Author(s): Luke R.G. Pike, MD, DPhil1; Emily Miao, PharmD1,2; Lillian A. Boe, PhD3; Tejas Patil, MD4; Brandon S. Imber, MD1; Nathaniel J. Myall, MD5; Erqi L. Pollom, MD, MS6; Caressa Hui6; Vera Qu, MD6; Jacob Langston, MD7; Veronica Chiang, MD8; Michael Grant, MD9; Sarah B. Goldberg, MD, MPH9; Joshua D. Palmer, MD10; Rahul N. Prasad, MD, MBA10; Tony J.C. Wang, MD11; Albert Lee, MD11; Catherine A. Shu, MD12; Lanyi Nora Chen, MD12; Nicholas J. Thomas, MD13; Steve E. Braunstein, MD, PhD14; Brian D. Kavanagh, MD7; D. Ross Camidge, MD, PhD4; Chad G. Rusthoven, MDedu7
PURPOSE
Newer-generation tyrosine kinase inhibitors (TKIs) for non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) 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.
MATERIALS AND METHODS
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.
RESULTS
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 (P < .001) and neurologic symptoms (P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .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]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .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.
CONCLUSION
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- and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.
Author Affiliations
1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; 2Albert Einstein College of Medicine, Bronx, NY; 3Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; 4Division of Hematology and Oncology, Department of Medicine, University of Colorado, Aurora, CO; 5Division of Hematology and Oncology, Department of Medicine, Stanford University, Palo Alto, CA; 6Department of Radiation Oncology, Stanford University, Palo Alto, CA; 7Department of Radiation Oncology, University of Colorado, Aurora, CO; 8Department of Neurosurgery, Yale University, New Haven, CT; 9Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT; 10Department of Radiation Oncology, Ohio State University, Columbus, OH; 11Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY; 12Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY; 13Department of Medicine, University of California San Francisco, San Francisco, CA; 14Department of Radiation Oncology, University of California San Francisco, San Francisco, CA
