| Eligibility |
Inclusion Criteria:
1. Histologically confirmed initially unresectable MSS/pMMR-type RAS-mutant metastatic
colorectal adenocarcinoma;
2. ECOG score of 0 or 1;
3. Ability to swallow oral medications;
4. Have at least one measurable lesion (according to RECIST v1.1 standard);
5. No anti-tumor treatment has been received after recurrence and metastasis;
6. Neoadjuvant or adjuvant chemotherapy containing fluorouracil drugs is allowed before
or after radical resection of colorectal cancer, but the treatment needs to be
completed for = 6 months; if oxaliplatin is used in neoadjuvant or adjuvant
chemotherapy, it includes The oxaliplatin regimen needs to be completed for =12
months;
7. Adequate organ function: On the premise of no component blood transfusion within 14
days: white blood cells = 3.5*10^9/L and neutrophils = 1.5*10^9/L, hemoglobin = 90g/L,
platelets = 100* 10^9/L; serum bilirubin = 1.5 times the normal value, alanine
aminotransferase (ALT) = 2.5 times the normal value, aspartate aminotransferase (AST)
= 2.5 times the normal value; Urinary protein <2+. Or urine protein 2+ but 24-hour
urine protein quantity = 1 g; serum creatinine = 1.5 times of normal value, creatinine
clearance rate = 60ml/min; Doppler ultrasound evaluation: left ventricular ejection
fraction (LVEF) = lower limit of normal value (50%);
8. Expected survival period = 3 months;
9. Patients fully understand this research, voluntarily participate in this clinical
trial and sign an informed consent;
10. Women with reproductive potential (< 2 years after the last menstrual period) and men
use effective contraceptive methods until half a year after the last treatment.
Exclusion Criteria:
1. Previously received bevacizumab or anti-CTLA4, anti-PD-1/PD-L1 therapeutic antibodies
or pathway-targeted drugs;
2. Received radiotherapy within 4 weeks before the evaluation;
3. Symptomatic peripheral neuropathy > grade 2 (CTCAE5.0 standard);
4. Received live vaccine or systemic immune stimulant (including but not limited to
interferon or interleukin 2) within 1 month;
5. HIV-positive and other immunodeficiency diseases;
6. Active hepatitis B or hepatitis C (except for those who have been infected or cured
before, that is, HBsAg negative and hepatitis B core antigen anti-HBc antibody
positive; except for hepatitis C patients whose HCV RNA is negative by PCR);
7. Existing autoimmune diseases or other diseases that require immunosuppressant
treatment, except for type 1 diabetes; except for hypothyroidism that only requires
hormone replacement therapy; skin diseases that do not require systemic treatment
(such as vitiligo, psoriasis, alopecia areata); inhaled or topical steroids or
equivalent steroids in excess of 10 mg prednisone per day, except for inactive
autoimmune disease on adrenal replacement therapy;
8. Received systemic hormone therapy or treatment with a daily dose of more than 10 mg
prednisone equivalent dose or other forms of immunosuppressive treatment within 7
days, but inhaled or topical steroids or daily application of more than 10 mg
prednisone, etc. Except for inactive autoimmune diseases treated with adrenal
replacement therapy with potent steroids;
9. Have a history of organ transplantation;
10. Uncontrolled central nervous system (CNC) metastasis (symptomatic or metastatic sites
are midbrain, pons, medulla or spinal cord) or other central nervous system diseases;
11. Those who have undergone major surgery, open biopsy or obvious traumatic trauma within
1 month, or who may need major surgery during the study period; those who have
undergone open biopsy or obvious traumatic trauma, or may need major surgery during
the study period;
12. Combined with other malignant tumors other than intestinal cancer (except cured basal
cell carcinoma or squamous cell carcinoma of the skin and carcinoma in situ of the
cervix; the treatment of other malignant tumors has been completed for more than 1
year, and there is no clinical and imaging evidence of recurrence or progression
except);
13. Combined active and refractory infection;
14. Cardiovascular diseases with clinical significance, such as cardiovascular accident
(CVA) (= 6 months before treatment), myocardial infarction (= 6 months before
treatment), unstable angina, chronic heart failure of NYHA = 2 (CHF), uncontrolled
arrhythmia; uncontrolled hypertension; thromboembolic or bleeding events within 6
months before treatment;
15. Evidence of causing coagulation disease;
16. With dysphagia, active peptic ulcer, complete or incomplete intestinal obstruction,
active gastrointestinal bleeding, perforation, malabsorption syndrome or
uncontrollable gastrointestinal inflammatory disease (such as Crohn's disease or
ulcerative colon inflammation);
17. Severe unhealed wounds/ulcers or severe fractures;
18. Any serious acute or chronic medical condition that may affect the patient's
participation in the study or interfere with the interpretation of the study results;
19. There are mental illnesses, serious social and psychological illnesses, or researchers
believe that there are factors that may affect research compliance;
20. Pregnant or lactating women;
21. No therapeutic anticoagulant or antiplatelet drugs or NSAIDs (aspirin = 325 mg/day
allowed);
22. Severe allergic reaction to the test drug;
23. Reluctance to use alternative therapies such as (but not limited to) bisphosphonates
if receiving RANKL inhibitors (eg, denosumab).
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