Inclusion Criteria:
1. Have fully understood the study and voluntarily signed the informed consent;
2. Age ≥18 years old, gender unlimited;
3. Advanced metastatic colorectal adenocarcinoma confirmed by histopathology;
4. The patient progressed or was intolerant after receiving at least previous standard therapy containing fluorouracil, oxaliplatin, and irinotecan.
* Each first-line treatment must include one or more chemotherapeutic agents for a duration of ≥1 cycle;
* Allow pre-adjuvant/neoadjuvant therapy. If recurrence or metastasis occurs during or within 6 months after completion of adjuvant/neoadjuvant therapy, adjuvant/neoadjuvant therapy is considered a failure of first-line chemotherapy for advanced disease;
* Prior chemotherapy combined with cetuximab or bevacizumab is permitted;
5. Have at least one measurable lesion (RECIST 1.1 standard);
6. Eastern Cooperative Oncology Group (ECOG) physical condition 0-1 score;
7. Expected survival ≥12 weeks;
8. The functions of vital organs during the first 14 days of enrollment meet the following requirements (the use of any blood components and cell growth factors during the first 14 days of enrollment is not allowed) :
* Absolute neutrophil count ≥1.5×109/L;
* Platelet ≥80×109/L;
* Hemoglobin ≥8g/dL;
* Total bilirubin \< 1.5 × upper limit of normal（ULN）;
* Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) \< 2.5 × ULN (\< 5 × ULN in patients with liver metastasis);
* Serum creatinine ≤1 × ULN;
* endogenous creatinine clearance \> 50ml/min;
9. Women of childbearing age or men whose partners wish to have children need to take effective contraceptive measures.
Exclusion Criteria:
1. Previous treatment with Fruquintinib or other anti-vascular endothelial growth factor receptor (VEGFR) inhibitors such as Apatinib, Regorafenib, and Anlotinib;
2. Previous treatment with Raltitrexed;
3. Participated in other drug clinical trials and received at least one drug therapy within four weeks prior to enrollment or received other systemic anti-tumor therapy, including chemotherapy, signal transduction inhibitors, hormone therapy, and immunotherapy within four weeks prior to enrollment;
4. The patient currently has a disease or condition that affects drug absorption, or the patient cannot take Fruquintinib orally;
5. The patient currently has gastrointestinal diseases such as gastric and duodenal active ulcers, ulcerative colitis, or active bleeding from unresectable tumors, or other conditions determined by researchers that may cause gastrointestinal bleeding or perforation;
6. Patients with active bleeding or bleeding tendency;
7. History of severe cardiovascular and cerebrovascular diseases:
* Cerebrovascular accident (excluding lacunar infarction, minor cerebral ischemia, or transient ischemic attack), myocardial infarction, unstable angina, and poorly controlled arrhythmias (including QTc interval ≥ 450ms for men and 470 ms for women) within 6 months prior to first administration of the study drug (QTc interval Fridericia) Formula calculation);
* New York Heart Association (NYHA) Heart Function Rating \> Grade II or left ventricular ejection fraction (LVEF) \< 50%;
8. Have had other malignancies within the past 5 years, except basal cell or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
9. Clinically uncontrolled active infections, such as acute pneumonia, active hepatitis B or C (hepatitis B virus infection regardless of drug control, hepatitis B virus DNA≥1×104 copies /mL or \> 2000 IU/ml);
10. There is known to be symptomatic central nervous system metastasis and/or cancerous meningitis. Participants with previously treated brain metastases may participate in the trial if their condition is stable (no evidence of radiographic progression at least 4 weeks prior to initial administration of the trial treatment), repeated radiographic studies confirm no evidence of new brain metastases or enlargement of the original brain metastases, and no steroid therapy is required at least 14 days prior to initial administration of the trial treatment. This exception does not include cancerous meningitis, which should be excluded regardless of whether it is clinically stable;
11. Women who are pregnant (positive pregnancy test before medication) or breastfeeding;
12. The patient currently has hypertension that cannot be controlled by drugs, which is prescribed as: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg after taking antihypertensive drugs;
13. Urine routine indicates urinary protein ≥2+, or 24-hour urinary protein volume \> 1.0g;
14. The patients considered by the investigators to be unsuitable for inclusion in this study.
