterilization during the trial and for 6 months after the last dose of investigational drug.

Exclusion Criteria:

1. Prior treatment with Trifluridine/Tipiracil;
2. Patients with known dMMR or MSI-H advanced colorectal cancer who have not previously received anti-PD-1 or PD-L1 inhibitors;
3. Participation in another drug clinical trial or receipt of systemic chemotherapy, radiotherapy, or biologic therapy within the past 4 weeks;
4. Known or suspected brain metastases;
5. Synchronous or metachronous cancer with a disease-free survival of ≥5 years (except for colorectal cancer) excluding cured or curatively treated mucosal cancers (esophageal cancer, gastric cancer, cervical cancer, non-melanoma skin cancer, bladder cancer, etc.);
6. Factors significantly affecting oral drug absorption, such as dysphagia, chronic diarrhea, and gastrointestinal obstruction; uncontrolled Crohn's disease or ulcerative colitis;
7. Symptomatic malignant effusion requiring symptomatic treatment (including pleural effusion, ascites, pericardial effusion);
8. Pregnant or lactating women; patients with reproductive potential unwilling or unable to use effective contraceptive measures;
9. Known allergy to the investigational drug, drug class, or its components;
10. Requirement for systemic corticosteroid therapy (excluding local steroids and cetuximab pre-treatment);
11. History of interstitial lung disease (interstitial pneumonia, pulmonary fibrosis, etc.) or radiographic evidence of interstitial lung disease;
12. Active local or systemic infections requiring treatment;
13. New York Heart Association (NYHA) functional classification ≥II or severe heart disease;
14. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) or history of active hepatitis B or hepatitis C;
15. Unresolved toxicity (CTCAE>Grade 1) or incomplete recovery from previous cancer surgery.
16. Patients deemed unsuitable for the study by the investigator.