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

The goal of this clinical trial is to explore the efficacy and safety of double-dose third-generation EGFR-TKI combined with bevacizumab and intrathecal chemotherapy in treating advanced non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis that progressed after prior standard-dose third-generation EGFR-TKI treatment. It also aims to investigate the correlation between cerebrospinal fluid genetic characteristics and prognosis as well as subsequent efficacy prediction in patients with leptomeningeal metastasis after resistance to standard-dose third-generation EGFR-TKI. The main questions it intends to answer are: Does this combined treatment regimen improve leptomeningeal metastasis response rate (LM-ORR) evaluated by RANO-LM? What adverse events occur in patients during the treatment with this combined regimen? Researchers will conduct a single-arm phase II prospective study to assess the effectiveness and safety of the combined treatment, without a control group comparison. Participants will: Receive double-dose third-generation EGFR-TKI (osimertinib 160mg qd, furmonertinib 160mg qd, or almonertinib 220mg qd) + intrathecal pemetrexed (induction phase: 10mg twice a week for 4 weeks; maintenance phase: 10mg once a week for 4 weeks; consolidation phase: 30mg every 4 weeks until disease progression or intolerable toxicity) + bevacizumab 7.5mg/kg. Undergo screening assessments within 28 days before enrollment, including tumor imaging, laboratory tests, and cerebrospinal fluid examination. During the treatment period, conduct regular checkups and tests (such as blood routine, blood biochemistry, electrocardiogram, and imaging examinations) according to the protocol (once every 4 weeks in the first two treatment cycles, then once every 8 weeks). Complete quality of life assessment using the QLQ-C30 scale every 4 weeks and record changes in neurological symptoms and ECOG scores.

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 be trial.show_full_description

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.