The goal of this multicenter, single-arm, observational cohort study is to investigate the efficacy and safety of irinotecan in combination with trifluridine-tipiracil and bevacizumab in colorectal cancer with prior oxaliplatin and fluoropyrimidine-based chemotherapy (including 5-FU/capecitabine/S-1) exposure in the metastatic setting or within 12 months of recurrence.

Inclusion Criteria:

1. All subjects are required to sign an informed consent form before starting the study-related procedure
2. Age 18-75 years old, male or female.
3. have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, life expectancy >3 months.
4. Histologically or cytological proven metastatic or recurrent adenocarcinoma of the colon or rectum.
5. Prior treatment with a fluoropyrimidine (5-fluorouracil [5-FU] or capecitabine) and oxaliplatin with bevacizumab or cetuximab targeted therapy as the first-line regimen.
6. Recurrence or metastasis within 12 months after completion of adjuvant/neoadjuvant therapy with oxaliplatin and fluoropyrimidine-based drugs is also considered as the failure of first-line chemotherapy.
7. At least one measurable metastatic lesion, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
8. Adequate organ function: bone marrow, kidney, liver function (within 7 days before treatment start) Absolute neutrophil count ≥ 1.5×109/L Platelet count ≥ 100×109/L Hemoglobin≥ 90g/L (no history of blood transfusion within 7 days); Creatinine clearance≥ 60 ml/min (Cockcroft-Gault formula) Bilirubin ≤ 1.5 x the upper limit of normal (ULN) Glutamate aminotransferase (AST)/ alanine aminotransferase (ALT) levels ≤2.5 x ULN or =< 5 x ULN if with hepatic metastases; Alkaline phosphatase (AKP) ≤ 2.5 x ULN or =< 5 x ULN if with hepatic metastases;
9. Urine protein <1+ or 24-hour urine protein <1 gram;
10. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN or within the range if receiving anticoagulant therapy;
11. Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence; IUDs, etc) during the study period and within 90 days of the last study medication. All female patients will be considered fertile unless they have spontaneous menopause, artificial menopause, or sterilization (e.g., hysterectomy, bilateral adnexectomy, or radiation ovarian irradiation).

Exclusion Criteria:

1. First-line treatment with irinotecan;
2. Patients with KRAS/NRAS/BRAF wild-type and not treated with cetuximab in the first line.
3. Patients with dMMR/MSI-H (deficient mismatch repair/microsatellite instability-high) status;
4. Symptomatic brain or meningeal metastases (except for brain metastases that have undergone local radiotherapy or surgery for more than 6 months and stable disease control)
5. Previous or current severe bleeding (bleeding >30ml within 3 months), coughing up blood (>5ml of fresh blood within 4 weeks) or cerebrovascular accident (excluding lacunar cerebral infarction, minor cerebral ischemia or transient ischemic attack, etc.) within half a year before the first use of the study drug, myocardial infarction, unstable angina, poorly controlled arrhythmias (including QTc interval ≥450 ms for men and 470 ms for women≥) (QTc interval is calculated by Fridericia formula). According to the New York College of Cardiology (NYHA) standard class III or IV cardiac insufficiency or cardiac ultrasound: left ventricular ejection fraction (LVEF) < 50%.
6. Uncontrolled hypertension: systolic blood pressure >140mmHg, diastolic blood pressure > >90mmHg;
7. Digestive tract diseases or states that the investigator determines may affect drug absorption, including but not limited to active gastric and duodenal ulcers, ulcerative colitis and other digestive tract diseases or active bleeding in unresected gastrointestinal tumors, or other conditions that the investigator determines may cause gastrointestinal bleeding or perforation or obstruction;
8. History of second primary malignancy within 5 years prior to enrollment, excluding basal cell skin carcinoma or in-situ cervical carcinoma after radical resection;
9. Have known active infection, including but not limited to human immunodeficiency virus (HIV) infection, a history of liver disease known to be significant, including but not limited to hepatitis B virus (HBV) infection and HBV DNA positive (≥1×104/ml); hepatitis C virus infection (HCV) with positive HCV RNA (≥1×103/ml), or cirrhosis, etc.
10. Unresolved toxicities from prior therapy of > grade 1, excluding alopecia; Any other disorders, metabolic abnormality, physical examination abnormality, or laboratory abnormality which has reason to suspect that the patient not suitable for the study or will affect the interpretation of the results. Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug.