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.

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.

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.