Pulsatile High-dose Furmonertinib in EGFR-mutant NSCLC With Leptomeningeal Metastasis

Overview

The goal of this clinical trial is to clarify the efficacy and safety of the high-dose alternate-day furmonertinib in NSCLC with leptomeningeal metastasis. It will also explore the mechanism by which the high-dose alternate-day administration regimen enhances efficacy from a pharmacokinetic perspective, and investigate the impact of co-occurring mutations on the efficacy and prognosis of furmonertinib in the treatment of EGFR-mutant NSCLC with leptomeningeal metastasis. The main questions it aims to answer are: Does the high-dose alternate-day administration regimen have definite efficacy? Does the high-dose alternate-day administration regimen have favorable safety? Does the high-dose alternate-day administration regimen improve efficacy by increasing the cerebrospinal fluid (CSF) concentration and CSF penetration rate of the drug? Which co-occurring mutations may affect the efficacy and prognosis of patients with EGFR-mutant NSCLC and leptomeningeal metastasis? Participants will enter Cohort A (320mg qod po) or Cohort B (160mg qd po) to receive furmonertinib based on their own willingness and the clinician's decision, until disease, progression or uncontrollable adverse reactions occur. All patients in Cohort A will undergo efficacy and safety evaluation, with some also participating in pharmacokinetic study; patients in Cohort B will only undergo pharmacokinetic study. Efficacy and safety evaluation will be conducted through imaging examinations, neurological function assessment scales, quality of life self-assessment scales, and adverse event records. Pharmacokinetic study will be carried out by detecting the plasma concentrations and CSF concentrations of furmonertinib and its active metabolites, and calculating the CSF penetration rate for evaluation.

Interventions

• Drug Furmonertinib 320mg qod po
  furmonertinib 320mg qod po until disease, progression or uncontrollable adverse reactions occur.
• Drug Furmonertinib 160mg qd po
  furmonertinib 160mg qd po until disease, progression or uncontrollable adverse reactions occur.

Primary outcome measures

• LM-DCR [Time frame: From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years.]

Secondary outcome measures (11)

• LM-ORR [Time frame: From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• neurological function [Time frame: From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• iDoR [Time frame: From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• iPFS [Time frame: From date of enrollment until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• PFS [Time frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• OS [Time frame: From date of enrollment until the date of death from any cause, assessed up to 5 years.]
• Quality of life evaluation [Time frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• Quality of life evaluation [Time frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• AEs [Time frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• CSF Penetration Rate [Time frame: Patients will undergo twice of specimen collection: the first before treatment (-14 to 0 days) and the second 4 weeks after treatment (4weeks ±7 days).]
• Gene Mutation [Time frame: at baseline and date of progression (assessed up to 3 years)]

Eligibility criteria

Inclusion criteria

• Patients with non-small cell lung cancer (NSCLC) confirmed by histopathological or cytopathological examination
• Patients with EGFR exon 19 deletion or exon 21 L858R mutation
• Patients with leptomeningeal metastasis (LMD) confirmed by positive cerebrospinal fluid (CSF) cytology (within 28 days prior to the first dose administration) and with at least 1 LMD lesion that can be repeatedly evaluated by magnetic resonance imaging (MRI)
• Patients with disease progression after first-line tyrosine kinase inhibitor (TKI) treatment
• Aged ≥18 years and ≤85 years, with no gender restrictions.
• Sufficient organ function, defined as: absolute neutrophil count ≥ 1.5×10⁹/L, platelet count ≥ 75×10⁹/L, hemoglobin ≥ 90g/L total bilirubin ≤ 1.5×upper limit of normal (ULN) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN (for patients with liver metastasis, total bilirubin can be relaxed to ≤ 3×ULN, and ALT/AST can be relaxed to ≤ 5×ULN) serum creatinine ≤ 1.5×ULN or creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula)
• For patients enrolled in the pharmacokinetic study: no prior treatment with furmonertinib (either in combination or as monotherapy)
• Patients who have signed the informed consent form, are willing to receive treatment under this protocol, can adhere to medication administration, and have good compliance.

Exclusion criteria

• Unable to complete the baseline assessment form
• Complicated with severe or uncontrolled systemic diseases, including active infection, electrolyte disturbance, bleeding tendency, etc.
• Pregnant or lactating women, or those with planned pregnancy during the study or within 6 months after the study ends
• Presence of central nervous system complications requiring emergency neurosurgical intervention
• Suffering from other malignant tumors or having a history of other malignant tumors
• Complicated with severe brain diseases or mental illnesses that affect the patient's ability to report symptoms by themselves
• Individuals without legal capacity, or those for whom medical or ethical reasons affect the continuation of the study
• Other circumstances deemed unsuitable for participation in this study by the researcher.
• Patients with a severe allergic diathesis, especially those who have experienced severe drug allergies or other serious adverse reactions during previous treatment with tyrosine kinase inhibitors (TKIs).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Guangdong Provincial Hospital of Chinese Medicine — Guangzhou

Identifiers

NCT: NCT07348965 · ZF2025-387-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗