Intrathecal Pemetrexed for Leptomeningeal Metastasis in EGFR-Mutant NSCLC

Leptomeningeal metastasis (LM) is a complication of advanced non-small cell lung cancer (NSCLC). The incidence of LMC in NSCLC patients is around 3-5 %, and reaches 9.4 % of those with an epidermal growth factor receptor (EGFR) mutation. Although EGFR tyrosine kinase inhibitors (TKIs) had markedly prolonged survival in advanced NSCLC patients, the prognosis of patients with LMC remains poor. In a Taiwanese NSCLC cohort, the median survival of patients after diagnosis of LMC was 4.5 months. The diagnosis of LM is difficult, and depends on clinical, CSF, and radiographic findings. A positive cerebrospinal fluid (CSF) cytology remains the gold standard for the diagnosis of LM, but the sensitivity of initial lumbar puncture has been reported to be as low as 50%. A gadolinium-enhanced MRI of brain and spine is the best imaging technique for the diagnosis of LM. In patients with metastatic NSCLC and typical presentations of LM, the typical abnormal enhancement on MRI alone can lead to the diagnosis of LMC. However, 20-30% of patients with LM have a normal or false negative MRI. The current diagnostic algorism is based on EANO-ESMO guideline including clinical findings, neuroimaging features and CSF analysis.

The management of LM in patients with NSCLC remained questioned. The aim of treatment is palliative, including amelioration of neurological symptoms, improvement of quality of life, and prolongation of survival. Generally, the efficacy of systemic treatment is limited due to blood-brain barrier. A retrospective study suggests that patients who received contemporary systemic treatment had a decreased risk of death compared to those who did not receive modern systemic therapy. The role of local radiotherapy, in the other hand, is to ease symptoms, to reduce bulky or nodular disease, and to correct CSF flow. There is no consensus on whether whole-brain radiotherapy is a beneficial treatment for patients with leptomeningeal metastasis from NSCLC. Other managements includes intrathecal chemotherapy, CSF diversion surgery, immunotherapy and palliative care.

Osimertinib, a third-generation EGFR-TKI targeting both EGFR sensitizing and T790M resistance mutations, prolonged survival in patients with NSCLC with T790M mutation after EGFR-TKI failure. Compared with other EGFR-TKIs, osimertinib has a high central nervous system (CNS) penetration rate, making it the preferred first-line treatment for EGFR-mutant NSCLC. Previous studies indicated that osimertinib had shown promising efficacy in pretreated patients with EGFR T790M mutation and LM. However, intracranial disease progression eventually develops and the prognosis of patients with LM progression after osimertinib is poor, with a median survival of 7.2 months. Dose intensification of osimertinib to 160 mg per day is a treatment option in patients with EGFR mutant NSCLC and LM after osimertinib failure. In a phase II study by Park et al., patients with T790M-positive NSCLC with brain metastasis and LM were treated with osimertinib 160 mg. Their median PFS and OS were 8.0 and 13.3 months, respectively. A total of 42 percent of patients in the LM cohort received prior T790M targeted agents (osimertinib: 12.5%), and the intracranial disease control rate was 88.2%. In the LM cohort, PFS was not significantly different between patients who had received prior T790M targeted agents and those who did not. In a retrospective study in United States, the median duration of CNS control in patients who received high dose osimertinib was 6.0 months in isolated leptomeningeal progression. The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were mild in the previous study. More treatment options were needed in this group of patients.

Pemetrexed in a standard chemotherapy regimen in patients with advanced non-squamous NSCLC and showed efficacy in patients with symptomatic brain metastasis. Recently, intrathecal chemotherapy with pemetrexed was reported to be an alternative treatment in patients with NSCLC and LM. In a pilot phase 1 study in China, Pan et al. enrolled thirteen patients and found that maximally tolerated dose of intrathecal pemetrexed (IP) was 10 mg. Severe adverse events were noted in 31% (4/13) of the cases, including myelosuppression, radiculitis, and elevation of hepatic aminotransferases. Another case report also showed a good treatment response to IP (30mg) via Ommaya reservoir in a patient with EGFR mutant NSCLC and LM. Furthermore, Fan et al. published the results from a phase I/II trial examining the efficacy and safety of IP in patients with EGFR mutant NSCLC after failure of previous TKI, and 83% of study enrollees received osimertinib before intrathecal pemetrexed. The clinical response rate was 84.6% and the median overall survival was 9.0 months. The recommended dose of IP was 50 mg with few adverse effects. Despite initial promising efficacy, further trials are need to verify the results.

Therefore, the investigators plan to conduct a prosepctive study to exam the safety and efficacy of IP combined with EGFR-TKI for patients with EGFR mutant NSCLC after osimertinib failure.