Central Nervous System Progression During Longitudinal Treatment of Anaplastic Lymphoma Kinase-Positive Non-small Cell Lung Cancer: A Real-World Cohort Study

Background: Central nervous system (CNS) progression remains clinically important in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), even in the era of CNS-active ALK tyrosine kinase inhibitors (ALK-TKIs).Because systemic treatment commonly changes over time, first-line treatment alone may not accurately represent drug exposure when CNS progression occurs.Methodology: We retrospectively reviewed 46 patients with ALK-positive NSCLC who initiated anticancer treatment at a single center between August 2010 and January 2026.Routine clinical follow-up information through February 28, 2026, was available in the medical record.Research-specific data extraction, creation of the study dataset, and statistical analyses were performed only after institutional review board approval.We identified the first new or progressive CNS event after treatment initiation and described the systemic treatment being administered at the time of the event, brain-directed therapy, continuation of the same systemic regimen, and subsequent treatment.Analyses were primarily descriptive.Results: Twelve of 46 patients (26.1%) experienced a first post-treatment CNS event, and 13 CNS events occurred in total.The median time to the first CNS event was 631 days (interquartile range, 404-1,306 days).At the first CNS event, nine of 12 patients (75.0%) were receiving an ALK-TKI: alectinib in seven, crizotinib in one, and brigatinib in one.Five of the seven patients whose initial treatment had been non-ALK therapy were receiving a later-line ALK-TKI when CNS progression occurred.Ten of 12 patients received braindirected radiotherapy.Among seven CNS events occurring during alectinib treatment, alectinib was continued for at least 30 days after five events, usually with local CNS therapy.Conclusions: The systemic therapy being administered at CNS progression frequently differed from the initial treatment.Patient-level longitudinal treatment history therefore provided a more clinically meaningful description of CNS progression than classification by first-line therapy alone.CNS progression was commonly managed with brain-directed local therapy combined with continuation of the current ALK-TKI or a transition to another ALK-TKI.