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tively low, these were real-world unselected cases without known PD-L1 status and the PFS was in line with
pivotal immunotherapy trials in the 2nd-line setting. More importantly, the RR appears to be equivalent for
both intracranial and extracranial disease.

The single-agent activity of pembrolizumab in the brain was also studied in a phase II trial including both
NSCLC and melanoma patients with at least 1 BM between 5 and 20 mm that was asymptomatic and either
untreated or progressing after prior local therapy. The result was recently updated at 2018 ASCO annual
meeting [41,42] . Two cohorts of NSCLC patients were enrolled with 34 PD-L1 positive (PD-L1 ≥ 1%) patients in
cohort 1, and 5 PD-L1 negative or unevaluable patients in cohort 2. Pembrolizumab 10 mg/kg was adminis-
tered every 2 weeks. None of the patients had previously received immunotherapy. 10 of 34 (29.4%) patients
in cohort 1 had a response in CNS. Interestingly, 7 patients had discordance between CNS and systemic
responses (4 with PD in brain and PR in body, and 3 with PR in brain and PD in body). Intracranial PFS
among patients with BM response or stable disease was 10.7 months. Median OS among all patients was
8.9 months, with 31% of patients living at least 2 years. No patients in cohort 2 had a BM response, but 2
of the 5 patients lived past 1 year. Treatment was well-tolerated, with no neurologic adverse events (AEs) >
grade 1 related to treatment, although 2 patients developed grade 3 pneumonitis related to pembrolizum-
[42]
ab . Although large prospective studies are lacking, taken together, it appears that a PD1 inhibitor can have
activity in brain and may be a safe and active treatment option for patients with small, asymptomatic BM in
NSCLC patients.

The role of immunotherapy has been more extensively studied in melanoma patients with BM. Ipilimumab,
a CTLA4 inhibitor, achieved intracranial disease control in 12/51 (24%) patients in patients with asymp-
[43]
tomatic small BM without steroid use . More recently, two phase 2 studies combining nivolumab and
ipilimumab were investigated in the same patient population. The Checkmate 204 study comprised short-
[44]
term follow-up of 75 asymptomatic patients. The ICRR was 56% with 20% of patients experiencing CR .
In an Austrialian study, 35 and 25 patients with asymptomatic BM and no previous immunotherapy were
randomized to cohort A (nivolumab plus ipilimumab) and B (nivolumab only), respectively. 16 patients in
whom local therapy had failed or who had neurological symptoms or leptomeningeal disease were enrolled
[45]
in cohort C . The ICRR, CR for cohort A was 46% and 17%, respectively. The median intracranial PFS was
not reached at data cutoff. Of note, for treatment-naïve patients, the ICRR was 56%. By contrast, the cohort B
of 25 patients receiving nivolumab only had ICRR of 20% and CR of 12%, respectively with median intracra-
[45]
nial PFS of 2.5 months . In contrast to cohort A and B, only one of 16 patients in cohort C had intracranial
response (6%) and this patient had BRAF wild type, no leptomeningeal disease and neurological symptoms
[45]
only . As expected, more treatment-related adverse events (AEs) happened in cohort A patients who re-
ceived combination. Three patients (9%) in cohort A and one patient in cohort C (6%) developed peripheral
neuropathy. Grade 3 AEs occurred in 54% of cohort A, 16% of cohort B and 13% of cohort C and the most
common AEs were diarrhea or colitis, and hepatitis. Three patients in cohort A experienced grade 4 hepa-
titis, pulmonary edema or hypophysitis. One patient in cohort B and one patient in cohort C experience
[45]
severe headache due to cerebral edema. No death occurred because of study treatment . No CNS demyelin-
ation occurred, although it was reported previously in a patient treated with nivolumab after progressing on
[46]
ipilimumab . These results suggest that combination immunotherapy with ipilimumab and nivolumab may
represent a valuable option in patients with asymptomatic melanoma brain metastases, long-term follow-up
[45]
with OS data is eagerly awaited .

FUTURE PERSPECTIVE
In general, the response of systemic (extra-cranial) disease correlates well with that of intracranial BM with
immunotherapy although discordance has been reported [42,45] . Using the available biomarkers, we might be
able to tease out the patients with asymptomatic small BM who might respond well to immunotherapy or an
immunotherapy combination. At this time, there are no data demonstrating the use of combination immu-