Intrathecal pemetrexed for leptomeningeal metastases after osimertinib in lung adenocarcinoma

An Open-label, Single-arm, Phase II Trial of Intrathecal Pemetrexed for Leptomeningeal Metastasis From Lung Adenocarcinoma That Progressed After a Double Dose of Third-generation TKIs, Including Osimertinib

This trial will try giving pemetrexed directly into the spinal fluid to treat leptomeningeal metastases in people with EGFR‑mutant lung adenocarcinoma whose cancer progressed after double‑dose osimertinib.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Guangzhou Medical University (Academic / other)
• Drugs / interventions: Osimertinib, chemotherapy
• Locations: 1 site (Huizhou, Guangdong)
• Trial ID: NCT06296745 on ClinicalTrials.gov

What this trial studies

This is a single‑arm, open‑label phase II trial enrolling patients with leptomeningeal metastases from EGFR‑mutant lung adenocarcinoma who progressed after double‑dose third‑generation TKIs such as osimertinib. Treatment is intrathecal pemetrexed (15 mg) combined with dexamethasone via lumbar puncture, given twice weekly for two weeks (induction), once weekly for four weeks (consolidation), then monthly for maintenance. Clinical and radiographic responses will be measured using the RANO leptomeningeal criteria, and safety and tolerability will be closely monitored. The trial targets a population with limited standard options after targeted therapy resistance.

Who should consider this trial

Good fit: Adults 18–75 with histologically confirmed lung adenocarcinoma carrying EGFR exon 19 deletion or L858R, confirmed leptomeningeal metastasis, progression after double‑dose third‑generation TKIs, and adequate blood, liver, and kidney function are eligible.

Not a fit: Patients with severe neurologic failure (for example GCS <11), extensive untreatable systemic disease, severe marrow or organ dysfunction, or poor compliance are unlikely to benefit.

Why it matters

Potential benefit: If successful, this approach could better control leptomeningeal disease and improve neurological symptoms or survival for patients who no longer respond to osimertinib.

How similar studies have performed: Prior case series and guideline guidance (including CSCO) report promising results for intrathecal pemetrexed in NSCLC leptomeningeal disease, but prospective data specifically after osimertinib resistance remain limited.

Eligibility criteria

Inclusion Criteria:

1. Male or female aged between 18 and 75 years.
2. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del).
3. Confirmed diagnosis of leptomeningeal metastasis according to ESMO/ EANO guidelines.
4. Progression after previous double doses of third-generation TKIs such as Osimertinib.
5. Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.
6. No history of severe nervous system disease.
7. No severe dyscrasia.

Exclusion Criteria:

1. Any evidence of nervous system failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy on imaging, and Glasgow Coma Score less than 11.
2. Any evidence of extensive and lethal progressive systemic diseases without effective treatment.
3. Patients with poor compliance or other reasons that were unsuitable for this study

Where this trial is running

Huizhou, Guangdong

• The Affiliated Huizhou Hospital, Guangzhou Medical University — Huizhou, Guangdong, China (Recruiting)

Study contacts

• Principal investigator: Zhenyu Pan — Guangzhou Medical University
• Study coordinator: Zhenyu Pan

Conditions Leptomeningeal Metastasis; Leptomeningeal metastasis; Intrathecal chemotherapy; Pemetrexed; Osimertinib; Epidermal growth factor receptor mutation; Non-small-cell lung cancer