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 » Introduction
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  Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 5  |  Page : 31-37
 

Management of CNS metastases in patients with EGFR mutation-positive NSCLC


1 Department of Medical Oncology, K.S. Hegde Medical Academy, Mangalore, Karnataka, India
2 Medical Oncologist, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India

Date of Web Publication29-Nov-2019

Correspondence Address:
Vijith Shetty
Department of Medical Oncology, K.S. Hegde Medical Academy, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_455_19

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 » Abstract 


Central nervous system (CNS) metastases are a frequent and severe complication associated with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have shown considerable efficacy in EGFR-mutated NSCLC. However, their limited potential to cross the blood–brain barrier (BBB) renders them less effective in the management of CNS metastases in NSCLC. Osimertinib, a third-generation irreversible EGFR-TKI with good potential to cross the BBB, has shown significant clinical activity and acceptable safety profile in patients with EGFR-positive NSCLC brain and leptomeningeal metastases. The progression-free survival (PFS) of up to 15.2 months in CNS metastases patients in the FLAURA trial and the CNS objective response rates (ORRs) of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, have established the role of osimertinib in patients with NSCLC with CNS metastases. The AURA3 trial also reported a PFS of 8.5 months and overall ORR of 71%. These data have supported osimertinib to be recognized as a “preferred” first-line treatment for EGFR-positive metastatic NSCLC by the National Comprehensive Cancer Network (NCCN). With limited treatment options available, upfront administration of osimertinib in patients with NSCLC irrespective of EGFR T790M and CNS metastases may improve the overall response rate and potentially reduce the adverse effects of radiotherapy. Our review focuses on the management of EGFR-mutated NSCLC CNS metastases in the context of recent NCCN guidelines.


Keywords: Central nervous system metastases, epidermal growth factor receptor, National Comprehensive Cancer Network, non-small cell lung cancer, osimertinib


How to cite this article:
Shetty V, Babu S. Management of CNS metastases in patients with EGFR mutation-positive NSCLC. Indian J Cancer 2019;56, Suppl S1:31-7

How to cite this URL:
Shetty V, Babu S. Management of CNS metastases in patients with EGFR mutation-positive NSCLC. Indian J Cancer [serial online] 2019 [cited 2019 Dec 8];56, Suppl S1:31-7. Available from: http://www.indianjcancer.com/text.asp?2019/56/5/31/272014





 » Introduction Top


Central nervous system (CNS) metastases are a major complication associated with non-small cell lung cancer (NSCLC) and are seen in >30% of patients.[1],[2] About 25% of patients with NSCLC have CNS metastases at initial presentation, whereas 80% of patients develop it within 2 years of NSCLC diagnosis.[3] The rising incidence of CNS metastases in NSCLC is probably due to better control of extracranial disease and increase in detection rates of asymptomatic CNS metastases with improved magnetic resonance imaging techniques.[4] This review compares the efficacy and safety of various available options in the management of NSCLC with CNS metastases.


 » Epidermal Growth Factor Receptor-Mutant Nsclc and Cns Metastases Top


Certain molecular alterations aid the development of CNS metastases in NSCLC. The frequent genetic alterations seen in patients with NSCLC with CNS metastases include EGFR, TP53, and KRAS mutations.[5] The frequency of epidermal growth factor receptor (EGFR) mutations is reported to be higher in patients with NSCLC with CNS metastases[6] and is up to 63% in the Asian population.[7] The prevalence is also more in women (79.2%) than in men and in never smokers (63.0%).[8] As per a study in an Indian population, the incidence of EGFR mutations is almost double in patients with NSCLC with CNS metastases compared with patients without CNS metastases.[7]

Patients with CNS metastases associated with NSCLC have a poor prognosis. Ali et al. revealed that survival after diagnosis of CNS metastases was similar to survival during diagnosis and later stages of the disease (4.8 months vs. 3.7 months, P = 0.53).[9] In patients with EGFR-mutant NSCLC, CNS metastases worsen the survival outcomes compared with extracranial metastases.[10]

The choices for the management of CNS metastases in EGFR-mutant NSCLC are finite. The goals of treatment options for CNS metastases in NSCLC are to increase local control and overall survival (OS) with minimal neurological sequelae and tolerable toxicity and improve the quality of life.[11] Depending on disease condition and patient's performance status, sometimes, a multimodal approach may be required. For extracranial metastases associated with this cancer type, osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), improves the quality of life, median progression-free survival (PFS), and disease control rate (DCR). The reported PFS and DCR with osimertinib are 18.9 months and 90%, respectively.[12] Based on these data, the National Comprehensive Cancer Network (NCCN) 2019 guidelines have recommended EGFR-TKIs as the standard of care/ first-line therapy in patients with EGFR-mutated metastatic NSCLC. Osimertinib has been identified as a first-line “preferred” therapy for treating patients with EGFR-mutated metastatic NSCLC including those with CNS metastases.[13] However, the data for optimum management of CNS metastases in NSCLC are emerging.

Brain as a sanctuary site in CNS metastases

Although various available therapies can effectively control the growth of extracranial tumors, they show poor penetration into the blood–brain barrier (BBB). Therefore, tumor cells invading the brain become resistant to these therapeutic agents, making the brain as a potential “sanctuary site” for metastases [Figure 1]. This also reflects insufficient control of cerebral tumor spread and growth by current treatment strategies.
Figure 1: Diagrammatic representation of brain as a “sanctuary site”. CNS, central nervous system; EGFR, epidermal growth factor receptor; EGFRm, epidermal growth factor receptor mutation; TKI, tyrosine kinase inhibitor

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The design and functions of the BBB play a key role in rendering a drug effective in the treatment of CNS metastases.[14] Lipid solubility, charge, tertiary structure, degree of protein binding, and molecular weight affect a drug's potential to cross the BBB. Drug penetration is inversely related to the square root of molecular weight.[15] Chemotherapy agents and large monoclonal antibodies are generally unable to cross the BBB.[16],[17]


 » Management of CNS Metastases in NSCLC Top


The management of CNS metastases in patients with NSCLC is summarized in [Figure 2].[18]
Figure 2: Recommendation for non-small cell lung cancer patients with central nervous system metastases. BM, brain metastasis; CNS, central nervous system; EGFR, epidermal growth receptor; Fr, fraction; Gy, Gray; NSCLC, non-small cell lung cancer, SRS, stereotactic radiosurgery, TKI, tyrosine kinase inhibitors; WBRT, whole-brain radiotherapy. *Data in second line setting suggest that immunotherapy is less effective, irrespective of PD-L1 expression, in tumors with an actionable mutation

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Role of stereotactic radiosurgery

Traditionally, whole-brain radiotherapy (WBRT) has been recommended in the management of CNS metastases in NSCLC. However, WBRT does not increase the quality of life or survival over the best supportive care and is associated with a decline in neurocognitive function. Stereotactic radiosurgery (SRS) is a noninvasive alternative treatment for patients with brain metastases (BM), where only the BM is irradiated sparing healthy brain tissue.[19] The NCCN recommends SRS for limited oligometastases to the brain in patients with good performance status.[13] Currently, SRS is an established treatment for patients with a maximum of four BM, and patients with more than four BM are treated with WBRT.[20] Yamamoto et al. suggested that SRS without WBRT in patients with 5–10 BM is noninferior to patients with 2–4 BM.[21] SRS may be used in patients with symptomatic limited brain lesions after progression on first- and second-line EGFR-TKIs, namely, erlotinib, afatinib, gefitinib, or dacomitinib. These therapies are also recommended for progression on third-line EGFR-TKIs. Noordijk et al. mentioned that surgery was an appropriate option in patients younger than 60 years with single metastasis of the brain and limited extracranial involvement. The authors demonstrated an increase in median survival time (MST) by adding surgery to radiotherapy (10 months vs. 6 months, P = 0.04).[22] Several other studies have suggested that SRS exhibits better prognosis than neurosurgery.[23] Kim et al., Mariya et al., and Williams et al. showed MST values of 10, 9, and 7.9 months, respectively, with SRS. The local control reported was 85%, 77% (at 1 year), and 100%, respectively.[24],[25],[26]

Compared with WBRT, however, SRS is associated with higher risk of radionecrosis and subsequently developing new BM.[27],[28]

Role of EGFR-TKIs: Potential to cross the BBB

Data from preclinical studies suggest that first-generation EGFR-TKIs are substrates of BCRP1 and P-gp transporters, which limit their penetration into the BBB.[29],[30] Although the plasma levels of erlotinib and gefitinib are high, studies have suggested that these drugs can cross the BBB only to a limited extent, and therefore achieve low concentrations in the cerebrospinal fluid (CSF).[31],[32]

Among the first-generation TKIs, CSF penetration rate and concentration of erlotinib in the CSF are better than those of gefitinib. However, both drugs showed insignificant differences in response.[33] Afatinib, a second-generation TKI, crosses the BBB partially.[34] A preclinical study showed that the pattern of afatinib CSF concentrations is closely related with that of plasma concentrations. The values for both concentrations were correlated (r = 0.844, P < 0.01). The half-life was 5.0 h in plasma and 3.7 h in the CSF.[35]

Osimertinib effectively penetrated the BBB of mouse and cynomolgus monkey compared with first- (gefitinib) and second-generation (afatinib) EGFR-TKIs.[25] The concentration of osimertinib in the mouse brain was 5–25 times more than that in plasma. The distribution of osimertinib to brain tissues was around 10 times better than that of gefitinib [Table 1].[36]
Table 1: CSF concentrations of EGFR-TKIs per a preclinical study[17]

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In clinical studies, osimertinib has demonstrated better penetration of the BBB compared with first-- and second-generation EGFR-TKIs. The maximum distribution time in brain tissues is 13 min (range 5–30 min) with a Cmax value of 1.4 ± 0.3 standardized uptake value (range 1–1.8). Osimertinib is distributed to almost all parts of the brain including the putamen, thalamus, frontal cortex, temporal cortex, caudate, cerebellum, and white matter.[37] As per an ongoing phase I clinical trial BLOOM (NCT02228369) in patients with NSCLC with leptomeningeal metastases, osimertinib is anticipated to achieve good pharmacokinetics and pharmacodynamics by overcoming the BBB.[38]

Another new-generation EGFR-TKI, AZD3579, effectively crossed the BBB in patients with EGFR-mutated NSCLC CNS metastases. This molecule has high passive permeability (29.5 × 10−6 cm/s) and does not act as a substrate of efflux transporters at the BBB.[39]

The combination of radiotherapy with EGFR-TKIs in patients with NSCLC-associated CNS metastases disrupts the BBB to give access to the TKIs within the CNS. This is possibly known to occur due to the synergistic effect of EGFR-TKIs and radiotherapy. A meta-analysis revealed that the combination therapy significantly prolonged the time to CNS progression [hazard ratio (HR) = 0.56, 95% confidence interval (CI) 0.33, 0.80; P < 0.0001] and median OS (HR = 0.58, 95% CI 0.42, 0.74; P < 0.0001).[40]

CNS metastases are considered to play a role in increased BBB permeability for TKIs. However, this correlation between CNS metastases and disruption of the BBB is yet to be established.[41],[42]


 » Clinical Outcomes With EGFR-TKIs Top


Per the NCCN Clinical Practice Guidelines 2019, erlotinib, gefitinib, afatinib, and dacomitinib are the first-line therapy for extracranial EGFR-positive advanced, recurrent, or metastatic NSCLC [Table 2].
Table 2: Treatment outcomes in EGFR mutation-positive patients with NSCLC with CNS metastases

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However, because of poor penetration of these drugs into the CNS, they are unable to provide considerable benefits to patients with CNS metastases.[49],[50],[51] A phase III study (ARCHER 1050) reported higher median OS (34.1 months vs. 26.8 months) and median PFS (14.7 months vs. 9.2 months (P < 0.0001) for dacomitinib than for gefitinib[52]; however, the study did not include patients with CNS metastases.[53]

In a retrospective analysis, Magnuson et al. compared the impact of three treatment strategies on survival outcomes of 351 patients with EGFR-mutated NSCLC and CNS metastases. The treatment options included SRS followed by EGFR-TKI (n = 100), WBRT followed by EGFR-TKI (n = 120), or EGFR-TKI followed by SRS or WBRT at the time of intracranial progression (n = 131). The results showed a significantly longer median OS in patients who received upfront SRS (46 months) than in patients who received WBRT (30 months) or upfront TKI (25 months) (P < 0.001), suggesting SRS followed by EGFR-TKI as the best treatment approach for these patients.[54]

Administration of higher doses of EGFR-TKIs improves the CSF levels of drugs; however, increased drug levels are associated with severe nausea and high-grade fatigue.[55],[56]

Grommes et al. retrospectively identified nine patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR-TKIs. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (six of nine patients, including two with isolated leptomeningeal metastases), stable disease in 11% (one of nine), and progressive disease in 22% (two of nine). The median time to CNS progression was 2.7 months (range 0.8–14.5 months) and the median OS was 12 months (range 2.5 months–not reached). Treatment was well-tolerated.[57]

Role of third-generation EGFR-TKI in CNS metastases

Osimertinib (category 1) has been added as a “preferred” first-line treatment for metastatic EGFR-positive metastatic NSCLC.[13]

Osimertinib has also demonstrated good activity and tolerability in patients with CNS metastases.[43] The CNS penetration capacity of osimertinib is better than that of gefitinib, rociletinib, and afatinib in several preclinical studies.[32] The efficacy of osimertinib as a second-line therapy was evaluated in 116 (28%) patients in CNS full analysis set (cFAS) and 46 patients in CNS evaluable for response (cEFR) set in the AURA3 study. For patients with baseline CNS disease, the median PFS was 11.7 months with osimertinib and 5.6 months with chemotherapy (HR, 0.32, P = 0.004). Osimertinib provided longer PFS of 8.5 months in patients with CNS metastases compared with 4.2 months with standard chemotherapeutic regimen. The CNS response rate was 70% (21 of 30) in the osimertinib group compared with 31% (5 of 16) in the chemotherapy group [odds ratio (OR), 5.13; 95% CI 1.44, 20.64; P = 0.015] and the PFS was 8.9 months compared with 5.7 months.[58] In the pooled analysis of AURA extension and AURA2 studies, 162 (39%) patients had CNS metastases at baseline. The objective response rate (ORR) in patients with CNS metastases at baseline was 56% (88 of 158; 95% CI 48, 64).[59]

In the first-line setting, in the FLAURA study, CNS metastases were diagnosed in 126 patients per baseline brain scans. A higher proportion of patients in the osimertinib (n = 61) group than in the control group (n = 67) achieved a CNS objective response (66% vs. 43%; OR = 2.5), while the incidence of CNS progression was lower (20% vs. 39%) as was the rate of CNS progression due to new lesions (12% vs. 30%).[60] Irrespective of CNS lesion status at study entry, fewer patients with new CNS lesions were found in the osimertinib group (3.9%) than in the EGFR-TKI group (12.3%). In the subset of patients without CNS lesions at baseline, there were a lower number of new CNS lesions in the osimertinib group than in the EGFR-TKI group (3.1% vs. 7.0%, respectively).[61] In a post hoc competing risk analysis of this study, after adjusting for non-CNS progression and death to estimate, osimertinib-treated patients had a 5% probability of experiencing a CNS event at 6 months and an 8% probability at 12 months compared with 18% and 24% in patients with EGFR standard of care (gefitinib or erlotinib).[62]

Another study, ASTRIS, demonstrated the efficacy of osimertinib in EGFRm T790M patients with NSCLC with or without CNS metastases. Patients with CNS metastases, without CNS metastases, and who were not evaluated showed response rates of 68%, 79.6%, and 69.7%, respectively. The median PFS reported was 12.4, 11.0, and 15.1 months, respectively. Time to treatment discontinuation was observed as 16.5, 11.2, and 14.7 months, respectively. The OS was not reached in the study (data maturity was 19.7%).[63]

A phase I study, BLOOM, included patients with CSF cytology-confirmed leptomeningeal disease. Among the results of 32 patients (23 evaluable) treated with osimertinib 160 mg once daily, 10 had radiographic improvement and 13 had stable disease. Seven of eight symptomatic patients showed improvement. The geometric mean decrease in EGFR-mutant deoxyribonucleic acid copy was 57% (95% CI 30, 74) in 22 patients with pre-dose and Cycle 2 Day 1 CSF samples.[37]

Thus, in patients with symptomatic CNS metastases, definitive local therapy (SRS) or continuation of osimertinib is suggested after progression on first-line therapy with osimertinib. For symptomatic isolated lesions, definitive local therapy with stereotactic ablative radiotherapy or surgery or continuation of osimertinib is recommended. For symptomatic multiple lesions, systemic therapy options are suggested.[13]

Apart from targeted EGFR-TKI monotherapy, various combination and other therapies are also available, which may be individualized per patient's performance status. These include EGFR-TKIs with radiotherapy,[64],[65] immunotherapeutic agents (nivolumab, pembrolizumab, atezolizumab, etc.),[66],[67] and EGFR-TKIs with angiogenesis inhibitors. A randomized phase II study (NCT02971501) is ongoing to explore the effects of the osimertinib–bevacizumab combination in EGFR-mutant patients with NSCLC with CNS metastases.[68]


 » Conclusion Top


Extensive research and advances in the field of therapeutic imaging have helped in identifying that the prevalence of CNS metastases in patients with EGFR-mutated NSCLC is rising. As CNS metastases are associated with dismal survival rates and poor quality of life, exploring effective and safe management modalities has become paramount. Among established therapies, WBRT may cause cognitive decline and SRS has been associated with radionecrosis or steroid dependence. The first-generation TKIs can cross the BBB only to a limited extent. Among the second-generation EGFR-TKIs, afatinib has the highest CNS efficacy, but the NCCN has marked it less safe than erlotinib and gefitinib. Although dacomitinib has shown improvement in the median PFS, the exclusion of patients with CNS metastases has rendered its efficacy questionable in these patients.

Osimertinib potently and selectively inhibits both EGFR-sensitizing mutations and EGFR T790M resistance mutations. Osimertinib has an established efficacy and safety profile as first- and second-line therapy in NSCLC. It penetrates the BBB and shows good activity and tolerability in patients with brain and leptomeningeal metastases. Hence, osimertinib can be administered upfront to patients with NSCLC irrespective of EGFR T790M and CNS metastases at the time of diagnosis. This would offer patients an opportunity for improved response and delay the risk of radiotherapy-associated adverse effects. SRS can also be considered for any considerable residual CNS lesions after initial response to osimertinib. However, the optimal sequencing of the available therapies and the ideal approach of multimodal therapy for CNS metastases in NSCLC need to be established.

Acknowledgement

The authors thank AstraZeneca Pharma India Ltd for providing medical writing assistance in the development of this manuscript, in collaboration with Sciformix Technologies Pvt. Ltd, Mumbai.

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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    Figures

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    Tables

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