Evaluation of the Efficacy and Safety of Furmonertinib Combined with Bevacizumab As First-Line Treatment for EGFR-Positive Non-Small Cell Lung Cancer with Brain Metastases: a Single-Arm, Open-Label, Prospective Phase II Clinical Study

Inclusion Criteria:

1. Aged 18-75 years. ECOG performance status (PS) score of 0-2. Expected survival timeof ≥3 months.

2. Histologically or cytologically confirmed non-squamous non-small cell lung cancer (NSCLC).

3. Baseline evaluation confirming the presence of EGFR-sensitizing mutations (19del/L858R) via first- or second-generation sequencing. Test samples can includearchived tumor tissue or fresh tumor tissue collected during screening. Ifunavailable, pleural effusion, cerebrospinal fluid, or blood samples may be used fortesting.

4. Asymptomatic brain metastases or those with controlled intracranial hypertensionsymptoms following dehydration treatment. Continued medication to maintain stablesymptoms at enrollment or during the study is allowed.

5. For patients with parenchymal or leptomeningeal brain metastases, MRI must confirmat least one brain lesion with a diameter ≥5 mm.

6. No prior systemic anti-tumor therapy for locally advanced or metastatic NSCLC.Patients who underwent radical surgery, chemoradiotherapy, or adjuvant therapy (chemotherapy or radiotherapy) for early-stage NSCLC may be included if theirdisease recurred or metastasized after treatment, provided the interval from thelast treatment to initial tumor recurrence exceeds 6 months.

7. Normal function of major organs, with the following criteria: Hematology (withouttransfusion or hematopoietic stimulating factors within 14 days): Hemoglobin (HB) ≥ 90 g/L. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L. Platelets (PLT) ≥ 80 × 10⁹/L.Biochemistry: Total bilirubin (TBIL) < 1.5 × upper limit of normal (ULN). Alanineaminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN (if livermetastases are present, ALT and AST < 5 × ULN). Creatinine (Cr) ≤ 1.25 × ULN orcreatinine clearance rate (CCr) ≥ 45 mL/min (using the Cockcroft-Gault formula).Proteinuria < 2+ (if baseline proteinuria ≥ 2+, a 24-hour urine proteinquantification ≤ 1 g is required). International normalized ratio (INR) ≤ 1.5 andactivated partial thromboplastin time (APTT) ≤ 1.5 × ULN. Left ventricular ejectionfraction (LVEF) ≥ lower limit of normal (50%) as assessed by Doppler ultrasound.

8. Women of childbearing potential must agree to use effective contraception (e.g.,intrauterine devices, oral contraceptives, or condoms) during the study and for 6months after its completion. Negative serum or urine pregnancy test within 7 daysprior to enrollment and non-lactating status are required. Male participants mustagree to use contraception during the study and for 6 months afterward.

9. Participants must voluntarily consent to participate in the study, sign an informedconsent form, and demonstrate good compliance.

Exclusion Criteria:

1. Active Bleeding with Brain and/or Leptomeningeal Metastases

2. Includes therapies with agents such as bevacizumab, endurance, or anlotinib.

3. ≥ Grade 2 toxicity (NCI-CTCAE v4.03) related to prior treatments not resolved at thestart of study treatment (excluding alopecia and Grade 2 neurotoxicity caused byplatinum agents).

4. Includes uncontrolled nausea/vomiting, inability to swallow, gastrointestinalresection, chronic diarrhea, or intestinal obstruction

5. Prior whole-brain radiotherapy (WBRT). Radiotherapy involving >30% of bone marrow orextensive radiation within 4 weeks before the first dose (palliative radiotherapyfor non-brain metastases, such as bone metastases, is exempt).

6. Poorly controlled hypertension (defined as blood pressure ≥160/100 mmHg despiteoptimal antihypertensive therapy). Cardiac criteria, including: QTcF ≥ 470 msec (average of three ECGs, corrected using Fredericia's formula) at rest. Clinicallysignificant arrhythmias, conduction abnormalities, or ECG changes (e.g., completeleft bundle branch block, third-degree AV block, second-degree AV block, PR interval ≥250 msec). Factors increasing risk of QT prolongation or arrhythmias, such as NYHAClass III-IV heart failure, hypokalemia, congenital long QT syndrome, family historyof long QT syndrome or unexplained sudden death under 40 years of age, or use ofQT-prolonging medications. Active or uncontrolled severe infections. Liver disease,including cirrhosis, decompensated liver disease, or chronic active hepatitis.Poorly controlled diabetes (fasting blood glucose >10 mmol/L). Urinalysis showing ≥2+ proteinuria, confirmed by 24-hour urine protein quantification >1.0 g.

7. Presence of unhealed wounds or fractures.

8. NCI-CTCAE > Grade 1 pulmonary bleeding within 4 weeks before enrollment. NCI-CTCAE >Grade 2 bleeding at other sites within 4 weeks before enrollment. Bleedingtendencies (e.g., active gastrointestinal ulcers) or patients on thrombolytic oranticoagulant therapy (e.g., warfarin, heparin, or similar agents).

9. History of arterial/venous thrombosis within 12 months before enrollment, includingstroke (e.g., transient ischemic attack, cerebral hemorrhage, or infarction), deepvein thrombosis, or pulmonary embolism.

10. Clinically significant hemoptysis (>50 mL/day) within 3 months before enrollment.Severe bleeding symptoms or conditions such as gastrointestinal bleeding, bleedinggastric ulcers, stool occult blood ≥2+, or vasculitis.

11. History of interstitial lung disease, drug-induced interstitial lung disease,steroid-requiring radiation pneumonitis, or clinically active interstitial lungdisease.

12. History of substance abuse or uncontrolled psychiatric disorders.

13. Poorly controlled pleural or ascitic effusions despite symptomatic treatment,causing Grade ≥2 respiratory syndrome (≥CTCAE Grade 2).

14. Known active infections, including: Active hepatitis B (HBsAg positive and HBV-DNA ≥ 2 × 10³ IU/mL during screening). Hepatitis C (HCV-Ab positive and HCV-RNA positiveduring screening). Active tuberculosis (evidence of active infection within 1 year).Syphilis (both specific and non-specific antibodies positive). HIV infection (HIVantibody positive). Active infections are not routinely screened unless clinicallyindicated.

15. Severe diseases or conditions deemed to pose risks to patient safety or impede studycompletion.

16. Severe diseases or conditions deemed to pose risks to patient safety or impede studycompletion.

17. Prior allogeneic bone marrow transplantation.

18. Prior allogeneic bone marrow transplantation. 19)Any other condition deemedunsuitable for the study by the investigator. 20)Major surgery within 28 days beforethe first dose (defined as surgeries requiring at least 3 weeks of recovery beforestudy treatment).