Phase II Trial of Fruquintinib With Sintilimab in Treating Selected Refractory Metastatic Colorectal Cancer Patients

Inclusion Criteria: 1. Fully understand the study and signed the Informed Consent Form (ICF) out of their own will; 2. Histologically or cytologically diagnosed with metastasis colorectal adenocarcinoma CRC (Phase IV) 3. MSS or MSI-low, MSI was assessed per local guidelines (immunohistochemistry and/or polymerase chain reaction \[PCR\]) prior to screening. Tumor samples with instability in 0 or 1 marker were identified as microsatellite-stable and MSI-low, respectively. 4. TMB≥5 mutations/Mb, TMB was performed on plasma samples by NGS. 5. Subjects who failed at least second line standard chemotherapies including Fluorouracil, Oxaliplatin, Irinotecan and VEGF inhibitors(e.g., bevacizumab). Pre-treatment with anti-EGFR(e.g., cetuximab) were mandatory if RAS wild and left side. Failed therapies are defined as the occurance of PD or intolerable toxicities during the treatment or within 3 months after the last dose. 6. Subject must not receive any systematically anti-tumor therapies during the last 4 weeks, and never receive any vascular endothelial growth factor (VEGFR) inhibitor or Immune checkpoint blockade. 7. 18-75 years of age (inclusive) 8. Body weight≥40Kg 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 10. Patients capable of taking oral medication 11. Patients with evaluable or measurable lesions as per RECIST version 1.1 12. Expected survival \>12 weeks Exclusion Criteria: 1. with MSI-H colorectal adenocarcinoma as defined per local assessment using standard of care testing 2. Previous treatment with Fruquintinib or immune checkpoint inhibitors 3. Absolute neutrophil count (ANC)\<1.5×109/L, or blood platelet count (PLT)\<100×109/L, or hemoglobin\<90g/L; blood transfusion within 1 week before enrollment for the purpose of enrollment is not allowed; 4. Serum total bilirubin\>1.5×Upper Limit of Normal (ULN);Alanine transaminase(ALT) and/or Aspartate transferase (AST)\>2.5×ULN (subject to the normal value at each site); or ALT and/or AST \> 5×ULN for patients with liver metastases; 5. Creatinineclearancerate\< 50mL/min; 6. Uncontrolled hypertension by monotherapy, i.e. systolic blood pressure \>140mmHg or diastolic blood pressure \>90mmHg after monotherapy treatment. 7. Clinical significant electrolyte abnormality; 8. Results of urine protein detection with 2+ or above, or urinary protein quantity ≥1.0g/24h; 9. Unrecovered toxicity fromprevious anticancer therapies(NCI CTC AE\>Grade 1, except for alopecia and ≤Grade 2 neurotoxicity caused by Oxaliplatin), not fully recovered from previous surgeries; or the time from the last anticancer therapy or surgery is less than 4 weeks; 10. Central Nervous System (CNS) metastatic disease or prior cerebral metastasis; 11. Subjects with presence of clinically detectable second primary malignant tumors at enrollment, or other malignant tumors within the last 5 years (excluding adequately treated skin basal cell carcinoma or carcinoma in situ of cervix). 12. Clinically uncontrolled active infection, such as acute pneumonia, active hepatitis B or hepatitis C(previous medical history of hepatitis B virus infection regardless of drug control, HBV DNA≥104×copynumberor ≥2000IU/mL); 13. Difficulty in swallowing or known drug malabsorption; 14. Duodenal ulcer, ulcerative colitis, intestinal obstruction, other gastrointestinal diseases or other conditions that may lead to gastrointestinal bleeding or perforation according to the investigator's judgment; or with a history of intestinal perforation or intestinal fistula, which were not fully recovered after surgery; 15. History of artery thrombosis or deep venous thrombosis within 6 months before enrollment, or have evidence or a history of bleeding tendency within 2 months before the enrollment, regardless of severity; 16. Occurrence of stroke or transient ischemic attack within 12 months before the enrollment; 17. Activated Partial Thromboplastin Time (APTT) and/or prothrombin time (PT) \> 1.5×ULN (subject to the normal range at each site); 18. Skin wounds, surgical site, trauma site, severe mucosal ulcers or fracture not completely healed; 19. Acute myocardial infarction, severe/unstable angina or received coronary artery bypass surgery within 6 months prior to enrollment; or patients with cardiac insufficiency of NYHA Grade 2 or above; 20. Pregnant or lactating women Or female subjects with childbearing potentials with positive pregnancy test result before the first time of study drug treatment; 21. Any clinical or laboratory abnormalities or compliance concerns unfit to participate in this clinical trial according to the investigator's judgment; 22. Serious psychological or psychiatric disorders; 23. Contraindications of immune checkpoint inhibitors 24. Participated in any other drug clinical trial during the last 4 weeks.