EGFR Mutation Subtype and Risk of Brain Metastases from Non-Small Cell Lung Cancer in the Osimertinib Era

Background: Mutations in the EGFR gene are common in lung adenocarcinoma and can be targeted by tyrosine kinase inhibitors (TKIs). However, many patients eventually develop brain metastases, which are difficult to treat because the blood–brain barrier (BBB) restricts the entry of most TKIs into the central nervous system. Previous studies have suggested that tumors with the EGFR L858R mutation have a higher risk of brain metastasis than those with Exon 19 deletions (Ex19Del), possibly reflecting biological differences between these subtypes. Objectives: We aimed to evaluate whether the higher risk of brain metastasis associated with the L858R mutation, compared with the Exon 19 deletion (Ex19Del) mutation, was present among patients treated with early-generation TKIs. We also examined whether this difference was reduced among those treated with osimertinib, a third-generation, brain-penetrant TKI with improved BBB permeability and central nervous system activity. Methods: We used MSK-CHORD, a clinicogenomic database that applies natural language processing (NLP) to extract treatment and metastasis data from electronic health records. Among 7,809 NSCLC cases, we studied 601 patients with EGFR mutations without brain metastasis at diagnosis and treated with either early-generation TKIs or osimertinib. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate brain-metastasis-free survival (BMFS) with hazard ratios (HR) and 95% confidence intervals. Results: Overall, BMFS was shorter for patients with L858R vs. Ex19Del mutations (49.3% vs 58.0% at 5 years, HR 1.38 [1.02–1.87], p = 0.038). For patients receiving early-generation TKIs (n = 225, 37.4%), BMFS was shorter for those with L858R vs. Ex19Del mutations (44.8% vs 65.5% at 5 years, HR 1.95 [1.21–3.14], p = 0.006). For patients on osimertinib (n = 376, 62.6%), no significant association was observed between mutation subtype and BMFS (50.3% vs 51.2% at 5 years, HR 1.11 [0.74–1.65], p = 0.616). Conclusions: Differences in brain metastasis development between EGFR L858R and Ex19Del mutations appeared to be mitigated among patients on osimertinib compared to early-generation TKIs. Future research is necessary to determine optimal brain metastasis screening, prevention, and management strategies for patients undergoing osimertinib with either EGFR mutation subtype.