Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From <i>EGFR</i> and <i>ALK</i> Oncogene-Driven Non-Small Cell Lung Cancer (TURBO-NSCLC).

Abstract

Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (<i>EGFR</i>) mutations and anaplastic lymphoma kinase (<i>ALK</i>) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors. From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm (<i>P</i> < .001) and neurologic symptoms (<i>P</i> < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 <i>v</i> 40 months, respectively; <i>P</i> = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; <i>P</i> = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; <i>P</i> < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR<i>-</i> and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.