Cadonilimab (AK104) Combined With Chemotherapy and Bevacizumab as First-line Treatment for RAS Mutated or Right Sided-metastatic MSS Colorectal Cancer

Inclusion Criteria:

1. Able to understand and voluntarily sign a written informed consent form, which mustbe signed before the designated research procedures required for the study arecarried out.

2. Age at the time of signing the Informed Consent Form (ICF) is ≥ 18 years old and ≤ 75 years old, both male and female.

3. The Eastern Cancer Collaborative Organization (ECOG) has a physical fitness score of 0 or 1.

4. The expected survival period is ≥ 3 months.

5. Recurrent or incurable metastatic colorectal adenocarcinoma confirmed byHistopathology.(UICC/AJCC colorectal TNM stage System (8th edition 2017))

6. Genetic testing revealed RAS (including KRAS and NRAS) mutations, or primary siteslocated in the right half of the colon (including cecum, rising Colon and proximal 2/3 transverse colon).

7. Did not receive systemic treatment for recurrent or metastatic disease.

8. According to the RECIST v1.1 standard, there is at least one measurable tumorlesion. Agree to provide archived or freshly obtained tumor tissue samples (formalinfixed paraffin embedded [FFPE] tissue wax blocks or at least 5 unstained tumortissue slice samples) to confirm PD-L1 expression.

9. The time interval between the end of adjuvant therapy was >12 months.

10. Having good organ function:

11. Blood routine examination (no blood components or cell growth factors were usedto support treatment within the first 7 days of randomization):

• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;
• Platelet count ≥ 100 × 10^9/L;
• Hemoglobin ≥ 9.0g/dL.

2. Kidney:Creatinine<1.5 × ULN, or creatinine clearance rate * (CrCl) calculated value ≥ 50mL/min; *The Cockcroft Fault formula will be used to calculate CrCl: CrCL (mL/min)={(140 age) × Body weight (kg) × F} /(SCr (mg/dL) × 72) Among them: F=1for males and F=0.85 for females; SCr=serum creatinine. Urinary protein<2+or 24-hour urine protein quantification<1.0g.

3. Liver:Serum total bilirubin (TBiL) ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN (AST and ALT ≤ 5 for subjects with liver metastasis) × ULN, but not accompanied by elevatedbilirubin);

4. Coagulation function:International standardized ratio (INR) and activated partial thromboplastintime (APTT) ≤ 1.5 × ULN

5. Thyroid function: thyroid stimulating hormone (TSH) ≤ ULN; If abnormal, T3 andT4 levels should be investigated, and normal levels Can be selected

6. Female subjects with fertility must undergo a serum pregnancy test within 72 hoursbefore the first medication, and the result should be negative. If a female subjectwith fertility engages in sexual activity with an unsterilized male partner, thesubject must adopt an acceptable contraceptive method starting from screening andmust agree to continue using the contraceptive method for 120 days after the lastdose of the study drug; Periodic abstinence and safe period contraception areunacceptable contraceptive methods. Whether to stop contraception after this timepoint should be discussed with researchers.

7. Women with fertility refer to those who have not undergone surgicalsterilization (i.e. bilateral fallopian tube ligation, bilateral oophorectomy,or total hysterectomy) or those who have not undergone menopause (defined asthose who have ceased menstruation for at least 12 consecutive months withoutalternative medical reasons, and whose serum follicle stimulating hormonelevels are within the laboratory reference range of postmenopausal women);

8. An efficient contraceptive method refers to a contraceptive method with a lowfailure rate (such as less than 1% per year) under continuous and correct use.Not all contraceptive methods are efficient. In addition to barriercontraception, female subjects with fertility can also use hormonalcontraception (such as birth control pills), intrauterine device contraception,etc. to ensure that pregnancy does not occur.

Exclusion Criteria:

1. Previously received treatment with PD-1 monoclonal antibody, PD-L1 monoclonalantibody, or CTLA-4 monoclonal antibody.

2. The tumor tissue was found to be dMMR or MSI-H

3. Received palliative local treatment within the first 2 weeks of randomization;Received systemic non-specific immunomodulatory therapy (such as interleukin,interferon, thymosin, etc.) within the first 2 weeks of randomization; In the first 2 weeks of randomization, they received Chinese herbal medicine or traditionalChinese patent medicines and simple preparations with anti-tumor indications.

4. Currently participating in another clinical study, unless it is an observational,non-interventional clinical study, or a follow-up period of an intervention study.

5. Had or was currently present with other malignancies within the first 3 years ofrandomization. The following conditions can be included: cured uterus cervicalcarcinoma in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (cancer in situ) and T1 (tumor infiltrating basalmembrane)].

6. Have active or untreated brain metastases, meningeal metastases, spinal cordcompression, or leptomeningeal diseases. However, participants who meet thefollowing requirements and have measurable lesions outside the central nervoussystem are allowed to be enrolled: asymptomatic after treatment, imageologicallystable for at least 4 weeks before the start of study treatment (if there are no newor expanded brain metastases), and have stopped systemic glucocorticoid andanticonvulsant drug treatment for at least 2 weeks.

7. Have clinical symptoms of pleural effusion, pericardial effusion, or pleural/ascitesthat require frequent drainage (≥ once per month).

8. Active autoimmune diseases that require systematic treatment within the first 2years of randomization, or autoimmune diseases that the researcher determines mayrecur or plan treatment. Except for the following:

9. Skin diseases that do not require systematic treatment (such as vitiligo,alopecia, psoriasis, or eczema);

10. Hypothyroidism caused by autoimmune thyroiditis requires only stable doses ofhormone replacement therapy;

11. Type I diabetes requiring only a stable dose of insulin replacement therapy;

12. Childhood asthma has completely relieved, and no intervention is required inadulthood;

13. Researchers have determined that the disease will not recur without externaltriggering factors.

14. Any of the following cardiovascular or cerebrovascular diseases or risk factors:

15. Myocardial infarction, unstable angina, cerebrovascular accident, transientischemic attack, acute or persistent myocardial ischemia, symptomatic heartfailure (grade 2 or above according to the New York Heart Associationfunctional classification), symptomatic or poorly controlled arrhythmia, or anyarterial thromboembolism event occurred within the first 6 months ofrandomization.

16. A history of deep vein thrombosis, pulmonary embolism, or other severethromboembolism within the first 3 months of randomization.

17. Have major vascular diseases such as aortic aneurysm, aortic dissectionaneurysm, internal carotid artery stenosis that may endanger life or requiresurgery within 6 months.

18. Uncontrolled hypertension (systolic blood pressure ≥150mmHg or diastolic bloodpressure ≥100mmHg after standard antihypertensive therapy)

19. Previous history of myocarditis and cardiomyopathy.

20. Left ventricular ejection fraction (LVEF)<50%.

21. Toxicity that has not been alleviated by previous anti-tumor therapy is defined asfailure to regress to the National Cancer Institute Adverse Event GeneralTerminology Standard ((NCICTCAE v5.0) level 0 or 1, or the level specified in theinclusion/exclusion criteria, except for hair loss/pigmentation, ≥ Level 2peripheral nerve disease).

22. The presence of interstitial lung disease or non infectious pneumonia is known, andthe disease is currently symptomatic or requires systemic glucocorticoid treatmentin the past. Researchers have determined that it may affect the toxicity assessmentor management related to the study treatment.

23. Active pulmonary tuberculosis is known to exist. Subjects suspected of activepulmonary tuberculosis need to undergo chest X-ray examination, sputum examination,and elimination through clinical symptoms and signs.

24. Received systemic anti infective therapy (excluding antiviral therapy for hepatitisB or C) within the first 2 weeks of randomization.

25. Known history of allogeneic organ transplantation and allogeneic hematopoietic stemcell transplantation.

26. Imaging (CT or MRI) shows that the tumor has invaded the large blood vessels or isnot clearly delimited from the blood vessels.

27. Have clinical active diverticulitis, abdominal abscess, and gastrointestinalobstruction, unhealed wounds, ulcers, or fractures.

28. Clinically significant bleeding symptoms or bleeding tendencies within the firstmonth of randomization, such as gastrointestinal bleeding, active hemoptysis, orbleeding, clotting disease are taking warfarin, aspirin, or other antiplatelet drugs (except maintenance doses: aspirin ≤100mg/ day, clopidogrel ≤75mg/ day), orregardless of severity，Subjects with any signs of bleeding or medical history thatthe investigator has determined are not suitable for enrollment.

29. Received major surgical treatment, open biopsy, or significant traumatic injury (except needle biopsy or gastroenteroscopic tissue biopsy) within the first 28 daysof randomization.

30. Individuals with a known history of immune deficiency or HIV testing positive,Knownactive syphilis infection.

31. Subjects who require systemic treatment with glucocorticoids (>10mg/day prednisoneor equivalent dose) or other immunosuppressive drugs within the first 14 days ofrandomization. Except for the following:

32. If there is no active autoimmune disease, it is allowed to use inhaled,ophthalmic, or topical corticosteroids or other corticosteroids with a dose ≤ 10mg/day of prednisone or equivalent.

33. The dosage of systemic glucocorticoids in physiological doses is ≤ 10mg/day ofprednisone or equivalent doses of other glucocorticoids.

34. Glucocorticoids are used as pretreatment for infusion related reactions orallergic reactions (such as medication before CT examination).

35. For untreated active hepatitis B subjects (HBsAg positive and HBV-DNA more than 1000copies/ml [200IU/ml] or higher than the lower detection limit), patients withhepatitis B are required to receive anti hepatitis B virus treatment during thestudy treatment period; Active hepatitis C subjects (with positive HCV antibodiesand HCV-RNA levels above the detection limit).

36. Received live vaccine within 30 days prior to randomization, or planned to receivelive vaccine during the study period.

37. Subjects who have a known history of allergic or hypersensitive reactions toCadonilimab, bevacizumab, capecitabine, oxaliplatin or any of their components. Ahistory of severe hypersensitivity to other monoclonal antibodies is known.

38. In the judgment of the investigator, there is a concomitant disease that seriouslyendangers the safety of the subjects or interferes with the completion of the study,or subjects who were not suitable for inclusion for other reasons.