High-dose firmonertinib plus chemotherapy injected into the spinal fluid for EGFR-mutant NSCLC with leptomeningeal spread

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

This tests whether high-dose firmonertinib combined with chemotherapy injected into the spinal fluid helps people with EGFR-mutant non-small cell lung cancer that has spread to the leptomeninges.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Academic / other)
• Drugs / interventions: famotinib, chemotherapy, Firmonertinib, fumatinib, osimertinib
• Locations: 1 site (Wuhan, Hubei)
• Trial ID: NCT07092202 on ClinicalTrials.gov

What this trial studies

Patients with stage IV EGFR-mutant NSCLC and confirmed leptomeningeal metastases will receive oral high-dose firmonertinib together with intrathecal pemetrexed at a single center. Treatment response and safety will be tracked prospectively with clinical exams, imaging, and regular cerebrospinal fluid (CSF) sampling. Investigators will use CSF cell-free DNA (cfDNA) to monitor tumor genetic changes and early treatment response in addition to standard neurologic and survival outcomes. The protocol is a Phase 4 interventional approach aimed at measuring tolerability and potential clinical benefit compared with historical outcomes.

Who should consider this trial

Good fit: Adults (≥18) with stage IV NSCLC harboring EGFR exon 19 deletion or L858R mutations and confirmed leptomeningeal metastases who can tolerate intrathecal therapy and have ECOG performance 0–3 are the intended candidates.

Not a fit: Patients without EGFR sensitizing mutations, those who cannot undergo lumbar puncture or intrathecal chemotherapy, or those with very poor prognosis or contraindicating comorbidities are unlikely to benefit.

Why it matters

Potential benefit: If successful, the combination could prolong survival and improve neurological symptoms by increasing CNS drug exposure and enabling earlier, more accurate response monitoring with CSF cfDNA.

How similar studies have performed: High-dose osimertinib showed promising activity in the BLOOM study and retrospective reports suggest benefit from high-dose firmonertinib, but prospective data specifically combining firmonertinib with intrathecal chemotherapy are lacking.

Eligibility criteria

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.

Where this trial is running

Wuhan, Hubei

• Wuhan Union Hospital — Wuhan, Hubei, China (Recruiting)

Study contacts

• Principal investigator: Xiaorong Dong, Dr — Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
• Study coordinator: Peng Ding, Dr

Conditions Leptomeningeal Metastasis; NSCLC; Intrathecal Chemotherapy; Tyrosine Kinase Inhibitor; Leptomeningeal metastasis; Firmonertinib; cfDNA