Inclusion Criteria:
1. Recurrent/metastatic colorectal adenocarcinoma confirmed by histopathological pathology report;
2. The patient received oxaliplatin in combination with fluorouracil as the first-line systemic therapy (with or without anti-EGFR mab or VEGF mab) and failed. Fluorouracil (5-FU, capecitabine, or S-1) and oxaliplatin must be included in the first-line regimens. Treatment failure was defined as: disease progression or intolerable toxicity occurred during treatment or within 3 months after the last treatment; Note: Early adjuvant/neoadjuvant therapy is permitted. If recurrence or metastasis occurs during adjuvant/neoadjuvant therapy or within 6 months after completion, adjuvant/neoadjuvant therapy is considered a failure of first-line chemotherapy for advanced disease;
3. With one or more measurable lesions, the longest diameter measured by spiral CT scan should be at least 10 mm, and the longest diameter measured by conventional CT scan should be at least 20 mm (RECIST standard, version 1.1);
4. the type of KRAS, NRAS, BRAF, and MSI were known, requiring wild type of BRAF. Cohort A required patients with MSS/pMMR status.
5. ECOG score was 0-1;
6. Life expectancy ≥12 weeks;
7. The patient has recovered from damage caused by other anti-tumor therapy, received cytotoxic drugs, radiotherapy or surgery for ≥4 weeks, and the wound has completely healed;
8. Bone marrow capacity and liver and kidney function were sufficiently reserved within 7 days before screening: absolute neutrophil (ANC) count ≥1.5x109 /L; Hemoglobin ≥ 8.0g/ dL; Platelet count ≥80 x109 /L; Total bilirubin \< 1.5 times upper normal limit (ULN); ALT and AST\< 2.5x ULN (with liver metastasis \<5x ULN); Serum creatinine ≤1 x ULN, the clearance rate of endogenous creatinine \>50ml/min;
9. Women of childbearing age should take effective contraceptive measures;
10. Subjects voluntarily joined the study and signed informed consent with good compliance and follow-up.
Exclusion Criteria:
1. A history of other malignant tumors within 5 years, except cured cervical carcinoma in situ or basal cell carcinoma of the skin;
2. Patients with hypertension that could not be controlled by antihypertensive medication (systolic blood pressure \>140mmHg, diastolic blood pressure \>90mmHg), coronary heart disease of grade I or above, arrhythmia of grade I or above (including prolonged QTc interval \> 450ms in males and \> 470 ms in females) and cardiac dysfunction of grade I or above;
3. Symptomatic brain or meningeal metastases (unless the patient was treated for \>6 months, imaging results were negative within 4 weeks prior to study entry, and tumor-related clinical symptoms were stable at study entry); with a history of uncontrolled epileptic seizures, central nervous system dysfunction, or mental disorders;
4. Uncontrolled pleural or abdominal effusion;
5. Undergoing kidney dialysis;
6. severe or uncontrolled infection;
7. pregnant or lactating women who are fertile but have not taken adequate contraceptive measures;
8. Multiple factors affecting oral medication (inability to swallow, chronic diarrhea and intestinal obstruction);
9. Abnormal coagulation function (PT\>16s, APTT\>43s, TT\>21s, Fbg\< 2G /L), bleeding tendency or receiving thrombolytic or anticoagulant treatment; patients with gastrointestinal bleeding risk should not be enrolled, including the following conditions :(1) active peptic ulcer lesions and fecal occult blood (++); (2) patients with history of black stools and hematemesis within 3 months;
10. Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy, or any other antibody or drug that specifically targets T-cell costimulation or immune checkpoint pathways.
11. Former treatment of irinotecan for 1 or more cycles;
12. Prior exposure to any anti-VEGFR small molecule inhibitors (e.g. Apatinib, regorafenib, Fruquintinib, Anlotinib, etc.)
13. Participated in clinical trials of other drugs within four weeks
14. Urine routine examination indicated urine protein \> 2+, or 24-hour urine protein quantification ≥1.0g/24h
15. Use of immunosuppressive agents within 4 weeks prior to the first dose of study therapy, excluding nasal, inhaled, or other topical or physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/ d of prednisone or equivalent doses of other glucocorticoids), or hormone use for the prevention of contrast agent allergy.
16. Residual liver volume is less than 50% of the total liver volume. -
