Intrathecal pemetrexed in NSCLC patients with leptomeningeal metastasis

Spread of lung cancer to the leptomeninges is rare and difficult to treat. Standard therapy comprises CNS-penetrant targeted agents with or without intrathecal chemotherapy. We performed a retrospective analysis of 16 patients with advanced NSCLC and leptomeningeal disease treated with intrathecal pemetrexed 50 mg. All tumours were adenocarcinoma histology; 13 (81.3%) had EGFR mutations, and 3 (18.8%) had no targetable mutations. Prior therapies included EGFR-directed tyrosine kinase inhibitors (TKI) with/without chemotherapy/antiangiogenic agents (9 [56.3%]), chemotherapy alone (4 [25%]), intrathecal methotrexate with/without hydrocortisone (3 [18.9%]), and radiation (12 [75%]). Presenting symptoms of leptomeningeal disease included headache (10 [62.5%]), dizziness (8 [50%]), and seizures (7 [43.8%]). Systemic therapy administered along with intrathecal pemetrexed included osimertinib (5 [31.3%]), gefitinib in 1 (6.3%), chemotherapy in 4 (25%) (pemetrexed + carboplatin-2, cisplatin + etoposide-1, paclitaxel-1), chemotherapy + oral TKI in 5 (31.3%) and no systemic therapy in 1 (6.3%). Neurological symptoms following intrathecal pemetrexed included headache in 1 (6.3%) patient which was likely due to raised intracranial pressure from underlying leptomeningeal disease, and anxiety/uneasiness in 1 (6.3%). Grade 3 or higher toxicities included thrombocytopenia (6 [37.5%]), anaemia (4 [25%]), neutropenia (4 [25%]), febrile neutropenia (3 [18.8%]), mucositis (4 [25%]), diarrhoea (1 [6.3%]), rash (1 [6.3%]) and hypokalemia (1 [6.3%]. Most toxicities were likely caused by systemic chemotherapy, rather than by intrathecal pemetrexed. Intrathecal pemetrexed was delayed in 9 (56.3%) patients, due to cytopenias/febrile neutropenia (8 [50%]) and poor general condition (1 [6.3%]). Median OS from diagnosis of leptomeningeal disease was 7.5 months (95% CI: 1.2-13.8). Median OS from start of intrathecal pemetrexed was 2.7 months (95% CI, 1.1-4.3). Thus, intrathecal pemetrexed combined with systemic antitumor therapy was tolerable, with promising clinical outcomes in patients with NSCLC and leptomeningeal disease. It is important to explore this option, especially in driver mutation-negative NSCLC patients.