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Page 4 of 8 Niu et al. Neuroimmunol Neuroinflammation 2018;5:32 I http://dx.doi.org/10.20517/2347-8659.2018.39

Thus, nivolumab plus ipilimumab may represent a new treatment option in metastatic NSCLC with high
TMB, though this combination has not been approved to be used clinically.

Immunotherapy as second-line treatment
Currently there are three agents available in the platinum-resistant setting. Two large phase 3 randomized
clinical trials made head-to-head comparison between nivolumab and docetaxel [29,30] . Checkmate 057 includ-
ed patients with non-squamous histology, and Checkmate 017 included patients with squamous histology
with identical trial design [29,30] . Both trials showed superiority of nivolumab in ORR, PFS and OS as well as
significant improvement in quality of life [29,30] . Nivolumab was reported to benefit both PD-L1 negative and
positive groups with a different antibody, and was approved for 2nd-line use irrespective of PD-L1 expression
based on these two trials. Pembrolizumab was compared with docetaxel in the Keynote 010 study wherein
it only included PD-L1 positive patients defined as TPS ≥ 1%. The pembrolizumab arm showed significantly
[31]
better ORR, PFS, OS with a very favorable side effect profile . Thus, pembrolizumab was approved in PD-
L1 positive NSCLC after platinum-based first-line therapy. Atezolizumab, a monoclonal antibody against
PD-L1, was compared directly with docetaxel in a phase 2 and a phase 3 randomized trial with similar re-
sults. Although there was no median PFS advantage in the atezolizumab arm, an OS advantage was found
in all subgroups, which led to the addition of atezolizumab to the armamentarium against NSCLC in the
second-line setting [32,33] . The landscape of immunotherapy for NSCLC is rapidly changing. These three agents
were all approved before first-line immunotherapy became available. With expected wide use of mono-
immunotherapy or chemo-immunotherapy combination in the frontline, there is unmet medical need for
immunotherapy to overcome immune resistance in previously treated population.

Immunotherapy in NSCLC with brain metastasis
The brain was once believed to be an immune privileged organ to actively suppress any immune response.
[34]
It is now known that the immune response in brain parenchyma is tightly regulated . In established brain
metastases, the tumor microenvironment is composed of the innate immune system, namely microglia
and blood-derived myeloid cells/macrophages; and the adaptive immune system, mainly represented by
T cells [34,35] . Brain metastases were shown to have higher PDL-1 expression and lower density of tumor in-
[36]
filtrating lymphocytes (TILs) than the matched NSCLC primary tumors . The immunogenicity of the
primary tumor probably influences the T cell response in brain metastases as denser TILs were observed in
[37]
melanoma-derived brain metastases followed by renal cell carcinoma and NSCLC . The density of TILs
[37]
seems to correlate well with extent of brain edema and OS . Therefore, the preconditions in the tumor mi-
croenvironment to respond to immunotherapy are present in BM.

Patients with active BM from NSCLC have been excluded from pivotal clinical trials of immunotherapy in
NSCLC, thus there is no high-level evidence available from the prospective studies. However, in the Key-
note 24, the Keynote 189 (trials of pembrolizumab in the frontline), and the OAK trial (atezolizumab in the
second-line setting), patients with previously treated brain metastasis were allowed to be enrolled. Specific
intracranial response was not available, but the OS benefit seemed to have been equally sustained [26,32,38] .
The expanded access program (EAP) of nivolumab in Italy included a cohort of 409 NSCLC patients with
symptomatic or controlled BM. The real-world experience demonstrated ORR of 17% and DCR of 40% re-
spectively, similar to the whole population of 1588 patients with median OS of 8.6 months and 11.3 months,
[39]
respectively . These results seem to suggest the overall benefit was able to be retained in the subgroup of
patients with BM. However, it remains unknown from these trials to what extent the intracranial control
derives directly from immunotherapy.

In a retrospective study, 43 NSCLC patients with BM were included, and 16 patients had active BM. Patients
treated with nivolumab achieved an ICRR and an extracranial RR of 9% and 11%, respectively. The median
[40]
intracranial and the general PFS were 3.9 months and 2.8 months, respectively . Although the RR was rela-