Simple SummaryRadiotherapy, in the form of either whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS), continues as the standard of care for patients of non-small cell lung cancer with brain metastases (NSCLCBM). Recently, targeted therapies have emerged as systemic options for brain metastases with certain genetic mutations. Tyrosine kinase inhibitors directed against EGFR protein (EGFR-TKI) have come forth as the preferred treatment of EGFR-mutated NSCLC and have also shown promise in NSCLCBM. However, there have been few studies comparing the synergistic effects of EGFR-TKIs and radiotherapy in NSCLCBM. This study is one of the few that investigates survival rates between standard radiotherapy modalities and a combination of radiotherapies and EGFR-TKIs. Our data may help guide clinicians in future treatment plans for EGFR-mutated NSCLCBM patients.AbstractIntroduction: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. Methods: A retrospective review of NSCLCBM patients diagnosed during 2010–2019 at a tertiary-care US center was performed and reported following the ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. Results: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17–0.84,p= 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82,p= 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08,p= 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09,p= 0.07). Conclusions: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.