Double-dose third-generation EGFR-TKI with bevacizumab and intrathecal chemotherapy for leptomeningeal NSCLC

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.

This trial will try whether giving a double dose of a third-generation EGFR-TKI together with bevacizumab and spinal (intrathecal) chemotherapy can help people with EGFR-mutant NSCLC whose leptomeningeal metastasis progressed after a standard-dose third-generation EGFR-TKI.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 99 Years
• Sex: All
• Sponsor: Second Affiliated Hospital of Nanchang University (Academic / other)
• Drugs / interventions: bevacizumab, osimertinib, furmonertinib, almonertinib, chemotherapy, radiation
• Locations: 1 site (Nanchang, Jiangxi)
• Trial ID: NCT07398599 on ClinicalTrials.gov

What this trial studies

This is a prospective, single-arm Phase II study testing a combined regimen of double-dose third-generation EGFR-TKI, bevacizumab, and intrathecal chemotherapy in patients with EGFR-mutant advanced NSCLC who have leptomeningeal progression after prior standard-dose third-generation EGFR-TKI. The primary efficacy measure is leptomeningeal objective response rate (LM-ORR) evaluated by RANO-LM, with safety and adverse events systematically recorded. The study will also collect cerebrospinal fluid for genetic analysis to explore associations between CSF mutations and prognosis or subsequent treatment response. Participants must be adults with confirmed EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R), ECOG 0-1, and adequate organ function, and all treatments and intrathecal administrations are given at the lead site.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18 years) with stage IV NSCLC harboring EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R) who developed leptomeningeal progression after standard-dose third-generation EGFR-TKI, have ECOG 0–1, and meet organ function requirements.

Not a fit: Patients without EGFR-sensitive mutations, with ECOG performance status >1, significant organ dysfunction, or contraindications to bevacizumab or intrathecal chemotherapy are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the regimen could improve leptomeningeal tumor control and delay neurological decline for a subset of EGFR-mutant NSCLC patients with LM.

How similar studies have performed: Some components—higher-dose third-generation EGFR-TKIs and combinations of EGFR-TKIs with bevacizumab—have shown CNS activity, but the exact triple combination including intrathecal chemotherapy is largely untested in prospective trials.

Eligibility criteria

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.

Where this trial is running

Nanchang, Jiangxi

• The Second Affiliated Hospital of Nanchang University — Nanchang, Jiangxi, China (Recruiting)

Study contacts

• Study coordinator: jing cai Jing Cai

Conditions Leptomeningeal Metastasis; Lung Neoplasms, Non-Small Cell Lung Cancer; non-small cell lung cancer