Curr Treat Options Neurol (2018) 20:48

DOI 10.1007/s11940-018-0533-2

Neuro-oncology (R Soffietti, Section Editor)

Novel Systemic Treatments

for Brain Metastases From
Lung Cancer
Bicky Thapa, MD1
Adam Lauko, BS (Medical Student)2
Kunal Desai, MD2
Vyshak Alva Venur, MD3
Manmeet S. Ahluwalia, MD, FACP2,*
Address
1
Fairview Hospital-Cleveland Clinic, Cleveland, OH, USA
*,2
Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute,
Cleveland Clinic, Cleveland, OH, 44195, USA
Email: ahluwam@ccf.org
3
Dana-Farber Cancer Institute and Massachusetts General Hospital, Boston, MA,
USA

* Springer Science+Business Media, LLC, part of Springer Nature 2018

This article is part of the Topical Collection on Neuro-oncology

Keywords Brain metastases I Lung cancer I EGFR I ALK I Targeted therapy I Immunotherapy I Clinical trials

Abstract
Purpose of review Brain metastases are frequent complication of lung cancer and are
associated with poor prognosis. Patients with brain metastases secondary to lung cancer
have traditionally been managed with surgery and radiation with limited role for systemic
chemotherapy. In the past decade, however, this paradigm has shifted largely due to the
advent of targeted therapies and immunotherapies, both of which have demonstrated
efficacy in the treatment of brain metastases and extracranial disease.
Recent findings While patients with brain metastases secondary to lung cancer have
historically been excluded from trials, recent data suggest efficacy of novel targeted
therapies and immunotherapies in these patients. In fact, there are multiple ongoing
trials to further evaluate these therapies in this patient profile.
Summary Targeted therapies and immunotherapies have the potential to improve out-
comes in patients with brain metastases secondary to lung cancer.
48 Page 2 of 17 Curr Treat Options Neurol (2018) 20:48

Introduction
Lung cancer is the most common cause of cancer-related
death in the USA [1]. Brain metastases (BM) are a fre-
quent neurological complication of lung cancer and
have historically been associated with a poorer progno-
sis. Lung cancer is the most common cause of brain
metastases as 16.3–19.9% of advanced lung cancer pa-
tients develop brain metastases [2, 3]. Approximately
170,000 cancer patients develop brain metastases each
year [4]. A recent population-based study showed that
lung cancer has the highest incidence of synchronous
brain metastases which ultimately has negative prognos-
tic impact on these patients [5].
Lung cancer is broadly divided into two categories:
non-small cell lung cancer (NSCLC) and small cell lung
cancer (SCLC). NSCLC accounts for 85% of cases with
three major pathologic subtypes: adenocarcinoma,
squamous cell carcinoma, and large cell carcinoma.
SCLC accounts for 15% of cases and is a highly malig-
nant tumor derived from cells exhibiting neuroendo-
crine characteristics [6–8]. Approximately 25–40% of
NSCLC patients develop brain metastases during the
course of their disease [9]. Approximately 10% of pa-
tients with SCLC have brain metastases present at the
time of diagnosis [10]. Historically, brain metastases
have been treated with surgical resection, whole brain
radiation therapy (WBRT), stereotactic radiosurgery
(SRS), and supportive care based on clinical status and
quality of life. The advent of targeted therapies and
immunotherapies has marked an improvement in pro-
gression free survival (PFS) and overall survival (OS) in
advanced malignancies including lung cancer. Interest-
ingly, the incidence of brain metastases in lung cancer
patients has increased over the past decade due to im-
proved imaging modalities and prolonged survival from
novel approved therapies.
Survival in lung cancer patients after development of
brain metastases depends on multiple factors, including
local and systemic treatments received. Several groups
have proposed prognostic indices to better predict out-
comes and guide treatment strategy [11]. A recently
published prognostic index known as Disease-Specific
Graded Prognostic Assessment (DS-GPA) associated re-
sponse to therapy with factors such as age, Karnofsky
performance status (KPS), extracranial metastases, and
number of brain metastases in patients with lung ade-
nocarcinoma [12]. With the emergence of molecular
markers in clinical practice, the original DS-GPA was
updated to include epidermal growth factor receptor
(EGFR) and anaplastic lymphoma kinase (ALK) muta-
tional status [13]. Furthermore, there is evidence to sug-
gest that the number of brain metastases does not im-
pact overall survival in NSCLC patients with EGFR and
ALK mutations due to the efficacy of targeted therapy in
these patients [14].

Pathogenesis of brain metastases

Brain metastases are propagated via hematogenous spread and are most com-
monly seen at the cerebral gray-white junction primarily in the territory of the
middle cerebral artery [15]. The most common site of brain metastases is the
cerebrum (80%), followed by the cerebellum (15%) and the brainstem (5%)
[16, 17]. Brain metastases also frequently involve the terminal “watershed”
areas of arterial circulations (i.e., vascular border zones), especially in the
territory between the middle cerebral artery and posterior cerebral artery [18]. In
1989, Stephen Paget hypothesized the “soil and seed” theory which proposed
that tumor cells (i.e., the “seed”) have the capacity to germinate in distant target
tissues. Metastasis itself is a complicated process, whereby tumor cells must
develop the ability to infiltrate the basement membrane, enter the circulatory or
lymphatic systems, extravasate, and ultimately establish themselves within a
new microenvironment before resuming proliferation [19]. Biological hetero-
geneity is a key trait of tumor cells which enables them to be reprogrammed
into diverse karyotypes with differential growth rates and tumor
Curr Treat Options Neurol (2018) 20:48 Page 3 of 17 48

immunogenicity; such a disorderly metabolic process presents a challenge for

therapeutic intervention [20, 21].
Both extrinsic and intrinsic factors drive cancer cell metabolism and metas-
tasis [22]. The brain’s increased demand and subsequently supply of glucose
provides a nutrient-rich environment for tumor cell growth. Tumor cells un-
dergo metabolic reprogramming in order to meet the higher energetic and
biosynthetic demands placed by rapid proliferation [23]. The blood-brain
barrier (BBB) is comprised of continuous, non-fenestrated endothelium with
tight junctions that prevent entry of circulating macromolecules into the brain
parenchyma [24, 25]. The brain is considered an immunologically privileged
site due to the BBB and the lack of a lymphatic system. The integrity of the BBB
however is altered by brain metastases [26, 27]. The BBB also prevents the entry
of most drugs and microorganisms but does not prevent the invasion of
circulating metastatic cells into the brain parenchyma [28, 29]. Astrocytes are
supportive glial cells involved in cerebral homeostasis against neurotoxicity;
however, activated astrocytes are also found to surround and infiltrate brain
metastases which contribute to the protection of tumor cells from chemother-
apeutic agents [21, 30].

Molecular markers
SCLC is considered more aggressive than NSCLC with approximately 15–20%
of newly diagnosed patients presenting with brain metastases [31]. Genomic
alterations in SCLC include mutation of tumor suppressor genes T53 and RB1,
c-Kit overexpression, vascular endothelial growth factor receptor (VEGFR) and
epidermal growth factor receptor (EGFR) mutations, PTEN mutations, and Myc
overexpression [32]. However, none of the currently available targeted thera-
peutic agents have shown efficacy in SCLC. The most common mutations
associated with NSCLC include Kirsten ras oncogene (KRAS), EGFR, and ALK
[33] while less common mutations include BRAF, RIT1, RET, ROS1, and
NTRK1. Identification of molecular markers in lung cancer has driven the
discovery of targeted therapies [34, 35] with corresponding clinical trials sum-
marized in Table 1.

EGFR
Epidermal growth factor receptor (EGFR) is a transmembrane protein receptor
found on epidermal cells that is activated by epidermal growth factor (EGF).
Upon binding of the ligand, the tyrosine kinase component along the inner
cytoplasmic domain is activated, thereby leading to cell growth and prolifera-
tion [46]. Overexpression of mutated EGFR within its intracellular component
has been observed in 43–89% cases of NSCLC [47]. Activating mutations
within the tyrosine kinase domain of the EGFR are seen in 10% of NSCLC
patients in the USA and 35% in East Asia [48, 49]. EGFR mutations in NSCLC
were first described in 2004 [50]. Studies have shown that NSCLC with EGFR
mutations have increased frequency of brain metastases and yet have better
survival with brain metastases [51]. The most common EGFR mutations are
exon 19 deletions and exon 21 L858R point mutations and comprise 90% of all
kinase-activating mutations leading to hyper-activation of pro-survival

Table 1. List of important prospective clinical trials in patients with lung cancer brain metastasis
Clinical trial Number of Characteristics
patients
Welsh 40 Multi-institutional phase
et al. [36] II trial of erlotinib with
concurrent WBRT for
patients with BM
from NSCLC.
Iuchi T 41 Phase II trial in Japanese
et al. [37] patients with gefitinib
alone without radiation
therapy in EGFR-mutant
lung adenocarcinoma.
Wu YL 48 Phase II, non-randomized,
et al. [38] open-label, multicenter,
single arm clinical trial.
Erlotinib as 2nd-line
therapy for patients
with asymptomatic BM
in NSCLC.
Lee SM 40 Two-stage randomized,
et al. [39] multicenter, phase II
double- blind trial,
placebo arm (n = 40),
erlotinib with concurrent
WBRT arm (n = 40)
Yang JJ 176 Multicenter, open-label,
et al. parallel, randomized
[40••] controlled trial.
48
Previous treatment Drug used Biomarker Conclusion
4 patients had SRS, Erlotinib + WBRT EGFR mutant: Overall response rate (ORR): 86%
21 patients were 9 patients (n = 36), Median survival time:
on cisplatin and 11.8 months (95% CI, 7.4 to
docetaxel or 19.1); 17 patients with known
Page 4 of 17
carboplatin and mutational status, median
paclitaxel, 2 patients survival time 19.1 months for
had pemetrexed. EGFR mutation versus
9.3 months for wild-type EGFR.
10 cases received Gefitinib EGFR mutant: 41 patients Response rate was 87.8%,
systemic chemotherapy median PFS was 14.5
prior to diagnosis of months (95% CI,
BM; 10.2–18.3 months), the
31 cases received no median OS was 21.9
prior treatment for BM. months (95% CI,
18.5–30.3 months).
Exon 19 deletion was
associated with better
outcome of patients after
treatment with gefitinib
in both PFS (p = 0.003)
and OS (p = 0.025) as
compared to L858R.
First-line platinum Erlotinib EGFR mutant: ORR: 58.3%, median OS
doublet chemotherapy 8 patients was 18.9 months (95% CI,
14.4–23.4). The median
PFS was 10.1 months
(95% CI, 7.1–12.3) for
intracranial progression
and 9.7 months (95% CI,
2.5–17.8) for intracranial
and systemic progression.
The median PFS for EGFR
mutation versus EGFR wild
type was 15.2 months
and 4.4 months.
No previous treatment Erlotinib + WBRT EGFR mutant: Median neurological PFS of
1 patient out of 35 1.6 months in both arms.
Median OS of 2.9 and
3.4 months in the placebo
and erlotinib arms.
No statistically significant
neurological PFS or
OS in patients treated
Curr Treat Options Neurol (2018) 20:48
with concurrent erlotinib
and WBRT followed by
maintenance erlotinib
compared to placebo.
No previous treatment Icotinib EGFR mutant: Median intracranial PFS was
91 patients 10.0 months with icotinib
versus 4.8 months with
Table 1. (Continued)
Clinical trial Number of Characteristics
patients
Icotinib versus WBRT in
patients with EGFR-
mutant lung cancer BM.
Icotinib group (n = 91),
WBRT group (n = 85, only
73 participated in the
clinical trial)
Mok TS 144 The randomized, international,
et al. open-label, phase III trial.
[41••] Patient progressed on
first-line EGFR TKIs were
randomly assigned in
2:1 ratio to receive
osimertinib or pemetrexed
plus carboplatin/cisplatin.
Osimertinib group (n = 93),
Platinum-pemetrexed
group (n = 51)
Solomon BJ 39 The randomized, phase III
et al. clinical trial. Randomly
[42••] assigned in 1:1 ratio,
Crizotinib arm (n = 39)
versus platinum-pemetrexed
arm (n = 40)
Crino` 100 Single-arm, open-label,
et al. multicenter, phase II study
[43••] in patients with ALK-
rearranged previously treated
with chemotherapy and
crizotinib
Peters S 122 The randomized, open-label,
et al. phase III trial; crizotinib
[44••]
Previous treatment Drug used Biomarker Conclusion
WBRT plus chemotherapy
(HR 0.56, 95% CI,
0.36–0.90; p value
of 0·014). Intracranial
ORR in icotinib and WBRT
plus chemotherapy was
65% versus 37%
respectively with p value
of 0.001. No difference in
OS between 2 groups.
First-line EGFR TKIs Osimertinib EGFR mutant: The median duration of PFS
144 patients was longer in osimertinib
group (8.5 months) than
Curr Treat Options Neurol (2018) 20:48
the group receiving
platinum therapy plus
pemetrexed (4.2 months);
HR, 0.32; 95% CI,
0.21 to 0.49.
No previous treatment Crizotinib ALK rearrangement: IC-DCR was significantly higher
39 patients with crizotinib (85%)
versus platinum-pemetrexed
(45%) at 12 weeks; p value
of .001 and at 24 weeks,
IC-DCR was 56% versus
25% respectively; with
p value of 0.006. PFS
was significantly longer with
crizotinib (9 months) versus
platinum-pemetrexed
(4 months) in both arms,
HR: 0.40; P value of .001.
Prior treatment with at Ceritinib ALK rearrangement: For patients with
least one platinum- 100 patients baseline BM (n = 100) ORR
based chemotherapy was 33.0% (95% CI,
regimen and crizotinib, 23.9 to 43.1%), the DCR
72 patients had prior was 74.0% (95% CI,
radiotherapy 64.3 to 82.3%), the median
DOR was 9.2 months
(95% CI, 5.5 to 11.1 months),
and the median PFS was
5.4 months (95% CI, 4.7
to 7.2 months. For patients
with active target lesions at
baseline (n = 20), ORR was
45.0% (95% CI, 23.1 to 68.5%)
Previously untreated Crizotinib, ALK rearrangement: A CNS response rate of 59% (95% CI,
Page 5 of 17 48
alectinib 122 46 to 71) was observed in
38 out of 64 patients in the
 48

Table 1. (Continued)
Clinical trial Number of Characteristics Previous treatment Drug used Biomarker Conclusion
patients
group (n = 58), alectinib alectinib group and a CNS
group (n = 64) response rate of 26% (95% CI,
15 to 39) occurred in 15 out
of 58 patients in the crizotinib
group; 29 patients (45%) in the
Page 6 of 17

alectinib group had a complete

CNS response, as compared
with 5 patients (9%) in the
crizotinib group.
Goldberg 18 A single-institution, two-cohort Surgical resection: 2, Pembrolizumab PD-L1 positive: 18 BM response rate of 33% (95% CI,
et al. phase II trial. Patients with WBRT: 6, SRS: 5 14–59), 4 had complete
[45••] NSCLC, untreated or response, 2 had partial response,
progressive BM 2 had stable disease and 6 had
progression of disease.

CNS central nervous system, BM brain metastases, SRS stereotactic radiosurgery, WBRT whole brain radiation therapy, EGFR epidermal growth factor receptor, TKI tyrosine kinase
inhibitor, ALK anaplastic lymphoma kinase, PD-L1 Program death-1 ligand, ORR overall response rate, CI confidence interval, HR hazard ratio, PFS progression free survival, OS overall
survival, IC-DCR intracranial disease control rate, DCR disease control rate, DOR duration of response
Curr Treat Options Neurol (2018) 20:48
Curr Treat Options Neurol (2018) 20:48 Page 7 of 17 48

signaling pathways [52, 53]. EGFR mutations are commonly found in patients
with lung adenocarcinoma who are light or never-smokers and in Asian pop-
ulations [54, 55]. These mutations have served as novel targets for drug devel-
opment and have led to the development of targeted agents such as gefitinib
and erlotinib. Treatment with gefitinib and erlotinib leads to T790M mutation
in EGFR at the exon 20 which encodes the kinase domain. The second-
generation EGFR tyrosine kinase inhibitors such as afatinib irreversibly block
the EGFR receptor with sustained action and are effective in patients who are
resistant to first-generation EGFR inhibitors. Osimertinib is a next-generation
EGFR tyrosine kinase inhibitor with activity in T790M mutant adenocarcinoma
of the lung [41••]. In fact, osimertinib has shown incremental PFS improve-
ment over standard first-line EGFR tyrosine kinase inhibitors [56••].

ALK
ALK is a tyrosine kinase receptor which belongs to the insulin receptor super-
family and is comprised of an extracellular domain, a hydrophobic stretch
corresponding to a single-pass transmembrane region, and an intracellular kinase
domain [57]. The most common ALK alteration is rearrangement with 3–7% of
NSCLC patients noted to have inversion of chromosome 2p leading to aberrant
fusion of the intracellular signaling portion of ALK to protein encoded by the
echinoderm microtubule associated protein like 4 (EML4 gene) [58]. This ALK
alternation is more commonly found in non-smokers and light smokers (G 10
pack years) with NSCLC [59–61]. Crizotinib is a first-generation ALK inhibitor
with efficacy against ALK-mutated NSCLC brain metastases as compared to
standard chemotherapy but has limited intracranial penetration with subsequent
acquisition of resistance to the drug. The second-generation ALK inhibitors such
as ceritinib, brigatinib, and alectinib have better CNS penetration and are effective
in patients who have developed resistance to crizotinib.

KRAS
An activating mutation in the KRAS gene leads to activation of the RAS GTPase
resulting in a sustained proliferative signal within the cell. Currently, no
targeting agents with activity against KRAS mutations have been approved for
NSCLC. Table 2 provides a summary of known mutations in lung
adenocarcinoma.

PD-1/PD-L1
Program cell death-1 (PD-1) receptor is type 1 transmembrane protein from the
CD28 family and is expressed on activated T cells, B cells, and natural killer (Nk)
cells [62]. PD-L1 binds to the PD-1 receptor and downregulates activation of T
cells, thereby leading to suppression of the immune system. Tumor cells inhibit
host innate immunity by various mechanisms including activation of immune
checkpoint pathways such as PD-1/PD-L1 [63]. Inhibition of PD-1/PD-L1 has
been shown to be effective in many advanced malignancies. Immune check-
point inhibitors such as nivolumab and pembrolizumab block PD-1/PDL-1
pathways, thereby resulting in antitumor activity. Currently, various clinical
trials in phases I and II are ongoing to assess the efficacy of the immune
checkpoint inhibitors in patients with brain metastases due to lung cancer
(NCT02085070, NCT02696993, NCT02978404, NCT02858869).
48 Page 8 of 17 Curr Treat Options Neurol (2018) 20:48

Table 2. Summary of mutations in adenocarcinoma of the lung

Known mutations Incidence rate Important targeted agents

EGFR mutation 15 Erlotinib, gefitinib, afatinib, icotinib, osimertinib
ALK translocation 5 Crizotinib, alectinib, ceritinib, brigatinib, lorlatinib
BRAF mutation 2 Vemurafenib, dabrafenib
RET fusions 1 Cabozantinib, vandetinib
ROS1 rearrangement 2 Crizotinib, loratinib
MET alteration 3 Crizotinib
HER2/MEK overexpression 2 Trastuzumab, lapatinib
KRAS mutation 30 None

*No known mutations in the remaining 40% of adenocarcinoma of the lung

Current therapeutic options in lung cancer brain metastases in

the era of molecular markers
Historically, patients with lung cancer brain metastases have been treated with
WBRT, surgery, stereotactic radiosurgery, and systemic chemotherapy for the
primary tumor. Historically, patients with brain metastases have been excluded
from clinical trials. With the advent of novel targeted therapies, there has been
improved survival benefit and revolutionized the use of medical therapy for
patients with brain metastases.

Targeted therapy for EGFR mutations

Erlotinib and gefitinib are the first-generation tyrosine kinase inhibitors (TKIs)
for EFGR mutations and have demonstrated significant PFS benefit compared
to patients without EGFR mutations [38, 64]. These are small molecules which
penetrate the BBB to some extent in patients with brain metastases. Deng Y et al.
found the BBB permeation rate of erlotinib to be 4.4 ± 3.2% in NSCLC patients
with brain metastasis [65]. Clinical studies have demonstrated that brain me-
tastases affect the permeability of the BBB leading to increase in concentration
of TKIs in cerebrospinal fluid (CSF) with good tumor control. Wang et al. found
significant penetration rate of gefitinib in CSF in patients with brain metastases
as compared to patients without brain metastases (1.5% vs 0.9%, p = 0.010)
[66]. However, we face challenges with the acquisition of resistance to standard
EGFR TKIs; third-generation EFGR TKI osimertinib has shown greater efficacy
than first- and second-generation EGFR TKIs in patients with EGFR-mutant
NSCLC [56••].

First-generation EGFR TKIs

Gefitinib and erlotinib were the first TKIs approved by the Food and Drug
Administration (FDA) for advanced NSCLC with EGFR mutations. Both drugs
Curr Treat Options Neurol (2018) 20:48 Page 9 of 17 48

are orally administered, reversible small molecules which inhibit EGFR auto-
phosphorylation by binding to the ATP binding site of the intracellular tyrosine
kinase domain [67]. In a retrospective study by Hotta K et al., gefitinib dem-
onstrated therapeutic efficacy in 14 NSCLC patients with brain metastases, of
which 1 patient showed complete response (CR), 5 patients showed a partial
response (PR), and 8 patients with stable intracranial disease [68]. In another
study of 23 never-smoker patients with lung adenocarcinoma complicated by
brain metastases treated with either gefitinib or erlotinib monotherapy as first-
line treatment demonstrated significant intracranial response in 17 patients
(73.9%), and median progression free survival (PFS) and overall survival (OS)
were 7.1 and 18.8 months respectively [69]. Porta et al. conducted a retrospec-
tive analysis of 69 lung cancer patients with brain metastases who were treated
with erlotinib (of which 17 patients had EGFR mutations); an intracranial
response rate of 82.4% was noted in EGFR-mutant patients versus those with-
out EGFR mutations. In the same study, OS was 12.9 months in EGFR-mutant
patients versus 3.1 months in EGFR-negative patients [70]. In a prospective
phase II trial of 41 Japanese patients with EGFR-mutant lung adenocarcinoma
and brain metastases, those treated with gefitinib demonstrated favorable
response and exon 19 deletions showed better outcome compared to L858R
[37]. This study reported an 87.8% response rate, median PFS of 14.5 months
(95% CI, 10.2–18.3 months) in all patients, and median OS of 21.9 months
(95% CI, 18.5–30.3 months) in patients with exon 19 deletion. There are
several clinical studies which have shown increased efficacy of EGFR TKIs with
radiation therapy. In a phase II clinical trial by Welsh JW et al., 40 patients with
NSCLC brain metastases were enrolled irrespective of EGFR status; patients
received erlotinib 150 mg orally once daily for 1 week, then concurrently with
WBRT, followed by maintenance dose [36]. The study reported an overall
response rate of 86% in a total of 36 patients; only 17 patients had known EGFR
status out of which 9 patients were EGFR mutated. The median overall survival
of 19.1 months was seen compared to 9.3 months in patients without EGFR
mutations. Subsequently, in a phase II clinical trial by Lee et al., 80 patients were
randomized to erlotinib (100 mg, N = 40) and placebo (N = 40) with concur-
rent WBRT and following WBRT, patients were continued either on placebo or
erlotinib (150 mg) until disease progression [39]. Median OS was 3.4 and
2.9 months in the erlotinib and placebo arms respectively; however, only one
patient out of 35 in erlotinib arms was harboring the EGFR mutation. There was
no significant difference in PFS and OS between two arms.
Pulsatile dosing increases CNS concentration via increased permeation
across the BBB, whereas both pulse dosing and low daily dose may delay
EGFR TKI resistance via the acquisition of the T790 mutation [71]. Icotinib is
another first-generation EGFR TKI which is approved in China for EGFR-mu-
tated NSCLC with brain metastases. In a phase II clinical trial that enrolled 20
Chinese patients with NSCLC brain metastases, they received 125 mg orally
three times/day until tumor progression or unacceptable toxicity, concurrently
with WBRT [72]. Out of 18 patients with known EGFR status, the median
survival time (MST) was 22.0 months for patients with an EGFR mutation
versus 7.5 months for those with wild-type EGFR (p = 0.0001). In another phase
III, multicenter, randomized controlled trial in China, icotinib demonstrated
superior efficacy in patients with multiple brain metastases in EGFR-mutant
NSCLC as compared to WBRT plus chemotherapy [40••]. Median intracranial
48 Page 10 of 17 Curr Treat Options Neurol (2018) 20:48

PFS was 10.0 months in the icotinib-treated cohort versus 4.8 months in the
WBRT plus chemotherapy cohort (HR 0.56; 95% CI, 0.36–0.90; p value of
0·014); however, there was no difference in OS between the two cohorts.
Intracranial ORR was 65% versus 37% in the icotinib and WBRT plus chemo-
therapy cohorts respectively with p value of 0.001.

Second-generation EGFR TKIs

Afatinib, dacomitinib, and neratinib are second-generation EGFR TKIs which
irreversibly block EGFR, HER-2, and ERbB4 receptors. Lung adenocarcinoma
patients treated with first-generation EGFR TKIs generally develop resistance
within 12–16 months of treatment [73, 74]. More than 60% of patients acquire
mutation through the T790M missense mutation encoded by exon 20 of EGFR
[75, 76]. Afatinib has also been approved as first-line treatment of advanced
NSCLC in patients with EGFR mutations. LUX-Lung 3 and 6, randomized phase
III studies of afatinib in metastatic lung adenocarcinoma with EGFR mutation,
included patients with asymptomatic brain metastases [77, 78]. Subgroup
analysis showed intracranial activity in afatinib group with significantly higher
median PFS compared to the conventional chemotherapy group in both the
trials (8.2 vs 5.4 months; HR, 0.50; p = 0.0297) [79••].

Third-generation EGFR TKIs

Osimertinib is the third-generation EGFR TKIs that was approved by the FDA;
soon after, preliminary data showed efficacy in previously treated patients with
EGFR-mutated advanced NSCLC and brain metastases [80–82]. Osimertinib is
a potent, oral, irreversible inhibitor of activating EGFR mutations and T790M-
resistant mutations. AURA 3, a randomized phase III clinical study of patients
with T790M-positive advanced NSCLC who had disease progression with first-
line EGFR TKI therapy, showed significant intracranial activity with osimertinib
[41]. In 144 patients with brain metastases, the patients who received
osimertinib had longer median PFS as compared to those who received plati-
num and pemetrexed (8.5 months vs 4.2 months; hazard ratio, 0.32; 95% CI,
0.21 to 0.49). As well, the study showed that patients in the osimertinib-treated
cohort had lower adverse events (23%) as compared to the platinum plus
pemetrexed cohort (47%). In FLAURA, a phase III trial study of osimertinib
versus first-generation TKIs, 53 patients with CNS metastases were treated in the
osimertinib arm compared to 63 CNS metastases in the standard tyrosine
kinase arm. Overall, 17 patients (6%) in the osimertinib-treated cohort had
CNS progression versus 42 patients (15%) in the standard treatment cohort
[56••]. In subgroup analysis of this clinical trial, osimertinib showed better
CNS PFS as compared to erlotinib or gefitinib (HR 0.48; 95% CI, 0.26–0.86)
[83••]. Osimertinib has consistently shown better intracranial activity com-
pared to first-generation EGFR TKIs; however, studies focusing only on brain
metastases are ongoing [84].

ALK inhibitor in lung cancer brain metastases

The ALK gene is located on the short arm of chromosome 2, and it encodes the
ALK receptor tyrosine kinase. ALK gene rearrangement occurs in 3–7% of
NSCLC patients while brain metastases have been reported in about 24% in
ALK gene fusion NSCLC patients at time of diagnosis [85, 86]. Crizotinib is a
Curr Treat Options Neurol (2018) 20:48 Page 11 of 17 48

first-generation ALK inhibitor approved for ALK-mutated NSCLC, and it has

also shown activity against ROS1 rearrangement and MET alteration [87]. In the
randomized phase III prospective clinical trial PROFILE 1014 of ALK-positive
advanced NSCLC patients, crizotinib as first-line treatment demonstrated su-
perior intracranial activity as compared to standard chemotherapy in patients
with treated brain metastases [42••]. Seventy-nine patients with brain metas-
tases were enrolled in this study that showed intracranial activity with crizo-
tinib. Intracranial disease control rate (IC-DCR) was significantly higher (85%)
with crizotinib as compared to 45% with chemotherapy at 12 weeks (p
G 0.001), and IC-DCR was 56% with crizotinib versus 25% with chemotherapy
at 24 weeks (p = 0.006). The median PFS was significantly better among patients
treated with crizotinib (9 months) versus standard chemotherapy (4 months)
with hazard ratio of 0.40 and p G 0.001. The retrospective pooled analysis was
done in patients with brain metastases from the phase II PROFILE 1005 and
phase III PROFILE 1007 trials compared crizotinib to second-line chemother-
apy [88]. Of the 275 patients who had asymptomatic brain metastases, 166 had
undergone prior treatment. In these 166 patients, the IC-DCR was 62% and the
median intracranial TTP was 13.2 months. Among 109 patients with untreated
asymptomatic brain metastases, the IC-DCR was 56% and the median intra-
cranial time to progression (TTP) was 7 months.
Ceritinib and alectinib are second-generation ALK inhibitors with better
CNS penetration with activity in patients resistant to crizotinib [89, 90]. The
phase I multicenter trial of ceritinib demonstrated preliminary evidence of
intracranial activity [91]. In 94 patients with confirmed brain metastases, ICR of
79% was reported in19 patients who had never received any prior ALK inhib-
itors and IC-DCR was 65% in 75 patients who had failed prior ALK inhibitor.
Six of 11 patients with measurable brain lesion achieved a partial intracranial
response. In the ASCEND-2 phase II trial, 100 patients had brain metastases at
enrollment with only 20 of these having measurable target lesions. Among
these 20 patients, the intracranial response rate was 45.0% (95% CI, 23.1 to
68.5%) while the IC-DCR was 80% (n = 20, 95% CI, 56.3–94.3) [43••]. In-
creasingly, clinicians are shifting from crizotinib to ceritinib in patients with
brain metastases.
The AF-002JG phase I/II study of alectinib in patients with crizotinib-
resistant ALK-rearranged NSCLC demonstrated promising intracranial activity
[92]. Of 21 patients with CNS metastases at baseline, 11 had an objective
response, 6 had a complete response, 5 had a partial response, 8 had stable
disease, and the remaining 2 had progressive disease. The J-ALEX phase III trial
showed an objective response rate of 85% in the alectinib group versus 70% in
the crizotinib group; in patients with brain metastases, the hazard ratio for
alectinib versus crizotinib was 0.08 (95% CI, 0.01–0.61) [93]. Furthermore, 14
patients with asymptomatic brain metastases in the alectinib arm showed IC-
DCR of 92.9% and only one of the patients had progressed at the time of data
cutoff. A multicenter, global, ALEX phase III randomized trial of alectinib versus
crizotinib in untreated ALK-positive NSCLC showed efficacy of alectinib in
patients with and without CNS lesions at baseline; 64 patients had CNS lesions
at baseline in alectinib arm and 58 patients in crizotinib arm [44••]. CNS
response was observed in 38 patients in alectinib group compared to 15
patients in crizotinib group with a complete response rate of 45% and 9% in
patients treated with alectinib and crizotinib respectively. This trial also
48 Page 12 of 17 Curr Treat Options Neurol (2018) 20:48

demonstrated that the time to CNS progression was significantly longer with
alectinib than with crizotinib (cause-specific hazard ratio, 0.16, 95% CI, 0.10 to
0.28; the rate of CNS progression was 12% with alectinib and 45% with
crizotinib). Another ALK inhibitor, brigatinib, has demonstrated encouraging
results in CNS metastases. In a multicenter, open-label phase I/II study
(NCT01449461), 6 out of 12 patients with lesions ≥ 10 mm had ≥ 30%
decrease in sum of longest diameters of target lesions and 8 out of 26 patients
with non-measurable lesions had disappearance of all lesions. Median intra-
cranial PFS for these patients was about 97 weeks [94]. Lorlatinib is a third-
generation ALK inhibitor with selective CNS penetration and also has activity
against ROS1; it has been developed as an agent to act against most of the
resistance mutations in patients treated with ALK-targeting agents. Preliminary
results from the phase I of the ongoing phase I/II study NCT01970865 dem-
onstrated an objective intracranial response rate (ICRR) of 44% in targetable
and non-targetable lesions in 16 patients and 60% in the targetable lesion in 12
patients respectively [95].

Immunotherapies
Immune checkpoint inhibitors have shown promising results in many ad-
vanced malignancies, but patients with brain metastases have been historically
excluded from such trials. Nivolumab and pembrolizumab are monoclonal
antibodies against program death-receptor-1 (PD-1) and work to block cyto-
toxic T lymphocyte tolerance. Nivolumab and pembrolizumab have been FDA-
approved for unresectable metastatic melanoma, metastatic NSCLC, renal cell
carcinoma, classical Hodgkin lymphoma, hepatocellular carcinoma, metastatic
colorectal cancer, urothelial carcinoma, and squamous cell carcinoma of the
head and neck. A number of case reports and retrospective studies reported
efficacy of immunotherapies in patients with brain metastases from lung cancer
[96–99]. The only prospective study was a single-institution, phase II trial of
pembrolizumab in which 18 patients with NSCLC brain metastases demon-
strated response rates of 33% (95% CI, 14–59), four had complete response,
two had partial response, 2 had stable disease, and 6 had progression of disease
[45••]. Furthermore, with growing evidence of durable response in various
advanced malignancies, there are ongoing clinical trials such as NCT01454102
(check mate-012), NCT02085070, NCT02681549, and NCT02858869 which
are specifically assessing the efficacy of immune checkpoint inhibitors in pa-
tients with brain metastases in lung cancer and melanoma.

Conclusion
Over the past decade, several actionable mutations that are present in NSCLC
have led to the development of promising novel targeted therapies with im-
proved CNS penetration. Newer targeted therapies against EGFR mutations and
ALK translocations have shown encouraging results with impressive response
rates. Immunotherapy has shown initial promising intracranial activity that is
comparable to the response rates seen extracranially. The future trials will need
to focus on the interactions, toxicity and efficacy of these targeted agents, and
immunotherapy with different forms of radiation. The management of brain
Curr Treat Options Neurol (2018) 20:48 Page 13 of 17 48

metastases should involve a multidisciplinary team of neurosurgeons, radiation

oncologists, and medical and neuro-oncologists to tailor treatment to each
individual patient.

Compliance with Ethical Standards

Conflict of Interest
Dr. Ahluwalia reports grants and personal fees from Elekta, grants and personal fees from Incyte, grants and personal
fees from BMS, grants and personal fees from Astrazeneca, grants from Tracon, grants from Novartis, grants and
personal fees from Novocure, personal fees from Monteris Medical, personal fees from Caris Life Sciences, personal
fees from MRI Solutions, grants and personal fees from Abbvie, personal fees from CBT Pharmaceuticals, personal
fees from Flatiron, personal fees from Varian, personal fees from VBI vaccines, and personal fees and others from
MImivax, outside the submitted work.
Dr. Bicky Thapa, Dr. Kunal Desai, Mr. Adam Lauko, and Dr. Vyshak Alva Venur each declare that they have no
potential conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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