Impact of genomic subtype on intracranial outcomes in treatment-naive <i>EGFR</i> -mutant NSCLC with osimertinib (IGnITE).

2020 Background: Osimertinib is the standard first-line therapy for EGFR -mutant NSCLC with brain metastasis (BM); however, alteration-specific patterns of CNS failure and mortality in treatment-naive patients remain poorly defined. Methods: We assembled an international muti-institutional cohort of TKI and radiation-naive EGFR -mutant NSCLC patients with BM treated with first-line osimertinib, with or without upfront stereotactic radiosurgery (SRS) (within 2 months of BM diagnosis). The primary endpoint was time to CNS progression. Time-to-event outcomes were analyzed using the Kaplan-Meier method. Multivariable hazard ratios (MHR) were estimated using Cox proportional hazards models. Fine and Gray hazard models were used for endpoints with competing risks. Results: From 2016-2024, 470 patients from 11 institutions were identified with the following alterations: exon 19 deletion (57%), L858R mutations (33%), and atypical/uncommon mutations (9.6%). Median follow-up was 25.6 months (IQR, 14.7-41.3 months). At 24 months, the cumulative incidence of CNS progression was 30% for exon 19 deletions, 47% for L858R mutations (MHR 1.68, p&lt;0.001), and 76% for atypical mutations (MHR 4.33, p&lt;0.001). Atypical alterations experienced markedly shorter time to local failure (MHR 4.88, p&lt;0·001). Compared to exon 19 deletions, L858R (MHR 1.73, p=0.001) and atypical alterations (MHR 2.86, p&lt;0.001) were associated with shorter time to distant CNS progression. L858R was also associated with higher risk of leptomeningeal disease (MHR 2.49, p=0.001). At 24 months, cumulative incidence of neurological death was 4.6% for exon 19 deletions, 7.8% for L858R, and 9.1% for atypical alterations (p=0.023). Upfront SRS was associated with improved CNS outcomes, with greater benefit for patients in L858R and atypical alterations. Conclusions: In the largest multi-institutional study of treatment-naive EGFR -mutant NSCLC with BM treated with first-line osimertinib, EGFR alteration subtype was an independent determinant of CNS progression, defined patterns of CNS failure, and identified patients most likely to benefit from treatment intensification with SRS.