Fruquintinib Plus Checkpoint Inhibitor Combined or Sequential TAS-102 in Colorectal Cancer Patients Who Progressed on Second-line Standard Therapy: a Prospective, Multi-cohort, Single-centered, Phase Ib/II Study

Inclusion Criteria:

* Fully informed about this study and voluntarily signed the informed consent form;
* Age 18-75 years (inclusive);
* Histologically confirmed unresectable metastatic colorectal cancer;
* Confirmed pMMR (proficient mismatch repair) status without protein loss, as determined by:PCR testing showing microsatellite stable (MSS) or low microsatellite instability (MSI-L), OR Immunohistochemistry (IHC) demonstrating intact DNA mismatch repair (MMR) protein expression (including MLH1, MSH2, MSH6, and PMS2);
* Failed or intolerant to two prior lines of standard systemic therapy for metastatic colorectal cancer;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
* Body Mass Index (BMI) ≥18 kg/m²;
* Life expectancy ≥3 months;
* Adequate organ function as defined below (no blood components or growth factors allowed within 14 days prior to enrollment):
* Hematologic Function:

Absolute neutrophil count (ANC) ≥1.5×10⁹/L; White blood cell count (WBC) ≥4.0×10⁹/L; Platelet count ≥100×10⁹/L; Hemoglobin ≥90 g/L; -Hepatic Function: Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5×ULN;

-Renal Function: Blood urea nitrogen (BUN) and creatinine (Cr) ≤1.5×ULN; Creatinine clearance (CCr) ≥50 mL/min;

-Cardiac Function: Left ventricular ejection fraction (LVEF) ≥50%; QT interval corrected by Fridericia's formula (QTcF) \<470 ms;

-Coagulation Function: International normalized ratio (INR) ≤1.5×ULN; Activated partial thromboplastin time (APTT) ≤1.5×ULN;

* Women of childbearing potential must use effective contraception;
* Good compliance and willing to cooperate with follow-up visits.

Exclusion Criteria:

* Unable to comply with the study protocol or study procedures;
* Prior treatment with TAS-102 (trifluridine/tipiracil);
* Prior treatment with VEGFR inhibitors;
* Prior treatment with immune checkpoint inhibitors;
* Concurrent use of any other investigational drugs, or participation in another clinical trial with investigational drug treatment within 4 weeks prior to enrollment;
* Vaccination with inactivated vaccines within 4 weeks prior to enrollment or planned vaccination during the study period;
* Major surgery, severe traumatic injury, fracture, or ulcer within 4 weeks prior to enrollment;
* Blood transfusion, blood products, or hematopoietic factors (such as albumin, granulocyte colony-stimulating factor \[G-CSF\], etc.) within 28 days prior to enrollment;
* Alcohol or drug abuse within 4 weeks prior to enrollment;
* Any factors affecting oral drug administration;
* Concurrent presence of any of the following conditions:
* Uncontrolled hypertension, coronary artery disease, arrhythmia, or heart failure;
* Uncontrolled severe concurrent infection resulting in disability;
* Proteinuria ≥2+ (1.0 g/24 h);
* Evidence or history of bleeding tendency within 2 months prior to enrollment, regardless of severity;
* Arterial/venous thromboembolic events within 12 months prior to first treatment, such as cerebrovascular accident (including transient ischemic attack), etc.;
* Acute myocardial infarction, acute coronary syndrome, or coronary artery bypass grafting (CABG) within 6 months prior to first treatment;
* Fracture or long-term unhealed wounds;
* Coagulation dysfunction, bleeding tendency, or currently receiving anticoagulant therapy;
* Evidence of central nervous system (CNS) metastasis, or accompanied by severe malignant pleural effusion or ascites;
* Other malignancies within 5 years prior to enrollment, except for basal cell or squamous cell carcinoma of the skin after curative surgery, or carcinoma in situ of the cervix;
* Active autoimmune disease or history of autoimmune disease within 4 weeks prior to enrollment;
* Prior allogeneic bone marrow transplantation or organ transplantation;
* Known hypersensitivity to study drugs or any of their excipients;
* Unresolved toxicities greater than CTCAE v5.0 Grade 1 from prior anti-cancer therapy, excluding alopecia, lymphopenia, and oxaliplatin-induced neurotoxicity ≤Grade 2;
* Any other disease, clinically significant metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, provides reasonable suspicion that the patient has a condition unsuitable for the use of the study drug (e.g., epileptic seizures requiring treatment), or that would affect the interpretation of study results, or would place the patient at high risk;
* Pregnant or breastfeeding women;
* Any patient deemed unsuitable for enrollment in this study by the investigator.