To Explore the Efficacy and Safety of Double-dose Third-generation EGFR-TKI Combined With Bevacizumab and Intrathecal Chemotherapy in Advanced NSCLC Patients With Progressive Leptomeningeal Metastasis After Prior Standard-dose Third-generation EGFR-TKI Treatment.

1. Study Overview This is a prospective, single-arm Phase II interventional clinical trial initiated by the Second Affiliated Hospital of Nanchang University, with funding from the Wu Jieping Medical Foundation. The study will be conducted from December 2025 to December 2027 (Version V1.0, dated November 20, 2025) and led by Principal Investigator Cai Jing (contact number: 0791-86260752). The core objective is to evaluate the efficacy and safety of a combined regimen consisting of double-dose third-generation EGFR-TKI, bevacizumab, and intrathecal chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) who have developed leptomeningeal metastasis (LM) after prior standard-dose third-generation EGFR-TKI treatment. Additionally, the study explores the correlation between cerebrospinal fluid (CSF) genetic characteristics and prognosis, as well as predictive value for subsequent efficacy, in patients with LM following resistance to standard-dose third-generation EGFR-TKI.
2. Study Population 2.1 Inclusion Criteria Participants must meet all the following criteria to be enrolled: aged ≥18 years at the time of signing the informed consent form, regardless of gender; histologically or cytologically confirmed advanced or metastatic 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 mutation), with LM progression after prior standard-dose third-generation EGFR-TKI treatment (allowed treatment sequences: 1st+3rd generation, 2nd+3rd generation, or direct 3rd generation), no restriction on the number of prior chemotherapy lines, and stable parenchymal brain and extracranial lesions; ECOG Performance Status (PS) score of 0-3; normal major organ function, including hemoglobin (Hb) ≥90g/L, absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet (PLT) ≥100×10⁹/L, white blood cell count (WBC) ≥3.0×10⁹/L (without blood transfusion or hematopoietic stimulants within 14 days), alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5×upper limit of normal (ULN), total bilirubin (TBIL) ≤1.5×ULN, serum creatinine (Cr) ≤1.5×ULN or creatinine clearance ≥50ml/min (for patients with liver metastasis: TBIL ≤3×ULN, ALT and AST ≤5×ULN), activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤1.5×ULN, and left ventricular ejection fraction (LVEF) ≥50% by Doppler ultrasound; compliance with washout period requirements (≥21 days since the last chemotherapy dose if no prior radiotherapy, ≥14 days since the end of local radiotherapy for parenchymal brain metastases, ≥30 days since surgical resection of parenchymal brain metastases with full recovery from acute toxicity); expected survival time ≥3 months; ability to swallow oral medications (or receive crushed medications via gastrostomy tube if unable to swallow); for women of childbearing age, negative pregnancy test (serum or urine) within 14 days before enrollment and agreement to use effective contraception during the study and for 3 months after the last study drug administration; for men, surgical sterilization or agreement to use effective contraception during the same period; voluntary participation, signed informed consent (or by legal representative), and good expected compliance with study procedures.

2.2 Exclusion Criteria Participants will be excluded if they meet any of the following: major surgery within 4 weeks before the start of study treatment or planned surgery during the study; human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS); active bacterial or fungal infections requiring intravenous antibiotics at the start of study treatment; history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or signs of clinically active interstitial lung disease; arterial/venous thromboembolic events within 6 months before enrollment (including cerebrovascular accident, deep vein thrombosis, or pulmonary embolism); significant cardiovascular disease history (New York Heart Association class >2 congestive heart failure, unstable angina, myocardial infarction within 3 months before signing the informed consent form, symptomatic arrhythmias requiring treatment, or mean corrected QT interval (QTcF) >470ms on 3 consecutive electrocardiograms); history of other systemic malignant tumors within 5 years (excluding cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and ovarian cancer); use of drugs or supplements known to be strong inducers of CYP3A4; known 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. 3. Study Design and Treatment Regimen 3.1 Study Design This is an open-label, single-arm Phase II prospective study with no randomization or blinding. The planned sample size is 30 patients, calculated based on a Pearson chi-square test to detect an increase in clinical response rate from 40% to 80% (power=0.8, one-sided significance level=0.20, 10% dropout rate).

3.2 Treatment Regimen The combined treatment includes three components: double-dose third-generation EGFR-TKI (oral osimertinib 160mg once daily, furmonertinib 160mg once daily, or almonertinib 220mg once daily); intrathecal pemetrexed (administered via lumbar puncture, Ommaya reservoir, or intrathecal pump, with induction phase: 10mg twice weekly for 4 weeks, maintenance phase: 10mg once weekly for 4 weeks, consolidation phase: 30mg every 4 weeks until disease progression or intolerable toxicity); and bevacizumab 7.5mg/kg administered intravenously.

3.3 Dose Adjustment and Management For missed doses: if vomiting occurs shortly after drug administration, no re-dose is given; for missed doses within 2 hours of the scheduled time, the dose is supplemented, otherwise, it is skipped without cycle adjustment. For intrathecal pemetrexed, administration requires ANC ≥1.5×10⁹/L, PLT ≥75×10⁹/L, Hb ≥80g/L, and ≤Grade 2 fatigue, oral mucositis, or neurotoxicity; for Grade ≥3 hematological or non-hematological toxicity, the next dose is reduced by 10mg. For bevacizumab, Grade 3-4 related adverse events (AEs) require treatment suspension until recovery to ≤Grade 1, then resumption at the original dose; permanent discontinuation is considered if toxicity fails to resolve or poses ongoing risks. 4. Study Procedures 4.1 Screening Period (D-28 to D-1) Within 28 days before enrollment, participants complete informed consent signing, collection of demographic and medical history data, tumor imaging (chest/abdominal/pelvic CT/MRI within 4 weeks), echocardiogram, drug allergy history review, and concurrent medication documentation. Within 14 days before drug administration, additional assessments include ECOG PS scoring, physical examination, laboratory tests (blood routine, urine routine, blood biochemistry, stool occult blood, coagulation function), electrocardiogram, pregnancy test, myocardial enzyme profile, HIV/hepatic B/hepatic C screening, thyroid function test, and CSF examination. Eligibility is confirmed only after all inclusion and exclusion criteria are met.

4.2 Treatment Period In Cycle 1 (Month 1), assessments include vital signs, physical examination, AE monitoring, concurrent medication recording, and drug administration on Day 1; ECOG PS scoring, laboratory tests, electrocardiogram, and AE monitoring on Day 14; and imaging assessment on Day 28. For Cycle 3 and beyond, Day 1 assessments are the same as Day 14 of Cycle 1, Day 14 includes ECOG PS scoring, vital signs, physical examination, and AE monitoring, and imaging assessment is performed on Day 56. Imaging assessment frequency is every 4 weeks for the first 2 cycles, then every 8 weeks, and every 12 weeks after 1 year of follow-up. Extracranial lesions are evaluated per RECIST v1.1, and intracranial lesions per RANO-LM criteria.