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  In this article
 »  Abstract
 » Introduction
 »  Brain Metastases...
 »  Prognosis of Non...
 »  Management of Br...
 »  T790m Mutation a...
 » Conclusion
 »  References
 »  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 5  |  Page : 37-44
 

Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients


1 Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Asian Cancer Institute, Somaiya Ayurvihar, Mumbai, Maharashtra, India
3 Max Super Speciality Hospital, Mohali, Punjab, India
4 Medical Advisor Oncology, Medical Affairs, AstraZeneca, India

Date of Web Publication29-Dec-2017

Correspondence Address:
Dr. U Batra
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_532_17

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 » Abstract 


Metastases to central nervous system (CNS) are very common in nonsmall cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-positive mutation. Brain is the most affected part of CNS where blood–brain barrier (BBB) presents a challenge to currently available chemotherapeutic agents as well as first- (erlotinib and gefitinib) and second (afatinib)-generation EGFR tyrosine kinase inhibitors (TKIs) due to their poor penetrability. A rapid development of EGFR T790M secondary mutation is another cause of treatment failure, and patients tend to progress despite initial response to first- and second-generation EGFR TKIs. Moreover, conventional treatments with heavy dose of radiation have a number of side effects compared to benefits attained. Recently, third-generation EGFR TKIs have been developed with proven efficacy in various clinical setups against EGFR mutation-positive cases of brain metastases in NSCLC. One such agent, osimertinib, is available in India. It has not only better penetration ability to BBB compared to other EGFR TKIs but also has significantly increased potency for most prevalent EGFR T790M mutations. Furthermore, it is active in patients who progress upon first- and second-generation EGFR TKIs. The purpose of this review article is to present an updated clinical preview of EGFR TKIs over conventional treatment, mainly radiation therapy to consider them as “use first” agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.


Keywords: Brain metastases, Epidermal growth factor receptor, Osimertinib, Non-small cell lung cancer, T790M, Tyrosine kinase inhibitors


How to cite this article:
Batra U, Lokeshwar N, Gupta S, Shirsath P. Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients. Indian J Cancer 2017;54, Suppl S1:37-44

How to cite this URL:
Batra U, Lokeshwar N, Gupta S, Shirsath P. Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients. Indian J Cancer [serial online] 2017 [cited 2019 Aug 24];54, Suppl S1:37-44. Available from: http://www.indianjcancer.com/text.asp?2017/54/5/37/221924





 » Introduction Top


Lung cancer accounts for 19% of cancer-related deaths worldwide, whereas, in India, this number constitutes 9.3%.[1] According to GLOBOCAN 2012 report, lung cancer was ranked fourth overall among the various types of cancer after breast, cervical, and oral cavity in India.[2] Lung cancers can be histologically subtyped as nonsmall cell lung cancer (NSCLC) and small cell lung cancer, of which NSCLC accounts for approximately 85%. Distant metastases at the time of presentation of NSCLC are a frequent clinical problem. Approximately 30%–40% of NSCLC patients present with metastatic disease at the time of diagnosis.[3],[4] The most common metastatic site is bone, followed by the lungs, brain, liver, and adrenal glands.[5]

Approximately 7.4% of patients have brain metastases (BMs) at baseline, and about 20%–40% of patients develop it as disease progression.[6],[7] The majority of BMs (80%) occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brain stem.[8] The reported median survival of these patients is 3.4 months with poor life expectancy. In addition, many suffer a substantial loss of autonomy because of neurocognitive and functional deficits, as well as morbidity associated with medications such as antiepileptic drugs and steroids.[6] Treatment options available for BM include surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), systemic chemotherapy, molecular-targeted drugs, immunotherapy, and combination therapy, of which WBRT is regarded as the standard therapy but not without a downside of abundant neurotoxic side effects.[7] With technological and molecular diagnostic advancements, SRS and targeted therapy are coming up in a big way for the treatment of BM with less toxic complications.

It is now revealed that many of the NSCLC clones are driven by a certain set of mutations which lead to altered signal transduction pathways. One such pathway is the epidermal growth factor receptor (EGFR) signaling pathway, wherein activating (sensitizing) mutations in tyrosine kinase (TK) domain result in reduced responses to chemotherapy. Activating mutations of the EGFR kinase domain are present in 10%–15% of patients with lung adenocarcinoma in North America and up to 60% of patients in Asia.[9] Patients with EGFR-mutant NSCLC may have a higher likelihood of being diagnosed with BMs because of prolonged survival from targeted systemic agents and the increased quality of central nervous system (CNS) imaging.[10]

Patients with EGFR-mutant NSCLC may have a higher probability of having BM.[11] Therefore, prognosis of NSCLC patients with BM may also be associated with the status of EGFR mutations.[12] Novel targeted EGFR tyrosine kinase inhibitors (TKIs) namely erlotinib, gefitinib ( first generation), and afatinib (second generation) are available and now considered as first-line treatment in EGFR mutation-positive NSCLC patients.[13] These agents have demonstrated superior clinical benefits in various randomized clinical trials compared with chemotherapy.[12]

However, most of the patients develop acquired resistance to first- and second-generation EGFR TKIs during the course of the treatment, and one of the common acquired mutations of clinical relevance is T790M mutation (50%–60% of all resistance cases) in EGFR TK domain.[14] Moreover, treatment in case of BM remains a challenge due to their poor blood–brain barrier (BBB) penetration ability.[15] Recently, the third-generation EGFR inhibitors, namely, osimertinib, rociletinib, HM61713, and others have emerged as potential therapeutics with better BBB penetration capabilities. More importantly, third-generation TKIs have a significantly increased potency for most prevalent EGFR T790M mutations as compared to first- and second-generation EGFR TKIs.[14]

The purpose of this article is to highlight the better BBB-penetrating ability of third-generation EGFR TKI osimertinib, and hence its importance in the treatment of EGFR T790M mutation-positive patients with BM, who progress upon first- and second-generation EGFR TKIs. The entire information has been aligned to create an awareness in the medical fraternity about the benefits of EGFR TKIs over conventional treatment, mainly radiation therapy, to consider this class of drugs as “use first” agents while starting the treatment.


 » Brain Metastases and Mutational Status of Nonsmall Cell Lung Cancer Top


Over the past decade, patients of NSCLC have been further defined at the molecular level on the bases of recurrent “driver” mutations that occur in multiple oncogenes including AKT1, anaplastic lymphoma kinase (ALK), BRAF, EGFR, FGFR1, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1.[16] However, EGFR mutations have been widely explored and seem to have significant implications in deciding targeted therapy in metastatic NSCLC [Table 1]. In a retrospective analysis, relationship between EGFR mutation status and BM at the initial presentation was analyzed. A strong association between EGFR mutation status and BM was found (adjusted odds ratio = 3.83, P = 0.001); nevertheless, no association was observed between EGFR mutation status and extracranial metastases (adjusted odds ratio = 1.73, P = 0.079).[18]
Table 1: Epidermal growth factor receptor mutation status in patients with nonsmall cell lung cancer and brain metastases

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In addition, multiple investigators have now reported several lines of evidence involving the importance of liver kinase B1 (LKB1, aka, serine-threonine kinase 11) as a tumor suppressor gene in lung cancer development and progression in both human and model organisms. Moreover, coordination between losses of LKB1 and the oncogene, KRAS, also predicted BM in NSCLC patients.[22]

Moreover, adenocarcinomas with FGFR1 gene amplification and ALK1 rearrangement correlated significantly with BM. FGFR1 amplifications in BM of adenocarcinomas were fivefold more frequent than in the primary tumors.[23] Moreover, CXCR4 protein seems to play a role in BM. It had been observed that CXCR4 protein was overtly overexpressed in patients with brain-specific metastases compared to NSCLC patients with metastases in other organ and without metastases.[23] Another factor ADAM9 levels were found to be relatively higher in BM than the levels observed in primary lung tumors. ADAM9 regulates lung cancer metastases to the brain by facilitating the tPA-mediated cleavage of CDCP1.[23]


 » Prognosis of Nonsmall Cell Lung Cancer Patients With Brain Metastases Top


Age, number of brain lesions, performance status, and the presence of extracranial metastases are the variables that better define prognosis. The Radiation Therapy Oncology Group (RTOG) performed a recursive partitioning analysis (RPA) from a historical database, where 1200 patients were treated with WBRT from three RTOG BM trials and published a prognostic scoring system. Three scoring classes were identified based on patients' Karnofsky performance score, age, status of primary tumor, and extent of extracranial disease [Table 2]. Median survival ranged from 2.3 months for patients in Class III to 7.1 months for those in Class I.[6] The RPA system can be applied to any patient with a BM, but a newer prognostic index, the diagnosis-specific graded prognostic assessment (GPA) score, provides a higher level of refinement where the median survival ranges from 2.79 to 25.3 months. The GPA accounts for primary tumor type and unique features applicable to each primary tumor, making the system relevant to daily clinical practice.[24]
Table 2: Prognostic indexes for brain metastases

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Molecular biomarkers such as EGFR (del-19 and L858R) have positive, and others have negative (e.g., ERCC1, BRCA1, TP53, and KRAS) prognostic value. It has been reported that among patients with a druggable oncogene driver (EGFR and ALK), between 44% and 60%, develop BM in the course of their disease.[25]


 » Management of Brain Metastases in Nonsmall Cell Lung Cancer Top


A summary of recommendations for the management of BM in NSCLC patients has been presented in [Table 3]. The approach to treat NSCLC patient with BM is based on each patient's clinical condition. The classical treatment approach for BM is WBRT.[27] However, NSCLC has been regarded as a relatively radio-resistant malignancy, and the usual dose of WBRT may not be sufficient to eradicate the lesions. Moreover, there remains a possibility of neurocognitive decline due to radiation.[28] In addition, associated side effects further worsen the patients' health and have a negative impact on quality of life (QoL).[29]
Table 3: Recommendations for the management of brain metastases in nonsmall cell lung cancer patients[25],[26]

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WBRT-related toxicities have been enlisted in [Table 4].[30]
Table 4: Classification of whole-brain radiotherapy-related toxicities

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Recently, a survival benefit has been reported for patients with a single BM treated with SRS; however, due to the poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the BBB, with reported response rates to chemotherapy ranging from 15% to 30% (overall survival: 6–8 months).[31] It is well-established fact now that treatment of EGFR mutation-positive patients with BM require different approaches. Such patients should receive EGFR TKI first and then delay brain irradiation until either CNS imaging or symptom progression, to delay WBRT-related neurological sequels.[32]

Role of first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors in the treatment of nonsmall cell lung cancer patients with brain metastases

Most recent clinical trials have reported the superior efficacy of first- and second-generation EGFR TKIs in EGFR-positive patient population [Table 5]. Overall, the data reported suggest that EGFR mutation may play a key role in the activity of EGFR TKIs, even in the presence of BM.
Table 5: Current clinical trials on first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors for epidermal growth factor receptor mutation positive nonsmall cell lung cancer patients

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Blood brain barrier penetration ability of first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors

First- and second-generation EGFR TKIs have proven efficacy in the treatment of intracranial BM. However, they may not achieve desired target concentration due to poor penetration of the BBB.[51] Evidences suggest that both erlotinib and gefitinib have limited concentrations in cerebrospinal fluid (CSF) despite their small molecular size.[52],[53] In fact, at standard dose of erlotinib and gefitinib, CSF levels are lower than plasma levels.[54] Preclinical studies demonstrated that EGFR TKIs are a substrate of BCRP1 and P-gp, drug efflux transporters.[52] Therefore, these transporters may be responsible for reduced brain penetration of erlotinib and gefitinib.

Based on the pharmacokinetic data and the reduced efficacy of these agents in BM, TKIs seem to have limited access to CNS metastases compared with extracranial metastases. The limited CNS exposure of TKIs can explain the high incidence of BM in EGFR-mutated NSCLC despite the good control of extracranial disease during EGFR TKIs therapy.[55] It is also evident that BM can damage the integrity of BBB and therefore may favor TKIs penetration. Hence, erlotinib and gefitinib at the standard dose may penetrate BBB in the presence of BM and improve their CNS concentration with a consequent improvement in central activity.[54]

Furthermore, greater penetration of erlotinib and gefitinib has been observed at higher doses, which allows EGFR TKIs to exert greater activity in CNS. However, this dose escalation is inevitably linked with more frequent and significant side effects such as high-grade fatigue, nausea, and liver damage.[54] Although afatinib shows incomplete penetration to BBB, it has potential to treat CNS metastases effectively due to lower median inhibitory concentration compared to erlotinib and gefitinib as shown in in vitro studies.[56] Hence, afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases.[57] [Table 6] summarizes the details of penetration characteristics of first- and second-generation EGFR TKIs.
Table 6: Central nervous system penetration of first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with nonsmall cell lung cancer and brain metastases

Click here to view



 » T790m Mutation and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Top


Although NSCLC patients harboring EGFR-sensitizing mutations derive significant clinical advantage from EGFR TKIs therapy, after about 9–13 months from the beginning of treatment, disease progression occurs.[54] This is because acquired resistance develops due to further mutations in TK domain. The most important mutation is T790M in exon 20, which is associated with ~62% of the patients with acquired resistance to first-generation EGFR TKIs. In this point, mutation T790M, methionine substitutes for threonine at amino acid position 790 of EGFR gene. The substitution of methionine with threonine at position 790 in the exon 20 blocks the binding of first-generation EGFR TKIs to the ATP pocket and increases their affinity to ATP rather than to EGFR TKIs. Re-biopsy results of various samples demonstrated that EGFR T790M mutation was present in approximately 50%–60% of resistant cases. Therefore, EGFR T790M mutation has emerged as a major culprit in developing acquired resistance against first- and second-generation EGFR TKIs.[61],[62],[63]

Third-generation EGFR TKIs (osimertinib, rociletinib, HM61713, and others) have been evolved as T790M mutant-specific inhibitors. Initial data support their efficacy and safety in NSCLC patients with BM. AZD9291 (osimertinib), a novel third-generation TKI, specifically and irreversibly binds the cysteine-797 residue in the ATP-binding site of EGFR. It has recently obtained the accelerated Food and Drugs Administration approval in -mutated NSCLC with documented T790M resistance mutation.[54]

CO1886 (rociletinib) is another irreversible third-generation mutant-selective EGFR TKI, specifically directed against common sensitizing EGFR mutations and T790M. Rociletinib had initially garnered great attention but has now been abandoned because of the initial reported ORR of 59% has been reduced to 45%.[64] Moreover, side effect profile of rociletinib has also raised concerns about the optimal pathway forward.[65] Results of activity in BM of other third-generation TKIs such as ASP8273, EGF816, and HM61713 are still awaited.[54]

Osimertinib - The third-generation agent

Recently, with the introduction of third-generation EGFR TKI, osimertinib in the US (November 2015) and European market (February 2016), the treatment has become possible in T790M mutant-positive advanced NSCLC patients who acquired resistance in the due course of first- and second-generation EGFR TKIs treatment.[57] Osimertinib (TAGRISSO™, AZD9291; AstraZeneca, London, UK) is a mono-anilino-pyrimidine, orally available, irreversible, third-generation EGFR TKI, which inhibits EGFR, through the C797 amino acid covalent bond, both sensitizing mutations (exon 19 deletion, L858R) and double mutants harboring T790M at a ninefold lower concentration compared with wild-type EGFR.In vitro assays showed that osimertinib also possesses a certain grade of activity at clinically relevant concentration against ERBB2, ERBB3, ERBB4, BLK, and ACK1. Consistently, preclinical models involving NSCLC cell lines and tumor xenografts showed that osimertinib exerts an impressive activity against those tumors harboring L858R, exon 19 deletions alone, or in coexistence with T790M mutations.[66]

Efficacy of osimertinib in various clinical studies

A joint analysis of AURA and AURA 2 studies reported that 39% of total enrolled patients (162/411) had BM. The systemic ORR of overall population was 61%, and it became 56% and 64% in patients with or without BM, respectively. In addition, cases of shrinkage of brain lesions were also reported.[54] Preliminary antitumor activity of osimertinib in the brain has been reported in the Phase I BLOOM trial. Moreover, the ongoing Phase III first-line FLAURA trial (NCT02296125), which is comparing osimertinib with erlotinib or gefitinib as first-line treatment in patients with common EGFR mutations will define whether a third-generation EGFR TKI could become standard first-line treatment in these patients.[67] Currently, the Real-World Treatment Study of osimertinib for Advanced/Metastatic EGFR T790M Mutation NSCLC (ASTRIS) is going on to assess the efficacy and safety of single-agent osimertinib in a real-world setting in EGFR T790M mutation-positive NSCLC, who have received prior EGFR TKIs therapy.[54] Results of most recent clinical trials support osimertinib to be recommended as first-line therapy in NSCLC patients with T790M EGFR mutation and who progressed upon first- and second-generation EGFR TKIs. The results have been summarized below.

Bloom trial: Blood–brain barrier penetration ability of osimertinib in patients with leptomeningeal metastases

Leptomeningeal metastases (LMs) occur in almost 5% of NSCLC patients with median survival of 4–6 weeks.[68] In the BLOOM study (NCT02228369), twenty patients with EGFR mutation advanced NSCLC who had progressed on prior EGFR TKI therapy and had LM confirmed by positive CSF cytology received, osimertinib 160 mg once daily (qd). Response was assessed (by investigator) in two cohorts: T790M unselected and T790M positive (by central test). It was demonstrated that osimertinib penetrates the BBB. Mean concentration of osimertinib in CSF was 7.51 nM (range: 2.19–21.1 nM) at steady state; CSF: free plasma ratio was 16%.[69] Osimertinib demonstrated radiological improvement in 33% patients and stable disease in 43% patients. For CNS lesions, osimertinib was associated with clinically promising activity. Additional observations included confirmed CSF cytology clearance (i.e., no tumor cells) in two patients and confirmed improved neurologic function in five patients.[51],[70] Hence, encouraging activity and manageable tolerability in patients with LM from EGFR mutation-positive NSCLC was observed at 160 mg once daily dose of osimertinib, with a median treatment duration of 6 months.[69]

AURA 3 clinical trial: Efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed

In this randomized Phase III trial, patients with T790M-positive advanced NSCLC, who had disease progression after first-line EGFR TKI therapy, received either oral osimertinib 80 mg once daily or intravenous pemetrexed in combination with carboplatin or cisplatin. The median progression-free survival (PFS) time and objective response rate were significantly greater with osimertinib than platinum therapy plus pemetrexed (P< 0.001). Among 144 patients with metastases to the CNS, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio: 0.32; 95% confidence interval: 0.21–0.49). It was concluded that osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced NSCLC (including those with CNS metastases) in whom disease had progressed during first-line EGFR TKI therapy.[71]


 » Conclusion Top


It is common to develop EGFR-positive BM in advanced NSCLC patients. Although surgical resection and radiation therapy remain the cornerstone of treatment for symptomatic patients, a plentiful of neurological toxicities associated with the RT/WBRT further deteriorate neurocognitive disorders in patients with BM and affect their QoL. Despite the efficacy and superiority of first- and second-generation EGFR TKIs in the treatment of extracranial NSCLC over conventional therapy, treatment of CNS metastases remains a challenge primarily due to acquired T790M mutation and secondarily due to their poor BBB penetration ability. The next generation EGFR TKI osimertinib has improved BBB penetration and recent clinical trials supported its efficacy in BM patients, who progress upon first- and second-generation EGFR TKIs. Moreover, osimertinib has shown promising potency to inhibit the major resistance mutation, T790M in EGFR TK domain. The trends have been changing and now a general consensus is building up to try EGFR TKIs before proceeding to RT or surgery in EGFR-sensitive cases. Further trials are going on to determine the role of EGFR TKIs in combination with SRS and WBRT modalities.

Acknowledgment

The authors acknowledge AstraZeneca Pharma India Ltd., and Jeevan Scientific for Medical writing and editing support.

Financial support and sponsorship

Financial support to authors - Nil.

The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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