Brain metastases occur in about 10% of NSCLC patients at the initial diagnosis and in about 40–55% of patients during the entire course of the disease. In particular, EGFR mutations show a strong association with the risk of brain metastases at the initial time of diagnosis and follow up in lung adenocarcinoma patients [
]. CNS brain metastasis confers a worse quality of life and prognosis [
]. Conventional chemotherapy drugs are difficult to pass through the blood brain barrier. NSCLC patients with multiple brain metastases treated with whole brain radiotherapy (WBRT) have an overall survival (OS) of 3–6 months and a 1-year survival rate of only 10–20% [
]. Concurrent chemotherapy with WBRT can improve the effective rate but cannot prolong OS of NSCLC brain metastases patients [
]. With continuous improvement of systemic treatment for NSCLC, possible therapeutic strategies for preventing and controlling brain metastasis to improve overall disease control and quality of life becomes more critical.
The outcomes from multiple prospective phase III clinical trials have shown significantly better clinical efficacy in EGFR mutant advanced NSCLC patients initially treated with first- generation EGFR inhibitors (gefitinib or erlotinib) compared with upfront chemotherapy, with an objective response rate (ORR) of 71–83% and PFS of 9–13 months [
]. Recently published data showed that erlotinib and gefitinib could efficiently pass through the blood brain barrier and target brain metastases of NSCLC patients harboring sensitive EGFR mutations [
]. For patients with brain metastases, gefitinib as the first-line treatment attained an intracranial objective response rate (iORR) of 87.8%, while erlotinib as second-line treatment reached an iORR of 75% [
]. Two retrospective analyses by Heon et al. [
] reported that first-line TKI gefitinib/erlotinib treatment for EGFR mutant advanced NSCLC patients resulted in lower rates of CNS progression compared with first-line chemotherapy. These results indicated that gefitinib and erlotinib might have an effective role in prevention and treatment of CNS metastases in NSCLS patients harboring sensitive EGFR mutations. However, there is currently no definitive conclusion regarding comparative effectiveness between the two first generation TKIs gefitinib and erlotinib in the prevention and treatment of brain metastases in NSCLS with EGFR mutations. Erlotinib might be more effective in the prevention and treatment for brain metastases than gefitinib since the concentration of erlotinib in the cerebro-spinal fluid (CSF) reaches higher levels than that of gefitinib [
To our knowledge, there are no reports that directly compare erlotinib with gefitinib in preventing and controlling brain metastases in NSCLC patients harboring EGFR-sensitive mutations. The aim of this retrospective study is to analyze the prevention and control of brain metastases in a cohort of EGFR mutant NSCLC patients initially treated with erlotinib in comparison to that in a cohort initially treated with gefitinib.
In the study, the effects of erlotinib versus gefitinib as first-line treatment on the risk of CNS progression in advanced NSCLC patients with EGFR mutations was retrospectively analyzed. nTTP was significantly improved in preexisting brain metastases patients with first line erlotinib treatment compared with gefitinib (30 months vs 15.8 months,
P = 0.024). Although the cumulative incidence of CNS progression at 6-, 12-, and 18-months was not significantly different (
P = 0.181) in the erlotinib group compared with the gefitinib group, the HR of CNS progression for upfront erlotinib versus gefitinib was 0.695 (95% confidence interval [CI], 0.406–1.190), suggesting a CNS progression risk reduction of 30.5% in the erlotinib group. To our knowledge, this is the first retrospective study examining the impact of initial therapy of two first generation EGFR-TKIs on the prevention and control of CNS progression in EGFR–mutant NSCLC patients, which could provide an important basis for standardized management of EGFR-TKI therapy for CNS progression of NSCLC with EGFR-sensitizing mutations.
The two first generation EGFR-TKIs have not yet been demonstrated to be the therapeutic choice for treatment of patients with CNS progression carrying EGFR mutations. Heon et al. reported in retrospective studies that CNS progression in advanced NSCLC patients treated with chemotherapy was more than 40% and that the first generation TKIs (erlotinib or gefitinib) could significantly decrease CNS progression to about 30% [
]. However, there is no data to compare these two first generation TKIs with respect to CNS progression in advanced EGFR mutant NSCLC patients. In the present study,
-mutant advanced NSCLC patients without preexisting brain metastases showed no significant difference in the cumulative rates of CNS progression (
= 0.156) and the median nTTP (18 months vs 16 months,
= 0.392) between the erlotinib group and gefitinib group. However, for the advanced EGFR mutant NSCLC patients with prior CNS involvement, the time to occurrence of CNS progression was significantly prolonged after first-line erlotinib compared with gefitinib (30.0 months vs 15.8 months,
= 0.024), indicating the greater potential of erlotinib at slowing development of established CNS metastases from NSCLC than gefitinib. Our observations highlight the greater effectiveness and importance of controlling preexisting brain metastasis in
-mutant advanced NSCLC patients by erlotinib treatment.
Erlotinib significantly prolonged nTTP compared with gefitinib in the treatment of CNS metastases in NSCLC patients with preexisting brain metastasis. The related mechanism explaining such a result remains uncertain. However, data from several studies allows us to infer some possible hypotheses. The higher penetration of erlotinib through the brain blood barrier might explain why erlotinib treatment could prolong nTTP in preexisting brain metastasis. In phase I trials of targeted therapy, erlotinib and gefitinib delivered at standard daily dosing is the maximum tolerated dose or optimal biological dose, respectively, resulting in a plasma exposure concentration of erlotinib 7 times greater than that of gefitinib [
]. In addition, when EGFR-TKI serum concentrations were associated with CSF concentrations, the erlotinib CSF concentration was significantly higher than that of gefitinib (66.9 ± 39.0 nM vs. 8.2 ± 4.3 nM,
= 0.0008) [
]. Another experimental study from Carey and Li et al. [
] using kinetic analysis showed that erlotinib has a stronger antitumor effect than gefitinib when using the conventional recommended dose. Furthermore, a report performed by Masuda et al. [
] showed clinical improvements following the change to erlotinib therapy in lung adenocarcinoma patients with EGFR mutations who developed leptomeningeal metastases during gefitinib therapy. Our observations highlight the importance of elucidating the potential CNS efficacy of erlotinib.
For CNS progression in NSCLC patients without prior CNS metastases, no significant difference was found between erlotinib and gefitinib treatment. Notably, EGFR mutation status as a poor prognostic factor for the risk of brain metastasis in NSCLC has previously been demonstrated. In a retrospective trial of 314 lung adenocarcinoma patients with EGFR mutations, the multivariate model analysis showed a strong association between EGFR mutation status and brain metastasis (adjusted odds ratio = 3.83, 95% CI: 1.72-8.55,
= 0.001) [
]. While resistance to continued EGFR inhibition is common, acquired systemic resistance through the selection of resistance mutations or amplification of other oncogenes is usually detected after 6 to 12 months of therapy [
]. Previous studies have shown that CNS penetration of erlotinib and gefitinib at standard daily dosing is limited [
]. One additional recognized mechanism of pharmacokinetic resistance, a poor CSF-to-plasma ratio, occurs in patients who continue to have systemic disease controlled with gefitinib or erlotinib but display progression or new-onset CNS disease. Further clinical cohort studies need to be performed to examine this further. To achieve adequate CNS concentrations, the dosing schedule may also be important, for example pulsatile dosing schedules [
], concentrations of gefitinib [
] or designing new drugs (such as AZD3579) [
]. Additional possibility is another first generation EGFR-TKI, afatinib, which is much less commonly used in China due to the limited availability and cost-effect reasons. Martin Schuler et al. [
] showed afatinib significantly improved the ORR versus chemotherapy in patients with NSCLC and asymptomatic CNS metastases. Their findings suggested the clinical activity of afatinib in EGFR mutation–positive NSCLC patients with brain metastases. However, to our knowledge, there are no study comparing the effectiveness on the NSCLC patients with CNS metastases of three first generation EGFR-TKIs in parallel.
Another concern when considering to put this strategy forward in clinical practice would be the neuro recognition function or the quality of life (QoL). As both the neuro recognition function and QoL measurements require special methodologies, these data are missing in our cohort. However, previous report showed that grade 3/4 adverse event rates were similar (70.0%) in WBRT with or without erlotinib, except for rash was higher and fatigue was higher. No statistically significant quality of life differences was found [
]. But, again, the neuro recognition function were not reported. With the survival improvement of NSCLC patients with CNS metastases, additional studies focusing on these long term effects will be in need.
Our findings are limited to those of any retrospective analysis. First, the number of brain metastases patients at the time of diagnosis was not balanced in the erlotinib group and gefitinib group. However, the therapeutic measures for preexisting CNS metastasis were well balanced between the two cohorts and the results of nTTP for patients with preexisting CNS metastasis should be valid. Second, the CSF-to-plasma concentration ratios were not detected in this study. In addition, we did not evaluate other clinically important genetic changes besides EGFR mutations, for example, KRAS mutation, c-Met amplification, or the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (ALK) translocation. Thus, we were unable to evaluate possible interactions between these genes and CNS progression. Despite these limitations, our study was valuable in view of the new insights that erlotinib showed significantly prolonged nTTP compared with gefitinib in the treatment of CNS metastases in NSCLC patients with preexisting brain metastasis, and that no difference exists in treatment of micrometastatic CNS disease and CNS progression in NSCLC patients without prior CNS metastases.
At present, there is still a lack of effective drugs for brain metastasis of NSCLC. Our findings provide a rationale for physicians to use erlotinib for the treatment of CNS progression in EGFR mutant NSCLC. Our findings need to be further confirmed in prospective studies with a larger sample size. Due to some evidence of the beneficial effect and low toxicity of erlotinib [
], the clinical use of EGFR inhibitors concurrently with radiation therapy is currently being investigated in several clinical trials including the NCT 01887795 trial.
We are grateful to Dr. Nan Hu for critical reading and editing the manuscript, to Dr. Shi-Heng Zhang for the help in manuscript preparation.
This study was supported by grants from the National Natural Science Foundation of China (No. 81272499) to Prof. Zhen-Zhou Yang in collection and analysis of data, writing and preparation of the manuscript and Wu Jieping medical fund (No. 320.6799.1132) to Prof. Zhen-Zhou Yang in the design of the study and collection, analysis, and interpretation of data.
Availability of data and materials
All data generated or analysed during this study are included in this published article as Additional file
Conception and design: ZZY, BZ, MXL, HH, RQL. Development of methodology: HH, XH, ZZY. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): MXL, HH, GW, BZ, ZHR, YXZ, YW, ZZY. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): HH, XH, ZZY, BHL, ZMZ. Writing, review, and/or revision of the manuscript: MXL, HH, GDL, BHL, ZMZ, ZZY. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): MXL, HH, GW, HLX, ZZY. Study supervision: MXL, HH, ZZY. All authors read and approved the final manuscript.
ZZY Authorized prescription doctor for China Charity Federation Gefitinib charity project donated medicine; authorized prescription doctor for China Charity Federation Erlotinib charity project donated medicine doctor. No potential conflicts of interest were disclosed by the other authors.
Consent for publication
Ethics approval and consent to participate
The research protocol of current study has been approved by the ethics committees of Daping Hospital, Xinqiao Hospital and Southwest Hospital of Third Military Medical University as well as First Affiliated Hospital of Chongqing Medical University. Patients’ consent to participate is not applicable to this retrospective study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.