Page 233 - Read Online

Niu et al. Neuroimmunol Neuroinflammation 2018;5:32 I http://dx.doi.org/10.20517/2347-8659.2018.39 Page 3 of 10

T790M positive NSCLC with BM were treated with 80 mg osimertinib. The ICRR was 54% (12% CR) and
[18]
the brain disease control rate (DCR) was 92%; 75% of patients were still in response at 9-month follow-up .
Osimertinib showed very impressive PFS as well as intracranial control over gefitinib or erlotinib in newly
[19]
diagnosed NSCLC with EGFR mutation and has been approved for first-line use .
Anaplastic lymphoma kinase (ALK) rearrangement defines another subset of mutations in 3%-5% of NSCLC.
BM has been reported in 24% of patients upon diagnosis and up to 70% during the course of disease [20,21] . It is
not entirely clear that it is due to poor brain penetration of first-generation TKI, crizotinib, or that the brain
is the preferential site of metastasis of ALK + NSCLC. Second-generation ALK TKIs such as ceritinib, briga-
tinib and alectinib all showed much better brain penetration and great activity against BM. In ALEX trial,
a subset of ALK+ NSCLC patients with measurable CNS lesions at baseline were treated with alectinib vs.
[22]
crizotinib. The ICRR and PFS were 81%, 50% and 17.3 months, 5.5 months, respectively . Moreover, 45% of
[22]
the patients with BM (measurable or nonmeasurable) treated with alectinib achieved CR . Thus, alectinib
represents a great treatment option for patients with ALK + NSCLC presenting with BM.

IMMUNOTHERAPY AND NSCLC
Immune checkpoint inhibitors have transformed the treatment paradigm for advanced-stage NSCLC in
both frontline and platinum-resistant settings. These agents inhibit a key inhibitory signaling pathway in T
cell activation by blocking programmed cell death a (PD-1) from binding to the ligand 1 or 2 (PD-L1/PD-
[23]
L2), thereby allowing activation of the inactivated T cells .
Immunotherapy as first-line treatment
In the pivotal Keynote 024 study, 305 treatment naïve, PD-L1 positive (tumor proportion score, TPS ≥ 50%)
patients with advanced-stage NSCLC without EGFR, ALK mutations were randomized to receive pembroli-
zumab, an anti-PD1 monoclonal antibody vs. platinum-based chemotherapy. Pembrolizumab was associated
[24]
with higher ORR (44.8% vs. 27.8%) and prolonged median PFS (10.3 months vs. 6.0 months) . Based on this
study, the FDA approved the use of pembrolizumab in PDL1 positive patients with advanced-stage NSCLC
in frontline setting.

Combinations of immunotherapy with chemotherapy or another immunotherapy agent have also been
extensively studied in the past few years. Keynote 189 was another landmark study that confirmed the re-
sult of the previously published small phase 2 study on first-line chemo-immunotherapy with carboplatin/
pemetrexed/pembrolizumab in previous untreated non-squamous NSCLC patients [25,26] . 616 patients were
randomly assigned in a 2:1 ratio, to receive pemetrexed and a platinum-based drug plus either pembroli-
zumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo plus pemetrexed main-
tenance. The Pembrolizumab–combination group was demonstrated to have a better RR (47.6 % vs. 18.9%),
a longer PFS (8.8 months vs. 4.9 months) and median OS (not reached vs. 11.3 months). The benefit was seen
in all subgroups, including those with a PD-1 TPS < 1%. The RR was highest in patients with PD-1 TPS ≥
[26]
50% (61.4% vs. 22.9%) . Thus, there are two FDA-approved options for NSCLC in the first-line setting at this
time. For metastatic squamous NSCLC, platinum/taxane with or without pembrolizumab was investigated
in Keynote 407 study. The ORR was 58.4% in the pembrolizumab-chemotherapy group compared with 35%
in the chemotherapy group. OS was 15.9 months vs. 11.3 months, respectively. PFS was observed in all PD-L1
TPS subgroups, although the PD-L1 high subgroup had a much longer PFS (8 months vs. 4.2 months). The
platinum/taxane/pembrolizumab combination represents a new standard of care in metastatic squamous
[27]
NSCLC . Immuno-immunotherapy combination is also under intense investigation. In the Checkmate
227 study, ORR and PFS among patients with a high tumor mutational burden (TMB) defined by at least 10
mutations per megabase was 45.3% and 7.2 months in the immuno-immunotherapy combination group with
nivolumab plus ipilimumab irrespective of PD-L1 expression level. The response was more durable, with 68%
[28]
of patients having an ongoing response after 1 year with combination group vs. 25% with chemotherapy .