Firmonertinib Combined With Intrathecal Injection for the Treatment of EGFR Mutant NSCLC With Leptomeningeal Metastases

July 27, 2025 updated by: Xiaorong Dong, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology

Exploratory Clinical Study on Dynamic Monitoring of cfDNA in Cerebrospinal Fluid and Peripheral Blood Using High-dose Firmonertinib Combined With Intrathecal Injection of Pemetrexed for the Treatment of EGFR Mutant NSCLC With Leptomeningeal Metastases

Leptomeningeal metastases (LM) are a relatively rare site of metastasis in advanced non-small cell lung cancer (NSCLC), and LM patients have a poor prognosis. Numerous retrospective studies have reported that high-dose Firmonertinib can also effectively increase patient prognosis and have tolerable side effects, but there is a lack of prospective studies to confirm this. In addition, there are currently no good biomarkers for monitoring the efficacy of LM treatment. cfDNA testing can be used for early cancer screening, monitoring tumor progression, evaluating treatment response, and discovering drug resistance mechanisms. Due to the influence of the blood-brain barrier, the level of cfDNA in the plasma of LM patients is often very low, and the detection of cfDNA in cerebrospinal fluid (CSF) is more advantageous. Therefore, exploring the dynamic monitoring of LM treatment efficacy using CSF cfDNA is of great significance for improving patient prognosis. Based on this, the applicant intends to conduct a prospective, multicenter, single-arm, post-market exploratory clinical trial on the treatment methods and efficacy monitoring of NSCLC-LM patients. The aim was to explore whether cfDNA has the potential to become a biomarker for LM efficacy monitoring and to validate the efficacy and safety of high-dose fumatinib combined with intrathecal injection in the treatment of NSCLC-LM patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Leptomeningeal metastases (LM) are a relatively rare site of metastasis in advanced non-small cell lung cancer (NSCLC), and LM patients have a poor prognosis. Once diagnosed, if left untreated, the overall survival (OS) is only 4-6 weeks, and the appearance of LM is often significantly associated with EGFR mutations. At present, the commonly used treatment for LM metastasis in clinical practice is systemic targeted therapy combined with local intrathecal injection of chemotherapy drugs, such as intrathecal injection of pemetrexed. The BLOOM study showed that increasing the dose of osimertinib (160mg) showed promising efficacy in advanced NSCLC patients with previous EGFR-TKI treatment failure and concomitant leptomeningeal metastasis, while double-dose targeted drugs had good safety and controllable adverse reactions. Numerous retrospective studies have reported that high-dose Firmonertinib can also effectively increase patient prognosis and have tolerable side effects, but there is a lack of prospective studies to confirm this. In addition, there are currently no good biomarkers for monitoring the efficacy of LM treatment. cfDNA testing can be used for early cancer screening, monitoring tumor progression, evaluating treatment response, and discovering drug resistance mechanisms. Due to the influence of the blood-brain barrier, the level of cfDNA in the plasma of LM patients is often very low, and the detection of cfDNA in cerebrospinal fluid (CSF) is more advantageous. Moreover, there are relatively few studies on this topic; therefore, exploring the dynamic monitoring of LM treatment efficacy using CSF cfDNA is of great significance for improving patient prognosis. Based on this, the applicant intends to conduct a prospective, multicenter, single-arm, post-market exploratory clinical trial on the treatment methods and efficacy monitoring of NSCLC-LM patients. The dynamic monitoring of cfDNA in cerebrospinal fluid and peripheral blood was used to evaluate the efficacy and safety of high-dose fumatinib combined with intrathecal injection of pemetrexed in the treatment of EGFR mutant NSCLC with leptomeningeal metastases. The aim was to explore whether cfDNA has the potential to become a biomarker for LM efficacy monitoring and to validate the efficacy and safety of high-dose fumatinib combined with intrathecal injection in the treatment of NSCLC-LM patients.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Hubei
      • Wuhan, Hubei, China, 430022
        • Recruiting
        • Wuhan Union Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Obtain an informed consent form signed by the patient or their legal representative;
  • Age greater than or equal to 18 years old;
  • According to the 9th edition TNM staging of lung cancer by the International Association for the Study of Lung Cancer and the Joint Committee on Cancer Staging in the United States, metastatic (stage IV) NSCLC with histological or cytological confirmation;
  • Confirmed by histological or cytological specimens tested in the central laboratory to have EGFR exon 19 deletion mutation (19DEL) or exon 21 L858R point mutation (L858R), which can exist alone or in combination;
  • ECOG physical condition score is 0-3 points, with an expected life expectancy of ≥ 12 weeks;
  • According to the criteria for evaluating the efficacy of solid tumors (RECIST 1.1), there should be at least one measurable lesion;
  • According to the "EANO-ESMO" diagnostic criteria for meningeal metastasis (Type I: positive cerebrospinal fluid cytology or biopsy; Type II: limited to typical clinical symptoms and neuroimaging findings), for clinical judgment. Patients with leptomeningeal metastases who can be included in the study are type I patients and type II patients with EGFR mutations in cerebrospinal fluid ctDNA; merged brain parenchymal metastases can also be included in the study;
  • Progress in first-line treatment with first and second-generation EGFR-TKI;
  • Progress in first-line conventional dose treatment with third-generation EGFR-TKI;
  • The subject must accept and be able to cooperate with the lumbar puncture procedure, and confirm that there are no contraindications to chemotherapy or lumbar puncture;
  • At least 4 weeks before treatment, all extracranial symptoms must be stable, and there must be no CNS complications requiring emergency neurosurgical intervention.

Exclusion Criteria:

  • Squamous cell carcinoma of the lung;
  • Known history of hypersensitivity reactions to drugs with or without active excipients or similar structures or categories to the investigational drug for famotinib/pemetrexed;
  • Confirmed EGFR exon 20 insertion mutation;
  • At the beginning of drug treatment, if the toxicity associated with previous anti-tumor therapy has not recovered to ≤ CTCAE Grade 1, except for peripheral neurotoxicity caused by hair loss or chemotherapy ≤ CTCAE Grade 2;
  • Excluding skin basal cell carcinoma, cervical carcinoma in situ, and ductal carcinoma of the breast that have been effectively controlled and have been diagnosed with other malignant tumors or have a history of other malignant tumors in the past 5 years;
  • Patients who are deemed ineligible by researchers to participate in this study, such as those who are highly likely to be unable to comply with the study protocol, constraints, and requirements, or other situations determined by the researcher at their discretion;
  • Pregnancy or lactation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Firm-ITp
  1. Firmonertinib 160mg po qd;
  2. Intrathecal injection of pemetrexed. Weight above 50kg: Induction period: 40mg/time, d1, d5 (q3w, x 4 cycles); Consolidation period: 40mg/time, q4w (pause when cerebrospinal fluid ctDNA is negative); Weight below 50kg: Induction period: 30mg/time, d1, d5 (q3w, x 4 cycles); Consolidation period: 30mg/time, q4w (pause when cerebrospinal fluid ctDNA is negative).
Drug: Firmonertinib
Firmonertinib 160mg po qd
Drug: Intrathecal injection of pemetrexed
Intrathecal injection of pemetrexed. Weight above 50kg: Induction period: 40mg/time, d1, d5 (q3w, x 4 cycles); Consolidation period: 40mg/time, q4w (pause when cerebrospinal fluid ctDNA is negative); Weight below 50kg: Induction period: 30mg/time, d1, d5 (q3w, x 4 cycles); Consolidation period: 30mg/time, q4w (pause when cerebrospinal fluid ctDNA is negative)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS
Time Frame: 2 years
From the date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology

Investigators

  • Principal Investigator: Xiaorong Dong, Dr, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 15, 2025

Primary Completion (Estimated)

May 1, 2027

Study Completion (Estimated)

November 1, 2027

Study Registration Dates

First Submitted

July 14, 2025

First Submitted That Met QC Criteria

July 27, 2025

First Posted (Actual)

July 29, 2025

Study Record Updates

Last Update Posted (Actual)

July 29, 2025

Last Update Submitted That Met QC Criteria

July 27, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DTO-20240928

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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