Volumetric Response of Brain Metastases in EGFR-Positive NSCLC Treated with CNS-Penetrant Tyrosine Kinase Inhibitors with or without Radiation Therapy

Abstract

<h3>Purpose/Objective(s)</h3> In patients with brain metastases (BM) from EGFR-positive non-small cell lung cancer, recent data has indicated that treating with central nervous system (CNS)-penetrant tyrosine kinase inhibitors such as osimertinib (osi) may enable radiation therapy (RT) to be deferred in select patients. How to appropriately select such patients remains unclear. The purpose of this study was to describe the radiographic response of newly diagnosed BM to osi alone and osi with stereotactic radiosurgery (SRS) or whole brain radiotherapy, to identify volumetric parameters that may be used to guide early versus delayed salvage RT. <h3>Materials/Methods</h3> 35 patients with a total of 186 newly diagnosed symptomatic or asymptomatic BM from EGFR-positive NSCLC who were started on osi between 2014 and 2020 at a single institution were retrospectively reviewed. This cohort had at least one MRI brain after initiating therapy. BM with initial tumor volume ≥ 0.1 cm³ were included in the volumetric analyses (N = 106 BM). Variables were compared using the Wilcoxon rank-sum test for continuous variables and the Chi-squared test for categorical variables. Survival times were estimated with the Kaplan-Meier method and univariable analysis was performed using log-rank tests. The Cox proportional hazards regression model was performed for multivariable analyses for local control, distant brain failure, and overall survival (OS). <h3>Results</h3> Of the 35 patients, 8 (23%) received osi alone. Median clinical and radiologic follow-up from the date of treatment initiation were 29 months and 26 months, respectively. The 1- and 2-year local control rates were 94% and 86%, respectively. The 1- and 2-year OS rates were 89% and 66%. Median time to distant brain failure was 24 months. Patients treated with concurrent osi with RT were more likely to have a significant radiographic volumetric response at early follow-up (4-12 weeks after treatment initiation), compared to patients treated with osi alone (median volumetric response of –80% vs. –41%, <i>p</i> = 0.05). Of the patients who received osi alone, 5 eventually developed intracranial failure, of whom 4 patients (50%) received SRS. Median per lesion BM volume at baseline was 0.22 cm³ for the osi alone group vs. 0.41 cm³ for the osi with RT group (<i>p</i> = 0.004). On per lesion analysis, early radiographic volumetric response of ≥ 80% was significantly associated with improved durable local control (3-year local control 98% vs 72%, <i>p</i> = 0.04). <h3>Conclusion</h3> The combination of osi and CNS RT is associated with a more significant early volumetric response in patients with BM from EGFR-positive NSCLC compared to administration of osi alone. BM with a significant volumetric response at early follow-up remain well-controlled in the long term. Patients whose BM demonstrate limited initial volumetric response may benefit from targeted radiotherapy to provide long term control.