Double-Dose Third-Generation EGFR-TKI Plus Bevacizumab and Intrathecal Chemotherapy for Refractory Leptomeningeal Metastatic NSCLC: A Phase II Study

Inclusion Criteria

* Aged ≥ 18 years at the time of signing the informed consent form, regardless of gender.
* Histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC), staged as IV according to the 8th edition of the IASLC TNM classification (2015).
* Presence of EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R mutation).
* Leptomeningeal metastasis (LM) progression after standard-dose first-, second-, or third-generation EGFR-TKI treatment.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
* Adequate major organ function, defined as: hemoglobin (Hb) ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L, platelet count (PLT) ≥ 100 × 10\^9/L, white blood cell count (WBC) ≥ 3.0 × 10\^9/L and ≤ 10.0 × 10\^9/L; total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × ULN; creatinine clearance ≥ 50 ml/min (for patients with liver metastases, TBIL ≤ 3.0 × ULN, ALT and AST ≤ 5.0 × ULN); activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤ 1.5 × ULN.
* At least 21 days since the last radiotherapy (including whole-brain radiotherapy or local radiotherapy for brain metastases).
* Expected survival ≥ 3 months.
* Ability to swallow oral medications (or receive crushed medications via gastrostomy tube if unable to swallow).
* For women: Agreement to use effective contraception (e.g., surgical sterilization or protocol contraception) within 14 days prior to enrollment, during the study, and for 3 months after the last study drug administration.
* For men: Agreement to use effective contraception (e.g., surgical sterilization or protocol contraception) during the study and for 3 months after the last study drug administration.
* Voluntary participation, signed informed consent, and willingness to comply with study procedures and protocols.

Exclusion Criteria

* Major surgery within 4 weeks prior to the start of study treatment, or need for major surgery during the study.
* Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
* Active bacterial/fungal/viral infections requiring intravenous antibiotic therapy.
* Drug-induced pneumonitis or interstitial lung disease, or evidence of clinically significant active pulmonary disease.
* Severe cardiovascular events within 6 months prior to enrollment, including cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.
* Significant cardiovascular disease, such as New York Heart Association (NYHA) class II or higher congestive heart failure, unstable angina, symptomatic arrhythmias requiring treatment, or corrected QT interval (QTcF) \> 470 ms on consecutive electrocardiograms.
* History of other systemic malignant tumors within the past 5 years (except for cured basal cell carcinoma, carcinoma in situ of the cervix, and ovarian cancer).
* Use of drugs or supplements known to be strong inducers of CYP3A4.
* Known severe allergy to any study drug or its excipients.
* Pregnancy, lactation, or refusal of effective contraception by patients of childbearing potential.
* History of definite neurological or psychiatric disorders (including epilepsy and dementia).
* Other conditions deemed unsuitable for enrollment by the investigator.