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

1. Previously received treatment with PD-1 monoclonal antibody, PD-L1 monoclonal antibody, 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 traditional Chinese 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 of randomization. The following conditions can be included: cured uterus cervical carcinoma in situ, non-melanoma skin cancer and superficial bladder tumors \[Ta (non-invasive tumor), Tis (cancer in situ) and T1 (tumor infiltrating basal membrane)\].

6. Have active or untreated brain metastases, meningeal metastases, spinal cord compression, or leptomeningeal diseases. However, participants who meet the following requirements and have measurable lesions outside the central nervous system are allowed to be enrolled: asymptomatic after treatment, imageologically stable for at least 4 weeks before the start of study treatment (if there are no new or expanded brain metastases), and have stopped systemic glucocorticoid and anticonvulsant drug treatment for at least 2 weeks.

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

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

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

2. Hypothyroidism caused by autoimmune thyroiditis requires only stable doses of hormone replacement therapy;

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

4. Childhood asthma has completely relieved, and no intervention is required in adulthood;

5. Researchers have determined that the disease will not recur without external triggering factors.

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

1. Myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, acute or persistent myocardial ischemia, symptomatic heart failure (grade 2 or above according to the New York Heart Association functional classification), symptomatic or poorly controlled arrhythmia, or any arterial thromboembolism event occurred within the first 6 months of randomization.

2. A history of deep vein thrombosis, pulmonary embolism, or other severe thromboembolism within the first 3 months of randomization.

3. Have major vascular diseases such as aortic aneurysm, aortic dissection aneurysm, internal carotid artery stenosis that may endanger life or require surgery within 6 months.

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

5. Previous history of myocarditis and cardiomyopathy.

6. Left ventricular ejection fraction (LVEF)\<50%.

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

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

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

14. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

15. Imaging (CT or MRI) shows that the tumor has invaded the large blood vessels or is not clearly delimited from the blood vessels.

16. Have clinical active diverticulitis, abdominal abscess, and gastrointestinal obstruction, unhealed wounds, ulcers, or fractures.

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

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

19. Individuals with a known history of immune deficiency or HIV testing positive,Known active syphilis infection.

20. Subjects who require systemic treatment with glucocorticoids (\>10mg/day prednisone or equivalent dose) or other immunosuppressive drugs within the first 14 days of randomization. Except for the following:

1. 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.

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

3. Glucocorticoids are used as pretreatment for infusion related reactions or allergic reactions (such as medication before CT examination).

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

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

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

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

What this study is about