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The high intracranial efficacy of EGFR-TKI challenges the role of upfront intracranial radiation therapy (RT) in non-small cell lung cancer (NSCLC) patients with EGFR mutation and brain metastases (BM). Therefore, we conducted a retrospective analysis to demonstrate the role of upfront RT in these patients. Materials and Methods: Patients that had histologically confirmed NSCLC with EGFR mutation, brain metastases, and received TKI or upfront RT with TKI were included in this study. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank test were used to evaluate and compare intracranial progression-free survival (iPFS), systemic PFS (sPFS), time to second-line systematic therapy (SST) and overall survival (OS). Results: Among the 93 patients included, 53 patients received upfront RT and TKI, and 40 patients received TKI only. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.38 (95% CI, 0.19 to 0.75, P = 0.006) and longer median time to sPFS (15.6 vs 8.9 months, P = 0.009). There were 9 out of 36 (25%) and 16 out of 34 (47.1%) patients who had oligo-progression received salvage RT in the RT group and TKI group, respectively. After the salvage RT, upfront RT did not prolong the median time to SST (23.6 vs 18.9 months, P =0.862) and OS (median time, 35.4 vs 35.8 months, P =0.695) compared to TKI alone. Conclusion: Compared to upfront intracranial RT, the salvage RT to oligo-progressive disease allowed patients getting TKI to have similar time on initial TKI and OS despite worse iPFS. The best timing of intracranial RT remains to be further verified.

The Efficacy of Upfront Intracranial Radiation with TKI Compared to TKI Alone in the NSCLC Patients Harboring EGFR Mutation and Brain Metastases