clinical trial The goal of this clinical trial is to learn whether the treatment of advanced non-small cell lung cancer with EGFR-TKIs, when combined with bevacizumab in the presence of positive circulating tumor cells in the cerebrospinal fluid, has better therapeutic efficacy. The main questions it aims to answer are:1.When EGFR-TKIs are sequentially combined with bevacizumab along with EGFR-TKIs for first-line treatment of advanced non-small cell lung cancer, how long can the participants survive? 2.What medical problems do participants have when using EGFR-TKIs sequentially combined with bevacizumab in conjunction with EGFR-TKIs.

Participants will:

Receive EGFR-TKIs treatment for a duration of 3 months, and upon a positive cerebrospinal fluid tumor cell status, subsequently receive bevacizumab combined with EGFR-TKIs treatment until disease progression.

Visit the clinic for check-ups and tests every two weeks, and have follow-up visits every six weeks after the treatment ends.

Keep a record of their symptoms and disease progression.

This study is an open-label, single-arm, multicenter, exploratory clinical trial designed to evaluate and observe the first-line treatment of locally advanced/advanced non-small cell lung cancer that is positive for EGFR mutations, based on the early warning of a novel cerebrospinal fluid CTC capture technology. Subjects who meet all inclusion criteria and none of the exclusion criteria will first receive EGFR-TKIs (osimertinib, amivantamab, or futibatinib) treatment (as per the instruction manual). After a positive cerebrospinal fluid tumor cell status, they will then sequentially receive bevacizumab (7.5mg/kg, intravenous injection, once every 3 weeks) combined with EGFR-TKIs treatment.

Participants Aged 18 years or older (including 18 years old) and up to 75 years of age (including 75 years old); confirmed non-small cell lung cancer through histology or cytology; confirmed EGFR sensitive mutation (exon 19 deletion or L858R) prior to treatment; planned to receive first-line monotherapy with EGFR-TKIs (osimertinib, amivantamab, or futibatinib).

This study is an open-label, single-arm, multicenter, exploratory clinical trial. The primary research objective is to evaluate the overall survival time (OS) of patients with locally advanced/advanced EGFR-mutant non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) sequentially combined with bevacizumab as a first-line treatment, based on the early warning of a novel cerebrospinal fluid circulating tumor cell (CSF CTC) capture technology. The study endpoint is the overall survival time (OS) of the patients. Referring to the results of our team's prospective study data and historical literature review study data, it is anticipated that the hazard ratio (HR) for overall survival (OS) of EGFR-TKIs sequentially combined with bevacizumab compared to EGFR-TKIs as a first-line treatment for high-risk patients with EGFR-mutant locally advanced/advanced NSCLC and leptomeningeal metastasis will be 0.78 (median OS improved from 18 months to 21 months). After the first subject is enrolled, with the longest observation period being 24 months, α set at two-sided 0.05, and a power of 80%, calculating with a 25% CSF tumor cell positivity rate and a 10% loss to follow-up rate, using the NCSS&PASS 15.0 software and the single-sample Logrank test method, after sample correction, this study plans to enroll approximately 100 subjects.

Based on the investigator-assessed Overall Survival (OS) as the primary efficacy endpoint, the median survival time will be estimated using the Kaplan-Meier method, and the median event time along with its two-sided 95% confidence interval will be presented. Additionally, the hazard ratio and its 95% confidence interval will be estimated as the main analysis.

Inclusion Criteria:

• 1.The subjects voluntarily joined this study and signed the informed consent form, showing good compliance and cooperation with follow-up.

  2.Ages between 18 years old (inclusive) and 75 years old (inclusive). 3.ECOG score: 0-2 points. 4.Expected survival of no less than 3 months. 5.According to the RECIST 1.1 criteria, the patient has at least one extracranial target lesion.

  6.Diagnosed with non-small cell lung cancer based on histology or cytology. 7.No leptomeningeal metastasis (EANO criteria). 8.The tumor tissue samples or blood samples are confirmed to have EGFR-sensitive mutations (including exon 19 deletions or L858R).

  9.Have not received systemic anti-tumor treatment, and are planned to receive first-line monotherapy with osimertinib, aumolertinib, or furmonertinib.

  10.The main organ functions are normal, that is, they meet the following criteria:

  1. The standard for routine blood test should meet: HB≥90 g/L; ANC≥1.5×10^9/L; PLT≥80×10^9/L.
  2. The biochemical examination should meet the following standards: TBIL<1.5×ULN; ALT and AST<2.5×ULN; serum Cr≤1.25×ULN or endogenous creatinine clearance > 45 ml/min (Cockcroft-Gault formula). 11.Women of childbearing age must have taken reliable contraceptive measures and have undergone a pregnancy test (serum or urine) within 7 days before enrollment, with a negative result, and must be willing to use appropriate methods of contraception during the trial period and for 8 weeks after the last administration of the trial medication. For men, they must agree to use appropriate methods of contraception during the trial period and for 8 weeks after the last administration of the trial medication or have undergone surgical sterilization.

Exclusion Criteria:

1. Subjects have received any of the following treatments:

   1. Previously used any EGFR tyrosine kinase inhibitors;
   2. Previously received any chemotherapy for lung cancer;
   3. Previously received any radiotherapy for lung cancer (except for palliative radiotherapy for bone metastases);
   4. Within 4 weeks before the first administration of the study medication, the subject had undergone major surgery;
   5. Within 7 days before the first administration of the study medication, used strong inhibitors or inducers of CYP3A4.

2. Subjects with concurrent other malignant tumors, except for basal cell carcinoma of the skin and in situ cancer.

3. Subjects have uncontrollable malignant pleural effusion and pericardial effusion.

4. Subjects who are allergic to contrast agents used in CT and MRI or who cannot tolerate MRI examinations.

5. As judged by the investigator, there are any serious or poorly controlled systemic diseases, such as poorly controlled hypertension, active bleeding diathesis, or active infection.

6. Clinically severe gastrointestinal dysfunction that may affect the intake, transport, or absorption of medication, such as the inability to take oral medication, uncontrollable nausea or vomiting, a history of extensive gastrointestinal resection, untreated recurrent diarrhea, atrophic gastritis, gastric diseases requiring long-term use of proton pump inhibitors that have not been cured, Crohn's disease, ulcerative colitis, etc.

7. Hepatic encephalopathy, hepatorenal syndrome, or liver cirrhosis.

8. Meet any of the following cardiac examination results:

   1. The average value of the corrected QT interval (QTcF) derived from three electrocardiograms (ECG) at rest using the Fridericia formula is > 470 msec;
   2. Resting ECG indicates conduction or ECG morphological abnormalities (such as complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, and PR interval > 250 msec, etc.);
   3. There are any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication of unexplained sudden death in direct relatives under 40 years old or prolonged QT interval;
   4. The left ventricular ejection fraction (LVEF) is < 50%.

9. Insufficient bone marrow reserve or organ function, meeting any of the following laboratory limits:

   1. Absolute neutrophil count <1.5×10^9/L;
   2. Platelet count <100×10^9/L;
   3. Hemoglobin <90 g/L (<9 g/dL);
   4. If there is no clear liver metastasis, alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN); if there is liver metastasis, ALT > 5×ULN;
   5. If there is no clear liver metastasis, aspartate aminotransferase (AST) > 3×ULN; if there is liver metastasis, AST > 5×ULN;
   6. If there is no clear liver metastasis, total bilirubin > 1.5×ULN; or with Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastasis, total bilirubin > 3×ULN;
   7. Creatinine > 1.5×ULN and creatinine clearance <50 mL/min (calculated by the Cockcroft-Gault formula); creatinine clearance is only required to be confirmed if creatinine > 1.5×ULN;
   8. Serum albumin (ALB) <28 g/L.

10. Active fungal, bacterial, and/or viral infections requiring systemic treatment.

11. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study period.

12. History of interstitial lung disease, drug-induced interstitial lung disease, history of radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease.

13. Subjects judged by the investigator to be likely non-compliant with the study procedures and requirements, such as those with a clear history of neurological or psychiatric disorders, or currently suffering from psychiatric disorders.

14. Subjects judged by the investigator to have any conditions that may endanger the subject's safety or interfere with the study assessment.