Based on the upstream signaling features of BRAFV600E and the bypass feedback mechanisms, considering the pro-apoptotic effects of chemotherapy and the synergistic effects of targeted therapy, previous IMPROVEMENT trial creatively explored a balanced chemotherapy-targeted combination approach (FOLFIRI + Vemurafenib + Cetuximab) in advanced colorectal cancer patients with BRAF V600E mutaiton using a signle-arm study design, demonstrating significant therapeutic efficacy in these patietns . To further validate the effectiveness and safety of this regimen and to solidify its clinical value, it is crucial to conduct a randomized, controlled trial. Investigators plan to use the current standard regimen as a control to compare this strategy (FOLFIRI + Vemurafenib + Cetuximab) on a large cohort of patients with BRAFV600E-mutant advanced colorectal cancer in the first-line setting, focusing on its efficacy and safety.

Inclusion Criteria:

• Patients with advanced colorectal adenocarcinoma confirmed by histology or cytology.
• Patients with BRAFV600E mutation confirmed by tissue or blood testing.
• Patients who have not received systemic therapy or who have experienced metastasis or recurrence 12 months after completing adjuvant therapy.
• Patients must have at least one measurable lesion according to RECIST 1.1 criteria.
• Patients who received local radiotherapy at least 3 weeks before the first drug treatment are allowed to enroll, but lesions evaluated by RECIST should not be within the radiation field.
• Patients aged ≥18 years and ≤80 years.
• ECOG performance status of 0-2.
• Expected survival of ≥12 weeks.
• Patients must have the ability to understand and voluntarily sign a written informed consent.
• Women of childbearing potential must have a negative pregnancy test within 7 days prior to the start of treatment. During the study, both the patient and their partner must use contraception.

Exclusion Criteria:

• Patients who have undergone major surgery or suffered severe trauma within 4 weeks prior to the first dose of the study drug.
• Patients with hypersensitivity to any component of the study regimen.
• Patients who are planning to conceive or are already pregnant.
• Patients with brain metastases who cannot accurately describe their condition.
• Patients with the following conditions within 6 months prior to the start of the study treatment: myocardial infarction, severe/unstable angina, congestive heart failure greater than NYHA Class 2, uncontrolled arrhythmias, etc.
• Abnormal laboratory test results:
• Absolute neutrophil count (ANC) <1,500/mm³;
• Platelet count <75,000/mm³;
• Total bilirubin >1.5 times the upper limit of normal (ULN); ALT (alanine aminotransferase) and AST (aspartate aminotransferase) >2.5 times ULN (for patients with liver metastasis >5 times ULN); Creatinine >1.5 times ULN;
• Patients who have had any cancer other than advanced colorectal cancer within five years prior to the start of the study treatment. Exceptions include cervical carcinoma in situ, cured basal cell carcinoma, and bladder epithelial tumors.
• Patients with a history of drug abuse, substance abuse, or alcohol dependence.
• Patients who are legally incapacitated or have limited civil capacity.
• Any other conditions deemed unsuitable for enrollment by the investigator.