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Mudra et al. J Cancer Metastasis Treat 2019;5:27 I http://dx.doi.org/10.20517/2394-4722.2019.09 Page 5 of 9

the high intracranial activity of osimertinib, it is preferred as the initial therapy for patients presenting
with asymptomatic BM in EGFR-mutated NSCLC. Osimertinib has not yet been evaluated with SRS, but
it is reasonable to use SRS in the case of isolated intracranial progression and continue to use osimertinib.
A clinical trial is open to evaluate osimertinib with or without SRS for EGFR-mutated NSCLC with BM
(NCT03497767). The trial is expected to be completed in 2022.

If osimertinib is unavailable, first- or second-generation anti-EGFR TKI can be used in patients with
asymptomatic BM, but not alone. Preclinical studies have shown a sensitizing effect of radiotherapy on EGFR
expression and an enhanced radiation response through the inhibition of EGFR [48,49] . Although limited,
clinical data is not yet reflective of preclinical data, but shows promise for future trials. A meta-analysis
including 363 patients and another retrospective study of 351 patients with EGFR-mutated NSCLC (treated
with first- and second-generation anti-EGFR TKI) suggested upfront intracranial radiation demonstrates
better overall survival [50,51] . SRS followed by anti-EGFR TKI resulted in the longest overall survival, with
WBRT followed by anti-EGFR TKI demonstrating intermediate overall survival and anti-EGFR TKI
followed by SRS or WBRT at intracranial progression resulting in the shortest median overall survival [50,51] .
Based on these data, for patients with asymptomatic BM started on a first- or second-generation anti-EGFR
TKI, upfront SRS is appropriate - particularly given its better outcomes compared to delaying radiation. The
concurrent use of anti-EGFR TKI with SRS or WBRT is more controversial, demonstrating mixed results. A
[52]
phase III study found decreased overall survival with WBRT + SRS + erlobinib compared to WBRT + SRS .
Another retrospective study found similar survival in patients receiving a concurrent administration of
[53]
radiation + anti-EGFR TKI vs. patients receiving radiation followed by anti-EGFR TKI . At this point, due
to the absence of data, we recommend stopping TKI administration during SRS treatment and resuming
after completion.

ALK-directed TKIs have also demonstrated intracranial activity. In a retrospective analysis, the first-
generation ALK inhibitor, crizotinib, showed an intracranial disease control rate of 56% in untreated BM and
[54]
62% in previously treated BM . Despite this intracranial efficacy, approximately 20% of patients progressing
[54]
on crizotinib developed BM . Second-generation ALK-directed TKIs (ceritinib, alectinib, brigatinib)
have better intracranial efficacy. Alectinib was compared to crizotinib in two phase III trials (J-ALEX
and ALEX) and showed improved survival and superior CNS activity with an incidence rate of CNS
progression at 12 months of 4.6% with alectinib compared to 32% with crizotinib in patients without BM at
baseline [55-57] . Brigatinib is also superior to crizotinib in the frontline setting, as seen in the ALTA trial, with
[58]
an intracranial response rate of 78% with brigatinib vs. 28% with crizotinib . Crizotinib, ceritinib, alectinib
and brigatinib are all approved as first-line therapies for ALK-positive advanced NSCLC. However, alectinib
[8]
is preferred per National Comprehensive Cancer Network guidelines . Alectinib alone is appropriate in
asymptomatic BM.

In patients who progress on crizotinib, ceritinib, alectinib or brigatinib are all appropriate as they have not
been directly compared in terms of BM efficacy. In a small case series, alectinib also showed intracranial
[59]
response in ceritinib-resistant patients . In the setting of alectinib-resistant disease, options include
switching to lorlatinib, which has documented CNS activity in patients who have failed second-generation
[60]
[61]
inhibitors or local therapy (such as SRS) if only oligometastatic disease is present .
[8]
Crizotinib is the standard first-line treatment for patients with ROS1-rearranged NSCLC , but as previously
discussed, it has poor intracranial activity. Other approved TKIs include ceritinib and lorlatinib that
demonstrate better intracranial activity [62,63] . There are no data available on the combination of radiation
therapy and TKI in ROS1-rearranged NSCLC.

In one study, patients with EGFR-mutated or ALK-rearranged NSCLC who had oligo-progression on
erlotinib or crizotinib were considered for local ablative therapy to the sites of progression and continuation