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Page 4 of 9 Mudra et al. J Cancer Metastasis Treat 2019;5:27 I http://dx.doi.org/10.20517/2394-4722.2019.09

the presence of significant tumor-infiltrating lymphocytes (TILs). In a series of 116 BM specimens (including
61 from NSCLC BM), more than 50% of all specimens had dense TIL infiltration - also associated with
[30]
improved survival .
Radiation therapy (RT) also induces an antitumor immune response by upregulating PD-L1 and inflammatory
[31]
cytokines as well as facilitating T-cell infiltration . Localized RT may induce an abscopal effect, which
reflects the regression of non-irradiated metastatic lesions due to systemic anti-tumor response. The dose and
[32]
fractionation of RT plays a role in its effects on the immune system. Schaue et al. found that fractionated
treatment with medium-sized radiation doses of 7.5 Gy per fraction yielded the best tumor control and anti-
[33]
tumor immune responses. Dewan et al. showed that 5 × 6 Gy and 3 × 8 Gy protocols of RT were more
effective in inducing immune-mediated abscopal effects than a single ablative dose of 20 Gy when combined
with an anti-CTLA-4 antibody. These preclinical data suggest a better systemic anti-tumor effect with hypo-
fractionated (e.g., fractionated SRS) than conventional RT. Most data regarding the abscopal effect are from
treating systemic disease; if the same impact occurs in the treatment of BM is uncertain. Although based on
[34]
small studies, there is growing evidence in favor of an abscopal effect when treating BM .

RT alone is a poor inducer of immune-mediated local and abscopal responses; but, evidence suggests these
responses are enhanced by combining radiation with ICI [31,35,36] . Although data regarding the combination
of ICI and radiotherapy in BM due to NSCLC are limited and mostly retrospective, data indicate that
combining ICI and radiation in BM is safe with similar adverse events [37,38] and support a concurrent
[38]
administration of ICI with radiation over a sequential administration . While most studies demonstrated
similar adverse events with combination ICI-radiotherapy, the role of ICI in radiation necrosis remains
controversial. One retrospective study with 61% NSCLC patients showed that the incidence of symptomatic
radiation necrosis after stereotactic radiation was higher in patients who received ICI - especially those with
[39]
melanoma . Other retrospective studies including patients with NSCLC and BM did not report a higher
indicence of radiation necrosis with combination ICI-radiotherapy [37,38,40] .

Many questions regarding the combination of ICI and RT remain unanswered including the optimal timing,
the impact of steroids and neurotoxicity. Questions such as these should be investigated through prospective
trials. Current clinical trials evaluating the combination of ICI and radiation therapy in NSCLC BM include
NCT02978404 (Nivolumab + SRS), NCT02858869 (Pembrolizumab + SRS) and NCT02696993 (Nivolumab
+ SRS/WBRT and Nivolumab + Ipilimumab + SRS/WBRT). These phase I and phase II trials include other
malignancies and are expected to finish by 2020.

BRAIN METASTASIS IN LUNG CANCER WITH DRIVER MUTATIONS
[41]
In NSCLC, sensitizing EGFR mutations are found in 10% of Caucasians as well as up to 50% of Asians .
[42]
[43]
ALK-rearrangement is found in 2%-7% and ROS proto-oncogene 1 (ROS1) occurs in 1%-2% of patients .
The incidence of BM is higher in patients with driver mutations. The rates of BM present at diagnosis is
24.2% and 23.8% in EGFR-mutated and ALK-rearranged lung cancers, respectively, and increasing to > 45%
[44]
of patients at three years post-diagnosis . ROS1-rearranged NSCLC also has a high incidence of BM (36%)
[45]
and is the common first site of progression .
First- (erlotinib, gefinitib) and second-generation (afatinib) anti-EGFR TKI have demonstrated improved
survival and brain response rates of over 50% in EGFR-mutated patients compared to EGFR wild-
[5]
type patients . The third-generation anti-EGFR TKI, osimertinib, demonstrated an even higher rate of
intracranial response (91% vs. 68% in patients with measurable BM lesions), a lower rate of central nervous
system (CNS) progression and longer progression-free survival when compared to first generation anti-EGFR
TKI in the FLAURA trial [46,47] . Though first- and second-generation anti-EGFR TKI have activity in patients
[5]
with BM, these agents have a much lower intracranial concentration as compared with osimertinib . Given