Bevacizumab, Sintilimab, Cetuximab and Irinotecan in Refractory RAS Wild-type Metastatic Colorectal Cancer: BOND-4 Trial

Primary endpoint: objective response rate Secondary endpoints: PFS, OS and adverse events

Inclusion Criteria: * Metastatic and unresectable colorectal adenocarcinom; * RAS wild-type and MSS tumor; * Measurable lesions; * Failed to at least two lines of standard treatment containing fluoropyrimidine, irinotecan and bevacizumab; * Eastern Cooperative Oncology Group performance status 2 or less; * White blood cell≥ 3\*10\^9/L, neutrophil≥ 1.5\*10\^9/Lplatelet count≥75\*10\^9/L, hemoglobin≥60g/L; * Total serum bilirubin≤upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5\*ULN or ≤5\*ULN for subjects with liver metastasis; * Creatinine ≤ ULN or creatinine clearance ≥ 80 mL/min; * Urinary protein negative or 24-hour urinary protein ≤ 2g; * Activated partial thromboplastin time≤ULN and international normalized ratio≤1.5; * Any major surgery ≥ 4 weeks and any minor surgery ≥ 1 week and fully recovered from the procedure; * Life expectancy \> 3 months; * Provide fully informed written consent; Exclusion Criteria: * Other aggressive malignancies within 3 years (Exceptions: non-melanoma skin cancer or carcinoma-in-situ of the cervix that has been treated); * Allergy or intolerance to any of the study drugs; * Human immunodeficiency virus positive; * Concurrent anti-cancer therapy including radiation therapy, chemotherapy, targeted agents or biological agents not otherwise specified within two weeks; * Malignant bowel obstruction; * Prior treatment with PD-1 antibody; * Autoimmune diseases; * Significant bleeding events or pre-existing bleeding diathesis within 6 months (unless the source of bleeding has been resected); * Gastrointestinal perforation within 12 months; * Serious or non-healing wound, ulcer, or bone fracture; * Blood pressure \>= 160/90 mmHg after active anti-hypertensive therapy; * Arterial or venous thrombotic or embolic events within 6 months (including but not limited to transient ischemic attack, cerebrovascular accident, unstable angina or myocardial infarction); * Uncontrolled illness including active infection, symptomatic congestive heart failure, cardiac arrhythmia, respiratory failure, symptomatic pulmonary fibrosis, interstitial pneumonitis or psychiatric illness that may interfere with the conduct of the study; * Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis; * Any of the following: pregnant, nursing, childbearing potential but unwilling to employ contraception.