277 - Alteration Subtype is Prognostic of Intracranial Outcome and Predicts the Benefit of Upfront SRS in EGFR-Mutant NSCLC Brain Metastasis
Presenter(s)
E. Wo1, E. Miao2, L. A. Boe3, J. Lee1, H. Walch4, H. Yu5, M. I. Parker2, J. S. Chiang6, C. Hui7, L. Ni8, S. E. Braunstein8, C. Hadley9, M. J. Khandekar10, A. W. Lee11, I. Messing12, E. Y. Y. Akdemir13, W. Shi14, H. Soliman15, C. G. Rusthoven16,17, and L. R. G. Pike3; 1Memorial Sloan Kettering Cancer Center, New York City, NY, 2Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 3Memorial Sloan Kettering Cancer Center, New York, NY, 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, 6Department of Radiation Oncology, Stanford University, Stanford, CA, 7Department of Radiation Oncology, Stanford University, Palo Alto, CA, 8Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 9Ohio State University, Columbus, OH, 10Department of Radiation Oncology, Mass General Brigham / Massachusetts General Hospital, Boston, MA, 11Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, 12Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 13Miami Cancer Institute, Miami, FL, 14Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 15Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 16Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, 17University of North Carolina at Chapel Hill, Chapel Hill, NC
Purpose/Objective(s):
Brain metastases (BM) are a major driver of morbidity and mortality in epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). While clinical guidelines support upfront tyrosine kinase inhibitor (TKI) monotherapy with osimertinib, treatment intensification with stereotactic radiosurgery (SRS) has been shown to improve local control and time to CNS progression. EGFR-mutated NSCLC is increasingly recognized as a heterogeneous disease with clinical outcomes varying by alteration subtype; however, the role of SRS in influencing intracranial outcomes by alteration subtype remains poorly defined.Materials/Methods:
Data on treatment-naive EGFR-mutated NSCLC patients with BM receiving osimertinib, with or without SRS, were gathered from 11 institutions. Patients receiving SRS within 8 weeks of initiating osimertinib were classified as having upfront SRS. The primary endpoint was time-to-CNS progression, analyzed using the Kaplan-Meier method. Multivariable hazard ratios (MHR) were calculated using Cox proportional hazards and Fine and Gray competing-risks models for survival and cumulative incidence endpoints, respectively.Results:
From January 2016 to July 2024, 470 patients were identified; 187 (40%) received upfront SRS. EGFR alterations included exon 19 deletions (57%), L858R point mutations (33%), and atypical alterations (9.6%). The addition of upfront SRS was associated with prolonged time to CNS progression (MHR: 0.66, 95% CI: 0.48–0.90, p=0.009) and local failure (MHR: 0.29, 95% CI: 0.18–0.47, p<0.001) compared with TKI alone. The greatest improvements in CNS progression with SRS was seen for patients with atypical alterations (MHR: 0.414, 95% CI: 0.177-0.966, p=0.041); SRS prolonged time to local progression across all alteration subtypes, with greater benefit observed in L858R (MHR: 0.309, 95% CI: 0.153-0.624 p=0.001) and atypical alterations (MHR: 0.093, 95% CI: 0.021-0.404, p=0.002). A prespecified test for interaction between SRS and EGFR alteration subtype was statistically significant among patients with atypical mutations (P-int=0.006). A composite endpoint that included either local progression or symptomatic radionecrosis (RN) demonstrated that patients with L858R and atypical alterations experienced a net benefit from upfront SRS, whereas no benefit was seen for those with exon 19 deletions. Conclusion: EGFR alteration subtype is prognostic for clinically relevant intracranial outcomes and may serve as a predictive biomarker to select patients most likely to benefit from upfront SRS.