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<0.001), and 76% for atypical mutations (MHR 4.33, p<0.001). Atypical alterations experienced markedly shorter time to local failure (MHR 4.88, p<0·001). Compared to exon 19 deletions, L858R (MHR 1.73, p=0.001) and atypical alterations (MHR 2.86, p<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.
Wo et al. (Wed,) studied this question.