The present study analyzed the outcomes of patients with EGFR-mutant NSCLC with BM who initiated first-line EGFR-TKI at our institution since 2011, when gefitinib had become reimbursable for first-line chemotherapy from the Korean national health insurance system. The outcomes of the current study cohort, including OS, PFS, and IC-PFS, were generally comparable with those of previous retrospective studies. In addition, we compared the treatment results of the present study with those of LUX-Lung 7, a randomized trial of afatinib versus gefitinib as a first-line treatment for EGFR-mutant NSCLC, with a preponderance of East Asian patients [10, 11]. The median OS of the current study cohort was somewhat shorter than that of the LUX-Lung 7 trial (27.9/24.5 months) [11]. However, the LUX-Lung 7 trial included only ECOG PS 0 or 1 patients with a small proportion of patients with BM (16%), whereas the present study consisted of a significant number of patients with ECOG PS 2 or 3 (26%) [10]. Furthermore, the median OS of patients with ECOG 0 or 1 (23 months) in the present study was almost similar to that of the LUX-Lung 7 trial [11]. Moreover, the median PFS of the present study cohort (9 months) was comparable to that of patients with BM (7.2/7.4 months) in the LUX-Lung 7 trial [10]. These findings suggest that the current treatment outcomes of real-world practice are at least not inferior to those of clinical trial that consisted of selected patients with a relatively good health status, despite the limitation of an indirect comparison of two studies.
The current study demonstrated that exon 19 deletion was the only prognostic factor associated with favorable OS among various clinical characteristics. In patients with BM as well as unselected population of EGFR-mutant metastatic NSCLC including the cohort of our previous study, several studies showed better OS in patients with exon 19 deletion than in those with other mutations such as L858R [1, 9, 12–14].
The most controversial issue in the management of EGFR-mutant NSCLC with BM is the incorporation of local treatment. Although many retrospective studies showed conflicting results [5–8, 15–20], a few meta-analyses revealed better OS by addition of local treatment [2, 21, 22]. Furthermore, a large retrospective study from the United States demonstrated improved OS using upfront local treatment compared with EGFR-TKI alone [1]. The benefit of additional local treatment in NSCLC patients with BM treated with EGFR-TKI has the following biologic basis. First, many studies have shown that EGFR-mutant NSCLC is highly radiosensitive in both clinical and preclinical settings [1, 23]. Second, radiation can disrupt blood-brain barrier, leading to increased penetration and cerebrospinal fluid concentration of EGFR-TKI [5, 20–22]. Third, EGFR-TKI may radiosensitize NSCLC cells [17, 22]. Finally, due to the discordance of EGFR mutations between the primary tumor and BM in some patients, EGFR-TKI can be ineffective to EGFR-wild type BM lesions [2, 5].
In terms of local modalities, SRS, such as GKS, combined with EGFR-TKI, seems to be the best approach because of its convenience and less toxicity, such as in neurocognitive dysfunction, and because several studies have indicated that it showed better OS than WBRT [1, 2, 21, 22, 24, 25]. However, in the present study, no difference was found in OS, PFS, and IC-PFS between GKS and WBRT despite the higher proportion of patients with poor PS and multiple BM lesions in the WBRT group. These results suggest that WBRT can be considered a useful alternative for patients unsuitable for SRS.
In contrast to previous large studies showing the advantage of additional local treatment [1, 2, 17, 20–22], no significant difference was found in the OS, PFS, and IC-PFS between patients who underwent local treatment and those who were treated with EGFR-TKI alone in the present study. The significantly higher proportion of asymptomatic BM patients in the EGFR-TKI alone group and the absence of a significant difference in the outcomes between the local treatment and EGFR-TKI alone groups in patients without CNS symptoms may explain such results. Several retrospective studies have investigated the benefit of adding local therapy to EGFR-TKI in EGFR-mutant NSCLC patients with asymptomatic synchronous BM, but they showed conflicting results in terms of OS [8, 16, 18, 19]. However, direct comparison with the current study seems to be difficult because some of these ones analyzed patient cohorts treated with WBRT alone [18] or including second or further line of EGFR-TKI therapy [8, 19]. Upfront EGFR-TKI may be a useful option for certain subgroups of EGFR-mutant NSCLC patients with BM such as those having no CNS symptom or a smaller number of BM lesions, given its antitumor activity in BM in addition to extracranial lesions [5, 7, 20]. Furthermore, the initiation of systemic treatment is not delayed with the avoidance of potential toxicity of local treatment [1]. However, a prospective randomized trial is essential to define the optimal treatment strategy for EGFR-mutant NSCLC patients with BM, although it seems to be difficult to conduct. In patients who receive upfront EGFR-TKI, close surveillance with brain imaging seems to be necessary to conduct a timely local treatment in case of IC progression.
This study analyzed all EGFR-mutant NSCLC patients with synchronous BM who had started EGFR-TKI as the first-line therapy in a single institution, during the defined period with a mature follow-up. Whereas many previous studies investigated WBRT alone cohorts or rather heterogenous population including second or more line of EGFR-TKI and metachronous BM [7, 8, 17–19], the current study analyzed only synchronous BM patients treated with first-line EGFR-TKI with more frequent usage of GKS than WBRT. Therefore, the results of the present study can reflect the treatment outcomes of real-world clinical practice in Korea.
However, this study has several limitations. First, this work is a retrospective analysis from a single institution with a relatively small sample size including patients treated with three types of EGFR-TKI. Second, the patients treated with local treatment only or best supportive care were not included in the analysis. Third, given the retrospective nature of the analysis, we did not analyze the potential toxicities associated with local treatment and their impact on quality of life. Fourth, because follow-up brain imaging was performed according to the discretion of the physician in many cases, not all patients were evaluated for IC-PFS. Finally, as osimertinib has been available in routine practice since December 2017 in Korea, the number of patients treated with third-generation EGFR-TKI such as osimertinib and olmutinib after progression was small (12 patients).
In conclusion, EGFR-TKI may result in favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of brain metastatic lesions or local treatment modalities. In addition, patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.