Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations

Approximately 40% of patients with non-small-cell lung cancer (NSCLC) develop brain metastasis during the course of their disease [1]. And the risk of brain metastasis is greater in patients harboring epidermal growth factor receptor (EGFR) mutations [2].

Compared with standard chemotherapy, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced NSCLC harboring EGFR mutations [3–6]. Several case reports and studies involving small patient series indicated successful treatment of brain metastasis using EGFR-TKIs [7–10]. However, few studies have compared individual EGFE-TKIs in terms of their efficacy against brain metastasis.

The aim of our study was to evaluate retrospectively the effect of two first-generation EGFR-TKIs (gefitinib and erlotinib) on brain metastasis in patients with NSCLC harboring EGFR mutations.

Several retrospective subset studies indicated that gefitinib was more likely to progress brain metastases in EGFR−mutant advanced NSCLC patients than erlotinib. Omuro et al. reported that 33% of patients treated with gefitinib showed CNS progression as the initial site of progression [11], and Yamamoto et al. reported 3.9% of patients treated with erlotinib showed CNS progression [12]. However, no prospective studies comparing gefitinib with erlotinib has been reported with regard to CNS progression.

In the PFS analysis of our study for patients with brain metastasis, there was a tendency toward a longer PFS in the erlotinib than in the gefitinib group (Fig. 1b). In the cumulative incidence analysis, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, among the patients who had brain metastasis before EGFR-TKI administration, there was a significant difference between the erlotinib and gefitinib groups (Fig. 2b). In the multivariate analysis, we found that receiving erlotinib (vs gefitinib) and absence of CNS metastasis before EGFR-TKI administration are favorable prognostic factor for CNS progression, while sex, age, and ECOG PS had no significant influence on CNS prognosis.

In a randomized phase 3 trial comparing gefitinib and erlotinib efficacy in lung adenocarcinoma patients pretreated with chemotherapy, Urata et al. reported equivalent PFS, overall survival (OS), response rate (RR), and disease control rate (DCR) between gefitinib and erlotinib treatments (8.3 and 10.0 months [HR, 1.093; 95%CI, 0.879 to 1.358; p = 0.424], 26.5 and 31.4 months [HR, 1.189; 95%CI, 0.900 to 1.570; p = 0.221], 58.9% and 55.0% [p = 0.476], and 81.7% and 84.4% [p = 0.517], respectively) [13]. The results of our study suggested that erlotinib has better efficacy to control CNS metastasis, and contributes to longer PFS among patients with brain metastasis than gefitinib. The maximum blood concentration and area under the curve were 2120 ng/ml and 38,420 ng/h/ml for an erlotinib dose of 150 mg daily (approved dose in Japan) [14] and 307 ng/ml and 5041 ng/h/ml for a gefitinib dose of 225 mg daily (the approved dose in Japan is 250 mg daily) [15], respectively. Togashi et al. reported that the cerebrospinal fluid concentration and penetration rate of erlotinib (150 mg daily) were significantly higher than those of gefitinib (250 mg daily) [16]. Because of these factors, erlotinib may be superior to gefitinib for controlling CNS metastasis.

Our study has some limitations. Baseline characteristics varied among the study subjects. This difference may have introduced potential bias, which in turn may have affected the study outcomes. First, more patients had brain metastasis in erlotinib group compared with gefitinib group. In the past report, disruption of the blood-brain barrier (BBB) in the presence of CNS metastasis is likely to lead to locally increased drug concentration [17]. Second, more patients had history of radiotherapy for brain metastasis in erlotinib group than gefitinib group. Zeng et al. reported that whole brain radiotherapy (WBRT) combined with an EGFR-TKI increase the BBB permeability of the EGFR-TKI [18]. Magnuson et al. demonstrated a tendency for upfront stereotactic radiosurgery (SRS) or WBRT followed by an EGFR-TKI to decrease intracranial disease progression better than an upfront EGFR-TKI followed by SRS or WBRT [19]. Third, Exon 19 deletion was detected more frequently in erlotinib group than gefitinib group in our study. Lee CK et al. reported that exon 19 deletions were associated with longer PFS than exon 21 L858R substitution in their meta-analysis [20]. Forth, more of the patients who received gefitinib, compared with the erlotinib, had a poor ECOG PS in this study. While few studies have compared PFS and OS after EGFR-TKI treatment between patients with a good PS and those with a poor PS, Kudoh et al. reported that elderly patients with a poor PS are more likely to develop interstitial lung disease than younger patients with a good PS [21]. These differences of baseline might have had a favorable influence on the patients in the erlotinib group of our study.

On the other hand, more patients had history of chemotherapy prior to EGFR-TKI therapy in erlotinib group than gefitinib group. Xu J et al. reported that first-line therapy with EGFR-TKI therapy achieved longer PFS and higher objective response rate (ORR) compared with second line therapy [22]. This factor could have had adverse influence on erlotinib group.

In addition, due to the retrospective nature of the study brain MRI or CT was not performed routinely but only when clinically indicated, which may have affected the evaluation of the time to CNS progression.

This retrospective study suggested the value of erlotinib as a more promising treatment for patients with EGFR mutant NSCLC with brain metastasis compared with gefitinib. Further pre-planned and large-scale studies are warranted to confirm these results.