Pemetrexed injected into the spinal fluid for EGFR‑mutant lung cancer that has spread to the leptomeninges.

Efficacy of Intrathecal Pemetrexed Combined With Tyrosine Kinase Inhibitor for Treating Leptomeningeal Metastasis in EGFR-Mutant NSCLC After Failure of Osimertinib

This tests whether giving pemetrexed directly into the spinal fluid helps people with EGFR‑mutant non‑small cell lung cancer whose cancer has spread to the leptomeninges after osimertinib has stopped working.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 23 (estimated)
• Ages: 20 Years and up
• Sex: All
• Sponsor: Taipei Veterans General Hospital, Taiwan (Government)
• Drugs / interventions: denosumab, osimertinib, chemotherapy, immunotherapy
• Locations: 1 site (Taipei, Taiwan)
• Trial ID: NCT05805631 on ClinicalTrials.gov

What this trial studies

This is a single‑center phase II interventional trial giving intrathecal pemetrexed to patients with EGFR‑mutant non‑small cell lung cancer and leptomeningeal metastasis who have shown intracranial progression on osimertinib. Eligible patients must have probable or confirmed leptomeningeal disease by EANO‑ESMO criteria, stable extracranial disease, ECOG performance status 0–3, and adequate organ function. Treatment consists of pemetrexed delivered into the cerebrospinal fluid with safety and intracranial disease control monitored by MRI, CSF analysis, neurological exams, and routine labs. The trial aims to measure neurological response, CSF cytology/radiographic changes, and safety outcomes.

Who should consider this trial

Good fit: Adults (≥20 years) with non‑squamous EGFR‑mutant NSCLC, probable or confirmed leptomeningeal metastasis, intracranial progression after osimertinib, stable extracranial disease, ECOG 0–3, and adequate marrow, liver, and renal function are the intended candidates.

Not a fit: Patients without EGFR activating mutations, with squamous histology, uncontrolled extracranial progression, poor organ function, or very limited life expectancy are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, this approach could reduce neurological symptoms and better control leptomeningeal disease, potentially prolonging survival for some patients.

How similar studies have performed: Previous phase I/II reports and case series have suggested intrathecal pemetrexed can have activity in NSCLC leptomeningeal disease, but evidence remains limited and not yet definitive.

Eligibility criteria

Inclusion criteria

* At least 20 years of age.
* Patients with metastatic non-squamous NSCLC harboring known EGFR activating mutation and with a diagnosis of probable or confirmed LM by the European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guideline. \[5\] EGFR activating mutations include exon19 deletion, T790M, L858R, G719X, L861Q, or S768I.
* Intracranial disease progression after osimertinib use, proved by contrast-enhanced MRI
* Stable extra-cranial disease status, judged by investigators.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-3 and a minimum life expectancy of 12 weeks
* Normal bone marrow and organ function as defined below:

  * Marrow: Hemoglobin ≥9gm/dL, ANC ≥1500/mm3 platelets ≥100,000/mm3
  * Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), ALT (SGPT) and AST (SGOT) ≤3 x ULN.
  * Renal: Creatinine clearance (Ccr) ≥45 mL/min.
* For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (\< 1% per year) when used consistently and correctly, and to continue its use for 5 months after the last dose of IP. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
* Ability to understand and willingness to sign an IRB approved written informed consent document.
* Willing to provide CSF and plasma samples for ctDNA analysis.

Exclusion criteria

* Uncontrolled extra-CNS disease which needs other systemic treatment than EGFR-TKI.
* Uncontrolled tumor-related pain
* Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN). Patients who are receiving denosumab prior to study enrollment must be willing and eligible to receive a bisphosphonate instead while in the study.
* Malignancies other than NSCLC within 5 years prior to study enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
* On chronic systemic steroid therapy more than 20 mg prednisolone per day (or equivalent) or on any other form of immunosuppressive medication
* Has received a live-virus vaccination within 30 days of planned treatment start
* Systemic cytotoxic chemotherapy or major surgery within 2 weeks of the first dose of study medication
* Active infection requiring therapy
* History of Human Immunodeficiency Virus (HIV) infection.
* Hepatitis B carrier: Patients with HBV infection were required to be receiving effective antiviral therapy and have a viral load less than 100 IU/mL at screening
* Active Hepatitis C
* Has received intrathecal chemotherapy within 2 weeks before the start of IP
* Has received whole-brain radiotherapy (WBRT) within 2 weeks before the start of IP
* Uncontrolled epilepsy
* History of allergic reaction to intravenous pemetrexed.
* Severe coagulation abnormality (INR \> 2).
* Severe symptomatic hydrocephalus that requires other treatment modalities other than IP
* Bulky intra-cranial lesion that requires other treatment modalities other than IP

Where this trial is running

Taipei, Taiwan

• Department of Chest Medicine, Taipei Veterans General Hospital — Taipei, Taiwan, Taiwan (Recruiting)

Study contacts

• Study coordinator: Chi-Lu Chiang, MD

Conditions Carcinoma, Non-Small-Cell Lung; Epidermal Growth Factor Receptor; Leptomeningeal Metastasis