Upfront Osimertinib Alone vs. Osimertinib and Radiotherapy for the Treatment of EGFR-Positive NSCLC Brain Metastases: A Multi-Institutional Series

Given the increased brain penetrance of osimertinib, the role of upfront radiotherapy (RT) has been questioned for the management of patients with EGFR+ NSCLC brain metastases (BM). We conducted a multi-institutional review of patients with EGFR+ NSCLC treated with upfront osimertinib or osimertinib in combination with RT for new or progressing BM.Our multi-institutional analysis included 128 patients with 714 BM treated between 2013 and 2022. Two BM treatment groups were evaluated: (1) upfront osimertinib alone (n = 66) and (2) osimertinib + RT [whole brain radiation therapy or stereotactic/fractionated radiosurgery (SRS/FSRT)] prior or concurrently with osimertinib (n = 62)]; both groups began treatment within 2 months of BM diagnosis. Time-to-event analysis was conducted with the Kaplan-Meier (KM) method, and outcomes included intracranial control (IC) [both local and distant], intracranial progression free survival (IPFS), and overall survival (OS). A Cox proportional hazards model was utilized for multivariate analysis (MVA).Median follow-up from BM diagnosis was 33.9 months (0.13-76.2 months). No differences in age (p = 0.46), sex (p = 0.72), DS-GPA (p = 0.08), KPS (p = 0.57), number of BM (p = 0.19) or volume of BM (p = 0.45), RT dose (p = 0.45), number of systemic metastases (p = 0.88), and patients symptomatic at presentation (p = 1.0) were noted. Prior treatment of BM was more common in the osimertinib + RT group (50% osimertinib + RT and 27% osimertinib; p = 0.01). The 12-month KM rates for osimertinib vs osimertinib + RT groups for IC were 72% vs 73% (p = 0.33); IPFS 53% vs 66% (p = 0.007); and OS 65% vs 80% (p = 0.025). On MVA, higher KPS (p = 0.002) was associated with increased OS and no extracranial metastasis with increased OS (p = 0.01) and IPFS (p = 0.001). MVA showed no association between osimertinib vs osimertinib + RT for IC, IPFS, or OS. Of the 66 patients treated with upfront osimertinib, 18 patients (27%) with 31 lesions eventually required RT for intracranial progression with the majority 72% being treated with SRS/FSRT at median of 13.5 months (1-22 months) following the start of osimertinib.This study suggests that upfront osimertinib alone may provide sufficient intracranial control to allow RT to be deferred until further intracranial progression in select patients. Prospective trials are warranted to further guide treatment.