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gefitinib, one patient had stable disease, and two patients was 5.3 months. An overall partial response rate at both
had progressive disease after a median of 48-week follow- intracranial and extracranial sites was achieved in 42%,
up period. Kim et al. reported 23 never-smoker patients and stable disease was achieved in 38%. Further data are
[87]
[97]
with synchronous brain metastases with a response rate to available from individual cases and population-based
[98]
either gefitinib or erlotinib of 69% and a disease control studies. New trials with CNS metastases are ongoing.
[99]
rate of 82%. The median overall survival was 18.8 months, Dabrafenib is an oral ATP-competitive inhibitor of BRAF
and time to salvage WBRT averaged 19.3 months. kinase. A multicenter clinical trial evaluated dabrafenib
in 172 patients both with and without prior brain therapy
Further evidence for first-line TKI comes from a for BRAF-mutated melanoma metastatic to the brain with
retrospective analysis of 155 patients screened for EGFR confirmed p.V600X mutation. [100] The primary outcome
mutations. The rate of CNS progression was lower in measure was overall response rate observed to be 29/74
[88]
EGFR-mutant patients with advanced NSCLC treated (39.2%) in patients without prior brain therapy and
initially with erlotinib or gefitinib compared with upfront 20/65 (30.8%) in patients with prior brain therapy. Thus,
cytotoxic chemotherapy (33% vs. 48%) at a median dabrafenib was helpful in patients with both new and
follow-up of 25 months, supporting a role for these drugs pretreated brain metastases. Duration of response was
in prevention of CNS metastases. Median overall survival, 20.1 weeks for patients without prior brain treatment and
on the order of 30 months, was not different between the 28.1 weeks for patients with prior brain treatment. Median
two groups. overall survival was 33 weeks in patients without prior
brain therapy and 31 weeks with prior brain therapy.
Erlotinib in combination with WBRT was evaluated
in a prospective phase II trial in 40 patients with brain Resistance to therapy with BRAF kinase inhibitors is
metastases from NSCLC regardless of EGFR status. The associated with a reactivation of the MAPK pathway.
overall response rate was 86% and the median overall Consequently, the combination of BRAF and MEK
survival was 11.8 months. Of these 40 patients EGFR status inhibitor was assessed and showed increased efficacy
was known in 17 patients. Interestingly, patients negative compared to BRAF monotherapy alone. [101]
for EGFR mutations had a median overall survival of 9.3
months, whereas patients who were positive for EGFR Current immunotherapy approaches focus mainly on
mutations had a median overall survival of 19.1 months. checkpoint inhibitors Ipililumab and PD1/PDL1 inhibition.
[89]
The clinical benefit and feasibility of targeting ALK was Ipililumab is a humanized monoclonal antibody against
demonstrated first with the multitargeted tyrosine kinase cytotoxic T lymphocyte antigen-4 (CTLA-4); it shows
inhibitor crizotinib that competitively binds to the ATP- activity in melanoma brain metastasis, particularly if
binding pocket of the ALK and MET tyrosine kinases asymptomatic, by improving overall survival. [8,102,103] A
and inhibits phosphorylation of activated ALK. This was phase 2 study of ipilimumab and fotemustine showed an
subsequently confirmed in phase II and III trials. [90-92] The overall immune disease control rate of 50% and median
ability of ALK-directed therapies to control and prevent progression-free survival of 4.3 months, with increased
the development of CNS metastases remains incompletely incidence in hematological and nonhematological toxicity.
studied, with early reports suggesting inefficient CSF Clinical trials for the assessment of immune checkpoint
penetration of crizotinib. [93-95] inhibition strategies in CNS metastases are ongoing.

Ceritinib is a second-generation ALK inhibitor with QUALITY OF LIFE AND
increased activity against common ALK point mutations. NEUROCOGNITION
The activity of ceritinib in ALK+ NSCLC has been
confirmed in phase I and II studies. Larger head-to-head The systematic assessment of neurocognitive function is
trials such as the phase III, ALEX “trial comparing alectinib often neglected in clinical routine but is crucial, mainly
to crizotinib will directly investigate PFS in the CNS and because neurocognitive function is a key feature of quality
may provide further information to inform treatment of life for patients. It is important to raise awareness and
decisions for ALK+ patients with brain metastases. encourage more frequent use of neurocognitive monitoring
tools (not only in large centers) as a regular part of the
Melanoma diagnostic workup. Certainly, there are multiple reasons
Activating BRAF mutations affect up to 60% of melanoma for cognitive decline in patients with CNS metastases,
patients; more than 95% are the p.V600E mutation, including the neuroanatomical location of the lesions,
with the remainder largely being p.V600L. Constitutive symptomatic seizures, depression, distress, and potentially
BRAF signaling activates the mitogen-activated protein also the effects of neurotoxic systemic therapies and whole
kinase (MAPK) pathway. Vemurafenib is an FDA- brain radiation therapy. It is notable that corticosteroids
[96]
approved BRAF inhibitor. In a pilot study of 24 patients are a very common cause of neurocognitive decline.
with melanoma metastatic to the CNS treated with Steroid-induced changes in mood and sleep certainly
vemurafenib, median PFS was 3.9 months, and median OS affect cognitive function, leading to measurable effects on

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 20, 2016 ¦