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Page 6 of 9 Mudra et al. J Cancer Metastasis Treat 2019;5:27 I http://dx.doi.org/10.20517/2394-4722.2019.09

[64]
[64]
of the TKI . The TKI was stopped on the days of radiation and restarted with the same dose . Twenty-
five of 51 patients who progressed were deemed suitable for local therapy and most received stereotactic
[64]
radiation . Ten of the 25 patients had intracranial progression . Post local ablative therapy, the median
[64]
[64]
[64]
progression-free survival was six months . Minimal grade three and four adverse events were seen .
Another study of ALK-rearranged NSCLC showed that combining stereotactic radiation with crizotinib is
[65]
safe and can achieve durable control, although the study only included extracranial sites of progression .
A retrospective study showed prolonged overall survival (49.5 months) of NSCLC patients with BM when
[66]
treated with ALK-directed TKI therapy and brain radiation . In the ALEX trial, patients with previous
radiation to BM had higher intracranial response rates (86% vs. 79%) compared with patients without prior
[57]
radiotherapy . In summary, data on the safety and outcome of combining radiation with ALK-directed
TKIs is limited and favors SRS over WBRT.
An ongoing clinical trial is evaluating ALK inhibitors and other targeted therapies in combination with
stereotactic brain treatment in patients with stage IV oncogene-driven (EGFR, ALK, or ROS1) NSCLC
(NCT02314364).

CONCLUSION
The development of novel, targeted agents and immunotherapy has advanced the systemic treatment of lung
cancer. These therapeutics demonstrate far greater intracranial efficacy than conventional chemotherapy
- transformative for BM treatment. However, this paradigm shift in treatment warrants the careful
consideration of systemic therapy as a frontline approach. While SRS remains an important aspect of the
management of BM, its role combined with novel systemic therapies is largely unclear. Limited available
evidence suggests combination is safe with favorable outcomes, but the sequence of administration remains
uncertain. Many clinical trials are underway that aim to further address these questions. As the results of
these studies emerge, clinicians will gain further evidence-based insight into the clinical management of
patients with lung cancer BM.

DECLARATIONS
Authors’ contributions
Made substantial contributions to the research, writing and editing of the manuscript: All authors

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.