ReviewTreatment options for EGFR mutant NSCLC with CNS involvement—Can patients BLOOM with the use of next generation EGFR TKIs?
Introduction
Lung cancer remains a leading cause of death worldwide and the majority of the non-small-cell lung cancer (NSCLC) is diagnosed in the advanced stage [1]. Brain metastases (BM) and leptomeningeal metastases (LM), are frequent sites of progression, accounting for 10–15% at the time of diagnosis and 30–50% cumulatively throughout the course of the disease [2], [3], [4]. Central nervous system (CNS) metastases can cause significant morbidity including neurological deficits, reduced quality of life and poorer survival with a median survival of 4–6 months [5], [6].
The treatment landscape of NSCLC had undergone a paradigm shift with the discovery of activating epidermal growth factor receptor (EGFR) [7] and subsequent trials have shown EGFR tyrosine kinase inhibitors (TKIs) to be superior to chemotherapy in terms of objective response rate (ORR), progression free survival (PFS) and quality of life [8], [9], [10]. With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of brain metastases has been observed during the course of the disease. In a study of NSCLC patients without baseline brain metastases, CNS progression occurred at a rate of about 50% at 3 years [11]. The effect of EGFR-TKI and NSCLC EGFR mutation status on the risk of CNS progression has been published with conflicting results. In a study of patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib, the 1- and 2-year cumulative risk of CNS progression was 7% and 19%, respectively [4]. In a larger study, the one and two year cumulative risk of CNS progression was 6%, and 21% in the EGFR-TKI group versus 19%, and 32% in the chemotherapy group [12]. One limitation of these two studies is the risk of CNS progression was not independently examined in a NSCLC cohort without EGFR mutations, thereby limiting the ability to evaluate a possible altered biologic predisposition of EGFR mutated lung cancer for CNS sites.
Whilst the systemic efficacy of EGFR TKIs has been well established, its activity in intracranial disease has, until recently, been less well established [13]. Patients with active or untreated CNS metastases are often excluded from the NSCLC clinical trials leading to the limited data in this patient subpopulation. Some early phase and retrospective data have reported activity of EGFR TKIs in CNS metastases, either as monotherapy or as part of multi-modality approach. Thus this is an area of unmet clinical need and new therapeutic approaches are warranted [4], [14], [15], [16].
This review article aims to review the current strategies in the management of patients with EGFR mutant NSCLC with CNS metastases or LMD with a focus on EGFR TKIs, and in particular, a new generation of EGFR TKI with potentially higher CNS activity.
Section snippets
Brain metastases and blood brain barrier (BBB)
The CNS is shielded by BBB and is considered a pharmacologic sanctuary site. The successful treatment of CNS metastases would need to take into account individual drug pharmacokinetics as the majority of drugs are substrates for the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistance protein (BCRP). These transporters are highly expressed in the BBB and actively remove drugs including chemotherapy from CNS [17], [18]. In addition, some chemotherapeutic agents and
Treatment strategies for EGFR mutant NSCLC with brain metastases
Several strategies are available to treat NSCLC patients with EGFR mutant with CNS metastases including the use of local therapy such as surgical resection, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) and the use of systemic therapy such as chemotherapy and EGFR TKIs (Table 2). More recently, there has been interest in using immune checkpoint inhibitors in patients with advanced NSCLC with brain metastases.
Treatment outcomes for leptomeningeal metastases (LM)
LM is become an increasingly common diagnosis due to prolonged survival of patients with metastatic disease and improved diagnostic methods. LM is detected in 1–28% of NSCLC patients at the time of diagnosis. The time from initial diagnosis to the onset of LM ranges from 7 to 17 months [51], [52], [53], [54], [55]. Patient with leptomeningeal metastases (LM) generally has poor outcome with median survival of around 3–6 months [55], [56]. Traditionally, in the era prior to the introduction of
New strategy: role of next generation EGFR TKIs osimertinib and AZD3759
Unfortunately, treatment options discussed above have its limitations especially for LM and there is need to develop treatment that can cross the BBB effectively. The BLOOM trial (NCT02228369) is a phase I trial investigating patients with advanced EGFR mutant NSCLC patients with CNS metastases and LM comprising of two treatment arms: osimertinib and AZD 3759.
Conclusion
The treatment paradigm of advanced NSCLC has changed dramatically with the discovery of sensitizing EGFR mutations and the effectiveness of EGFR TKI in this molecular subgroup of NSCLC. The development of CNS metastases is common in this patient group and is associated with a reduced quality of life and poorer survival and can often be a therapeutic challenge. Traditional therapies such as surgery or WBRT are associated with modest activity. The current generation of EGFR TKIs are active but
Conflicts of interest
Chee-Seng Tan has received honoraria from AstraZeneca, Merck, Boehringer Ingelheim, Novartis, Eli-Lilly, Eisai and Bristol-Myers Squibb; Byoung Chul Cho has received research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST and consulting role from Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly; Ross Soo has received honoraria from Astra-Zeneca, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho and research grant from
Acknowledgements
RAS is supported by the National Medical Research CouncilNMRC/CG/012/2013, the National Research Foundation Singapore, the Singapore Ministry of Education under its Research Centres of Excellence initiative.
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