The aim of the trial is to study the efficacy and safety of Cetuximab re-challenge for Chinese Patients with RAS/BRAF wild-type Metastatic Colorectal Cancer.

After first-line treatment of FOLFOX/FOLFIRI/FOLFOXIRI plus Cetuximab failure and defined as RAS/BRAF wild-type by molecular detection of cycle tumor DNA, the patients will be treated with Cetuximab and Irinotecan as a second-line or third-line treatment.

Inclusion Criteria:

• Age ≥ 18 and ≤75.
• Diagnosed as colorectal adenocarcinoma by histology.
• Initially confirmed as RAS/BRAF wild type by tissue molecular detection.
• Treated with first-line therapy of FOLFOX/FOLFIRI/FOLFOXIRI+Cetuximab effectively and the PFS is not less than 6 months.
• Tumor progression during Cetuximab treatment or after treatment within 3 months.
• Tumor progression again after second-line treatment.
• The interval time of re-challenge is more than 4 months after the last time treated with Cetuximab.
• Lesions can be measured by the standard of RECIST v1.1.
• Defined as RAS/BRAF wild-type by molecular detection of cycle tumor DNA,
• No hematologic dysfunction(Platelets >90×10^9/L; WBC >3×10^9/L; Neutrophil >1.5×10^9/L；Hemoglobin >10 g/100ml).
• Serum bilirubin ≤ 1.5 × ULN; aminotransferase ≤ 5 × ULN.
• No ascites; no coagulation dysfunction; albumin ≥ 30g/L.
• Hepatic function was classified as class A by Child-Pugh classification.
• Serum creatinine < 1 × ULN, or creatinine clearance rate(CCR) > 50ml/ min(calculated by Cockcroft-Gault formula).
• ECOG scored as 0-2.
• Life expectancy > 3 months.
• Informed consent.
• Willing and able to receive follow-up until death or trial is finished or trial is terminated.

Exclusion Criteria:

• RAS/BRAF mutation.
• Severe arterial embolism or ascites.
• Presence of hemorrhagic tendency or coagulation dysfunction.
• Presence of hypertensive crisis or hypertensive encephalopathy.
• Severe uncontrolled systemic complications, such as infection or diabetes.
• Severe clinical CVD(cardiovascular disease), such as cerebrovascular accident(within 6 months before recruitment), myocardial infarction(within 6 months before recruitment), uncontrolled hypertension; unstable angina pectoris; congestive heart-failure(NYHA 2-4 grade); arrhythmia that needs medication treatment.
• Previous diagnosed or physical examination showed presence of central nervous system(CNS) disease(i.e. primary brain tumor, epilepsy uncontrolled by standard treatment, any history of brain metastases or stroke).
• Previous history of other malignancy within 5 years(except basal cell carcinoma after radical resection and/or cervical carcinoma in situ).
• Received any medication under research within 28 days before the trial.
• Any residual toxicity of previous chemotherapy(except hair loss), i.e. peripheral neuropathy ≥ NCI CTC v3.0 Grade 2, will be excluded from oxaliplatin-based chemotherapy regimen research pair.
• Allergic to any medication involved in the trial.
• Pregnant and lactating women.
• Patient who does not use or refuses to take any appropriate contraceptive measures (intrauterine contraceptive ring, barrier contraception combined with spermicidal gel or sterilization operation), including women of childbearing age (within 2 years after the last menstrual period) and men who are with possible fertility.
• Unable or unwilling to comply with the research plan.
• The existence of any other disease, dysfunction caused by metastatic lesions, or suspicious disease found on the regular examination, which indicating contraindications to the use of study drugs or may bring high risks of treatment related complications