The varied treatments, including EGFR-TKIs, may affect the occurrence of SBM in mutated-EGFR patients. Some pilot studies demonstrated that first generation of EGFR-TKIs therapy impacted the development of BM progression in advanced NSCLC [24–26]. However, this issue was not further investigated nor concluded in the recently published reports [4–6, 20, 21], possibly due to limitation of the primary goals and designs of their studies. Our result showed that first generation of EGFR-TKIs treatment as 1st setting is associated with SBM occurrence in mutated-EGFR patients (P = 0.015). One of the popular explanations for this phenomenon is that the discordance of drug concentration of EGFR-TKIs between in cerebrospinal fluid and in serum [27, 28], and the overall survival benefit of EGFR-TKIs provide chance and time for cancer cell colonization and proliferation in the brain, respectively. We acknowledged that the study population in Table 5 was small and highly selected, therefore large-scale studies are warranted to draw a firm conclusion in this issue. In addition, the authors also recognized that this finding could not be directly employed to the patients who receive third generation of EGFR TKIs (eg., Osimertinib, AZD3759), which has been reported to effectively penetrate the blood-brain barrier and display anti-tumor activity in the brain [29, 30].