*April 2021*
Optimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy.