For a study, researchers sought to understand that in 9%–10% of instances of non-small cell lung cancer (NSCLC) with an EGFR mutation, leptomeningeal (LM) disease presents. Particularly in the era of osimertinib, the natural history and optimal systemic therapeutic options for this condition were not well understood. Between January 3, 2000 and March 31, 2020, a university oncology practice in Seattle, Washington, treated 54 patients with LM disease and EGFR mutant NSCLC. From the electronic medical record, they extracted information on demographics, malignancy, therapy, and results. To investigate the relationship between systemic therapy for post-LM illness and overall survival, univariate Cox models were used. Using the Student’s t test or a chi-squared test, differences in the natural history of LM illness and healthcare use between groups were evaluated. Prior to being diagnosed with LM disease, patients who received osimertinib had a longer median time to diagnosis and typically had higher performance status than individuals who received placebo. In comparison to those who did not receive systemic treatment for their post-LM illness, patients who did had a lower probability of dying (HR 0.17, P<.001) (suggesting that osimertinib-containing regimens result in longer median overall survival). The use of the hospital, emergency room, or hospice was not linked to receiving systemic therapy for a post-LM condition. The natural course of the LM disease appeared to be positively impacted by prior osimertinib exposure. Any systemic therapy after a diagnosis of LM illness was not linked to greater healthcare use but rather to a longer survivor time. More research was required to determine whether an osimertinib-containing regimen increases survival in patients who had already taken osimertinib.