A Prospective, Single Arm, Open Label, Phase II Clinical Study on the Efficacy and Safety of Ivonescimab (AK112) Combined With TAS-102 in the Treatment of Refractory MSS/pMMR Advanced Colorectal Cancer

Inclusion Criteria:

1. Age: 18 years old and above but 75 years old and below, regardless of gender;

2. Previously received at least two standard chemotherapy regimens for advancedcolorectal cancer and demonstrated disease progression or intolerance to the lastregimen. Patients who have received adjuvant/neoadjuvant chemotherapy and experiencerecurrence during or within 6 months after completion of adjuvant/neoadjuvantchemotherapy can be considered as a chemotherapy regimen for advanced disease;

3. There are sufficient tissue specimens that have been tested as pMMR (immunohistochemistry) or MSS (PCR or NGS)

4. Have at least one measurable lesion (RECIST v1.1);

5. ECOG PS score is 0 or 1;

6. Expected survival exceeds 3 months;

7. The main organ functions are normal, which meets the following criteria: Absolute neutrophil count ≥ 1.5 x 10 ^ 9/L Hemoglobin ≥ 9 g/dL Platelet count ≥ 100x 10 ^ 9/L Creatinine clearance rate ≥ 50 mL/min, evaluated using theCockcroft&Gault formula Serum total bilirubin<1.5 x upper limit of normal (ULN)Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤ 2.5 x ULN (unless liver metastasis leads to abnormal liver function, aspartateaminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 5 x ULN)All patients have normal coagulation function. For patients receiving anticoagulanttherapy (excluding platelet anticoagulants), it should be confirmed that the INR hasreached a sufficient therapeutic level.

8. The subjects voluntarily joined this study and signed informed consent forms,demonstrating good compliance and cooperation with follow-up;

9. Women with fertility: must agree to use reliable methods of contraception for atleast 180 days from the signing of the informed consent form until the lastadministration of the study drug. And the serum HCG test must be negative within 7days before starting the study treatment; And it must be non lactating. If a femalepatient has already menstruated, has not yet reached postmenopausal status (continuous absence of menstruation for ≥ 12 months, no other reasons found besidesmenopause), and has not undergone sterilization surgery (such as hysterectomy,bilateral tubal ligation, or bilateral oophorectomy), it is considered that thepatient has fertility;

10. For male patients whose partners are women with fertility, they must agree to usereliable methods of contraception for at least 180 days from the signing of theinformed consent form until the last administration of the study drug. Male patientsmust also agree not to donate sperm during the same time period.

Exclusion Criteria:

1. Previously received TAS-102 treatment.

2. Previously received immunotherapy, including immune checkpoint inhibitors (such asanti-PD-1/L1 antibodies, anti-CTLA-4 antibodies, anti-CD47 antibodies, anti-SIRP αantibodies, anti-LAG-3 antibodies, etc.), immune checkpoint agonists (such as ICOS,CD40, CD137, GITR, OX40 antibodies, etc.), immunotherapy, and any other treatmenttargeting the immune mechanism of tumor.

3. Severe wounds that do not heal, ulcers that do not heal, or fractures that do notheal.

4. Known coagulation disorders and bleeding disorders that increase the risk ofbleeding.

5. Researchers believe that patients are unlikely to comply with oral medicationtreatment plans or study requirements for scheduled evaluations.

6. Pregnant, lactating women or those who may become pregnant during the study period.

7. Symptomatic central nervous system metastasis with unstable nervous system or theneed to increase steroid dosage to control central nervous system diseases.

8. Suffering from severe or uncontrolled active acute or chronic infections.

9. Suffering from interstitial lung disease and/or pneumonia, or pulmonary arterialhypertension.

Researchers believe that uncontrolled arterial hypertension or uncontrolled or symptomatic arrhythmia.

11. Study whether there have been deep arterial thromboembolic events, includingcerebrovascular accidents or myocardial infarction, within 6 months prior to thestart of the first treatment. Study the occurrence of deep vein thromboembolismevents within 4 weeks prior to the first treatment.

12. Severe/unstable angina, symptomatic congestive heart failure, New York HeartAssociation (NYHA) class III or IV.

13. Other malignant tumors, including those that have received curative treatment andhave a remission period of less than 5 years during screening. Patients withcervical carcinoma in situ and basal cell carcinoma who can be cured withappropriate treatment are exempt from this minimum required remission period.

Receive systemic immunosuppressive therapy (excluding prophylactic or long-term low-dose steroids [≤ 20 mg/day prednisone equivalent]).