High-Dose Firmonertinib Combined With Bevacizumab and Intrathecal Pemetrexed in the Treatment of EGFR-Mutated Non-Small Cell Lung Cancer With Leptomeningeal Metastasis

Inclusion Criteria:

1. Have obtained written informed consent from the patient or his or her legalrepresentative.

2. Age ≥18 years, male or female.

3. Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC).

4. EGFR mutations confirmed by genetic testing (EGFR Ex19del/L858R/Ex20ins/PACC/L861Q).

5. Leptomeningeal metastasis diagnosed by comprehensive clinical assessment accordingto "EANO-ESMO" diagnostic criteria, including symptom evaluation, imagingassessment, and/or cerebrospinal fluid (CSF) cytopathological evaluation.

6. Both treatment-naïve leptomeningeal metastasis patients and those who progressedafter standard antitumor therapies in clinical practice are eligible. ≤3 prior linesof therapy allowed (patients with >3 prior lines may enroll in the real-world studycohort).

7. ECOG PS 0-2 (patients with ECOG PS >2 may enroll in the real-world study cohort).

8. Prior radiotherapy or surgical treatment targeting the central nervous system (CNS)is permitted.

9. Patients with CNS symptoms/signs are allowed if these manifestations are notlife-threatening.

10. Patients previously treated with standard-dose third-generation EGFR TKIs,pemetrexed intravenous infusion, or bevacizumab are permitted.

11. Adequate organ function: Absolute neutrophil count (ANC) ≥1.5×10^9/L, platelets ≥75×10^9/L, hemoglobin ≥80g/LTotal bilirubin ≤1.5×ULN, AST/ALT ≤2.5×ULN (≤3×ULN for bilirubin and ≤5×ULN forAST/ALT in cases with liver metastasis) Serum creatinine ≤1.5×ULN or creatinineclearance ≥50 mL/min (calculated by Cockcroft-Gault formula).

12. Sexually active males or females of childbearing potential must use highly effectivecontraception (e.g., oral contraceptives, IUD, abstinence, or barrier methods withspermicide) during the trial and for 12 months after treatment completion.

Exclusion Criteria:

1. Diagnosis of other malignancies within the past 5 years or history of othermalignancies (except adequately controlled basal cell carcinoma of the skin,cervical carcinoma in situ, or ductal carcinoma in situ of the breast).

2. Severe gastrointestinal disorders affecting drug administration or absorption,including but not limited to peptic ulcer disease, inflammatory bowel disease, etc.

3. Known or suspected hypersensitivity to the investigational drugs (Firmonertinib,Bevacizumab, Pemetrexed) or any of their excipients.

4. Prior treatment with high-dose third-generation EGFR TKI or intrathecal chemotherapywith Pemetrexed.

5. Evidence of any severe or uncontrolled systemic diseases, including uncontrolledhypertension, diabetes, active bleeding, or active infections (e.g., hepatitis B/C,HIV), which in the investigator's judgment may jeopardize patient participation orprotocol compliance.

6. History of steroid-requiring radiation pneumonitis or any evidence of activeinterstitial lung disease.

7. Clinically significant cardiac arrhythmias (e.g., QTc interval >500 ms) or heartfailure (left ventricular ejection fraction <50%).

8. Pregnant or lactating women.

9. Patients currently participating in or having received investigational drug therapywithin 2 weeks prior to enrollment.

10. Other severe acute/chronic medical or psychiatric conditions or laboratoryabnormalities that, in the investigator's opinion, may increase study-related risks,interfere with result interpretation, or compromise the patient's ability tocomplete the study or adhere to protocol requirements.