Study of Cadonilimab Combined With Bevacizumab and Chemotherapy for Advanced Nonsquamous Non-small Cell Lung Cancer Patients With Untreated Brain Metastases

Inclusion Criteria:

* The patient was over 18 years old.
* The Eastern Cooperative Oncology Group Performance Status score ranged from 0 to 1.
* Patients with asymptomatic brain metastases confirmed by histology or cytology as EGFR and ALK negative stage IV non-squamous NSCLC who have not received any chemotherapy or brain radiotherapy before.
* Patients with non-metastatic diseases who have received neoadjuvant chemotherapy, adjuvant chemotherapy or radiotherapy must experience a no-treatment interval of at least 6 months since the last chemotherapy and/or radiotherapy.
* Steroid therapy (dexamethasone) is allowed. When dexamethasone ≤ 4mg once a day, patients who are still asymptomatic or less symptomatic after 2 weeks of steroid use will be eligible.
* Extracranial measurable lesions assessed by CT (RECIST 1.1 standard), Intracranial measurable lesions (RANO-BM standard or brain MRI).
* Formalin-fixed paraffin embedded blocks (cell wax blocks are acceptable if no tumor biopsy is available) containing tumor tissue or 10 unstained slides can be obtained.
* Adequate hematopoiesis and liver and kidney function: ANC ≥ 1,500 cells/μ L, lymphocyte count ≥ 500 cells/μ L, platelet count ≥ 100,000 cells μ L, hemoglobin ≥ 9.0 g/dL (blood transfusion allowed); INR or aPTT ≤ 1.5 x upper normal limit (ULN); Patients receiving therapeutic anticoagulant therapy should use stable doses of ALT, AST and/or ALP ≤ 2.5 x ULN, except for the following (ALT and/or AST ≤ 5 x ULN in patients with known liver metastasis; ALP ≤ 5 x ULN in patients with known bone metastasis; Serum bilirubin ≤ 1.5 x ULN; Serum bilirubin ≤ 3 x ULN in patients with known Gilbert disease). Creatinine clearance rate (CRCL) ≥ 45 mL/min (based on standard Cockcroft and Gault formulas).
* For fertile women: agree to abstinence or use non-hormonal contraceptive methods during treatment and for 3 months after treatment in the last study. A woman is considered to have fertility potential if she is in the post-menarche state, has not reached the post-menopausal state (amenorrhea for 12 consecutive months, with no definite cause other than menopause) and has not undergone surgical sterilization (ovariectomy and/or uterus removal).
* For men: agree to keep abstinence or use condoms, and agree not to donate sperm. For fertile female partners or pregnant female partners, men must keep abstinence or use condoms during treatment and for three months after the last study treatment to avoid exposing embryos. In the meantime, men must avoid donating sperm.
* Sign the informed consent form.

Exclusion Criteria:

* History of other malignant tumors within 3 years before screening, except properly treated cervical carcinoma in situ, non-melanoma skin cancer or stage I uterine cancer.
* Patients with EGFR mutations or ALK fusion will be excluded.
* Metastasis of pia mater, brain stem, midbrain, pons and medulla or metastasis leading to obstructive hydrocephalus.
* Patients with neurological symptoms, including those receiving \> 4mg dexamethasone, will not be eligible for inclusion in this study.
* Spinal or hemorrhagic metastases will be excluded.
* Surgical treatment of brain or spinal lesions within 14 days before.
* The previous systemic treatment or neoadjuvant or adjuvant chemotherapy before admission was less than 6 months.
* With clinically significant complications affecting platinum chemotherapy administration.
* Autoimmune history, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granuloma, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis. Exceptions to the following：①Patients with a history of autoimmune-associated hypothyroidism and taking a stable dose of thyroid replacement hormone are eligible for this study.

  ②Patients with controlled type 1 diabetes who received a steady dose of insulin were eligible for this study.

  ③Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological manifestations (e.g. psoriatic arthritis patients will be excluded) provided they meet the following conditions: the rash covers less than 10% of the body surface area, the disease is well controlled at baseline, only inefficient topical steroids are required, and there is no acute attack in the past 12 months.
* History of idiopathic pulmonary fibrosis, drug-induced pneumonia or active radiation pneumonia in radiation field.
* Previous treatment was with immune checkpoint inhibitors or CD137 and OX-40 agonists.
* Receive research treatment within 28 days before starting the study drug, and screen for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg). Patients with previous or cured hepatitis B virus (HBV) infection (HBcAb positive but no HBsAg) are eligible regardless of their HBV DNA negative. Patients with positive HCV antibody are eligible regardless of whether HCV RNA is negative or not.
* Active tuberculosis or HIV infection.
* Abuse of drugs or alcohol within 12 months before screening.
* Any serious medical condition or abnormality in clinical laboratory examination prevents patients from safely participating in and completing the study according to the judgment of the researcher.