Inclusion Criteria:
1. Colorectal adenocarcinoma confirmed histologically or histopathologically.
2. Patients were clinically diagnosed with metastatic colorectal cancer based on computed tomography (CT) scan and magnetic resonance imaging (MRI) according to AJCC 8th edition.
3. Patients have received oxaliplatin-based first-line chemotherapy with or without targeted therapy, immunotherapy or radiotherapy.
4. Age ≥18 and ≤70.
5. ECOG physical status score is 0 or 1, and no obvious deterioration within 2 weeks prior to use on Day 1 of Cycle 1.
6. Appropriate organ function according to the following laboratory test values:
1. Hemoglobin value ≥90g/L.
2. White blood cell count ≥3.5\*109/L.
3. Absolute neutrophil count ≥1.5\*109/L.
4. Platelet count ≥100\*109/L.
5. Serum creatinine ≤ upper limit of normal (ULN) or creatinine clearance ≥60ml/min.
6. Total serum bilirubin ≤1.5\* upper normal limit (ULN).
7. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤2.5\* upper limit of normal value (ULN).
7. Signed the informed consent.
Exclusion Criteria:
1. The pathological types were squamous carcinoma, neuroendocrine carcinoma, adenosquamous carcinoma, and other histological types except adenocarcinoma.
2. Patients who had shown hypersensitivity to Irinotecan and Trifluridine/tipiracil (TAS-102) or any other component of them. Patients who previously received irinotecan while disease progressed. However, patients who previously received irinotecan while progressing during maintenance therapy are eligible.
3. Known hypersensitivity to Bevacizumab or hypersensitivity to any other component of Bevacizumab.
4. Patients unable to swallow or lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
5. Patients had recurrent episodes of bleeding (risk of gastrointestinal bleeding) or received transfusions in the previous 2 weeks.
6. Major surgery in the previous 4 weeks. (Biopsy is excluded)
7. Previous or concurrent cancer diagnosed within 5 years prior to study inclusion, except for curatively treated in situ cervical cancer, non-melanoma skin cancer, basal cell carcinoma, benign prostate cancer, ductal carcinoma in situ, well-differentiated thyroid cancers and superficial bladder tumors: staged Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor with lamina propria invasion). Carcinomas that can be cured by adequate treatment are also excluded.
8. History of abdominal fistula, gastro-intestinal perforation, intestinal obstruction, chronic diarrhea or inflammatory bowel disease including Crohns disease and ulcerative colitis within 6 months prior to the first study treatment.
9. Patients with severe cardiac dysfunction, such as LVEF\< 50%, CHF≥ grade 2, severe/unstable angina, history of stroke or transient ischemic attack or myocardial infarction in the previous 6 months.
10. Uncontrolled hypertension (systolic blood pressure \>160 mmHg or diastolic pressure \>100 mmHg despite treatment) and uncontrolled diabetes (fasting plasma glucose \> 8.9 mmol/l).
11. Patients with a history of ventricular tachycardia, torsades de pointes, prolonged QTc, complete left bundle branch block or third-degree atrioventricular conduction block.
12. Patients with active hepatitis B, hepatitis C, syphilis or human immunodeficiency virus infection.
13. Arterial or venous thrombotic or embolic events such as deep vein thrombosis, and pulmonary embolism within 3 months of starting study treatment (catheter-related thrombosis is excluded).
14. Patients with active pulmonary tuberculosis were taking anti-tuberculosis treatment or have taken anti-tuberculosis treatment within 12 months of starting study treatment.
15. Patients with severe primary respiratory diseases, interstitial lung disease, or history of pneumonitis.
16. Patients with current active infections requiring anti-infection treatment within 2 weeks of starting study treatment.
17. Patients with a history of psychiatric drug abuse or a history of drug abuse.
18. Pregnant or lactating women.
19. Patients of childbearing potential are unwilling to practice contraception.
20. Patients with any clinically significant disease, metabolic disorders or laboratory abnormality. Investigator could reasonably consider those patients not suitable for the study, affecting the results analysis or putting those patients at high risk.
