What is the treatment approach for leptomeningeal metastases in non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation using osimertinib (Tagrisso) and pemetrexed (Alimta)?

Treatment of Leptomeningeal Metastases in EGFR-Mutant NSCLC with Osimertinib and Pemetrexed

For patients with leptomeningeal metastases in EGFR-mutant NSCLC, osimertinib at a higher dose of 160 mg daily should be the primary treatment, with the potential addition of intrathecal pemetrexed for patients with inadequate response to osimertinib alone. 1

First-Line Approach for Leptomeningeal Metastases

Osimertinib as Primary Treatment

• Osimertinib is the preferred agent for EGFR-mutant NSCLC patients with CNS metastases, including leptomeningeal disease 1
• For leptomeningeal metastases specifically:
  • Standard dose: 80 mg daily for EGFR TKI-naïve patients
  • Preferred dose: 160 mg daily for patients with established leptomeningeal disease 1
  • The BLOOM study demonstrated good anticancer activity with osimertinib 160 mg in patients with cytologically confirmed leptomeningeal carcinomatosis 1

Treatment Algorithm Based on Response to Osimertinib

1. Initial treatment: Start with osimertinib 160 mg daily

2. If inadequate response (persistent neurological symptoms or detectable CSF tumor cells):

   • Add intrathecal pemetrexed (30-50 mg) every 2-3 months, with 2-3 administrations per course 2
   • Continue high-dose osimertinib concurrently

3. If disease progression despite combination therapy:

   • Consider platinum-based chemotherapy (particularly pemetrexed-containing regimens) 1
   • For patients with poor performance status, intrathecal therapy may be better tolerated than systemic chemotherapy 3

Evidence for Combination Approach

The combination of high-dose osimertinib with intrathecal pemetrexed has shown promising results:

• Case report demonstrated elimination of CSF tumor cells and significant improvement in neurological symptoms after three courses of intrathecal pemetrexed combined with double-dose osimertinib 2
• Survival extended to 28 months from diagnosis of leptomeningeal metastases in this case 2
• A retrospective analysis of 16 NSCLC patients with leptomeningeal disease treated with intrathecal pemetrexed showed tolerable toxicity profile 4

Monitoring and Response Assessment

• Regular neurological examinations to assess symptom improvement
• MRI imaging to evaluate radiographic response
• CSF cytology to detect presence of tumor cells
• Response evaluation should follow modified Response Assessment in Neuro-Oncology LM criteria 5

Important Considerations and Caveats

Prognostic Factors

• Median survival for leptomeningeal metastases in NSCLC is typically 3-6 months without targeted therapy 1
• Performance status at diagnosis is the most important prognostic factor 1
• Patients with interrupted cerebrospinal fluid flow have worse outcomes (median survival 4 vs 6 months) 6

Toxicity Management

• Monitor for common adverse effects:

  • Skin rash (most common with osimertinib)
  • Myelosuppression (leukopenia, thrombocytopenia)
  • Aseptic meningitis (common with intrathecal chemotherapy)
  • Fatigue

• Dose modifications may be necessary based on toxicity, but maintaining the highest tolerable dose of osimertinib is important for CNS control 2

Avoiding Common Pitfalls

1. Delayed diagnosis: Consider leptomeningeal metastases in any NSCLC patient with new neurological symptoms, especially those with EGFR mutations which have CNS tropism 1

2. Inadequate CNS penetration: Standard doses of TKIs may not achieve sufficient CSF concentrations; higher doses are often needed for leptomeningeal disease 1

3. Overreliance on radiotherapy: While radiotherapy plays a role in symptom control, targeted therapy with osimertinib has demonstrated better outcomes for EGFR-mutant disease 1

4. Neglecting systemic disease control: Remember that 70% of patients with leptomeningeal metastases have progressive systemic disease 1

The evidence strongly supports that osimertinib at 160 mg daily should be the cornerstone of treatment for leptomeningeal metastases in EGFR-mutant NSCLC, with the addition of intrathecal pemetrexed providing additional benefit in patients with inadequate response to osimertinib alone.