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J Neurooncol
DOI 10.1007/s11060-016-2190-1
CLINIcAL STUDY
Pembrolizumab: first experience with recurrent primary central
nervous system (CNS) tumors
Deborah T. Blumenthal1 · Michal Yalon2 · Gilad W. Vainer3 · Alexander Lossos4 ·
Shlomit Yust5 · Lior Tzach6 · Emanuela Cagnano3 · Dror Limon5 · Felix Bokstein1
Received: 4 May 2016 / Accepted: 23 June 2016
© Springer Science+Business Media New York 2016
Abstract Patients with progressive primary brain tumors
(PBT) are attracted to promising new treatments, even prior
to convincing data. Anti-PD1 immunotherapies have been
in the spotlight since publication of groundbreaking results
for metastatic melanoma with pembrolizumab (PBL). Our
objective was to report on the response and toxicity of
PBL in patients with advanced PBT. We retrospectively
reviewed the charts of 22 patients (17 adults and 5 children)
with recurrent central nervous system tumors treated with
PBL. We analyzed prior antineoplastic therapies, steroid
usage, and outcomes. Patients received a median of two
neoplastic therapies prior to PBL, and a median of three
infusions of PBL in adults and four in children. Twelve
patients (9 adults and 3 children) started PBL on steroids
(median dose in adults 4 mg; range 2–8, and in children
1.5 mg, range 0.5–4) and five patients received steroids
later during PBL treatment. Twelve patients (10 adults and
Deborah T. Blumenthal
[email protected]
1
Neuro-Oncology Service, Division of Oncology, Tel Aviv
Sourasky Medical Center, 64239 Tel Aviv, Israel
2
Pediatric Neuro-Oncology Service, Pediatric HematoOncology Department, Chaim Sheba Medical Center,
52621 Tel HaShomer, Israel
3
Molecular Pathology Service, Department of Pathology, Tel
Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel
4
Leslie and Michael Gaffin Center for Neuro-Oncology,
Department of Oncology, Hadassah-Hebrew University
Medical Center, 91120 Jerusalem, Israel
5
Oncology Institute, Davidoff Center, Rabin Medical Center,
49100 Petah Tikva, Israel
6
Oncology Institute, Chaim Sheba Medical Center,
52621 Tel HaShomer, Israel
2 children) received concomitant bevacizumab with PBL.
Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the
start of PBL was 2.6 months in adults and 3.2 months in
children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response
in these cases was unremarkable, and PD-L1 immunostaining was negative. In this series of 22 patients with
recurrent primary brain tumors, PBL showed no clinical
or histologic efficacy. We do not recommend further use
of PBL for recurrent PBT unless convincing prospective
clinical trial data are published.
Keywords Primary brain tumor · Anti-PD1 ·
Pembrolizumab · Glioblastoma · Immunotherapy
Introduction
Glioblastoma (GB) is the highest grade primary brain tumor,
with average median survival of 12 months [1]. Most patients
receive standard treatment of radiation with concurrent chemotherapy of temozolomide, followed by adjuvant temozolomide. Approved second-line therapies for G B include
intravenous bevacizumab [2] and carmustine wafers [3] (the
latter, if surgical gross total resection of the recurrence is feasible). Re-irradiation may add benefit to selected cases [4, 5]
and ongoing studies (RTOG 1205) continue to evaluate the
benefit of this approach. However, the utility of these secondline regimens is limited and often the tumor progresses despite
interventions, proving resistant to further salvage therapies.
The treatment options for brain stem gliomas (BSG) are even
more limited than those for GB. These precariously located
intrinsic and infiltrative tumors are not amenable to resection
although stereotactic biopsy may be feasible [6].
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Patients with progressive primary brain tumors (PBT)
are in desperate need of effective therapies. Many of these
patients continue to have independent level of function in
the face of progressive tumor on imaging. Such patients turn
in desperation to new “wonder drugs” despite lack of evidence of efficacy, due to lack of viable treatment options.
Immunotherapy with anti-programmed cell death protein 1 (PD1) agents has resulted in remarkable responses
in a significant percentage of cases of refractory metastatic
melanoma [7]. This immune-modulating therapy has also
shown a signal in certain head and neck, renal cell, and nonsmall cell lung cancer cases [8–10].
To date, there are no clinical studies published reporting
the response of PBT to anti-PD1 therapy.
We report our experience with a series of patients with
progressive PBT who were treated with pembrolizumab
(PBL), a monoclonal anti-PD1 antibody.
Materials and methods
We retrospectively collected data from 22 patients with progressive, advanced primary CNS tumors who were treated at
four major Israeli brain tumor centers with PBL as a salvage
agent. Identifying demographic data were blinded between
the centers’ investigators, to protect the patients’ privacy.
Response to treatment was assessed by clinical evaluation
by the treating physicians, and by standard MRI examination at 2–3 month intervals or sooner if clinical deterioration
warranted. Since the cohort was analyzed retrospectively,
the imaging intervals were not uniform for all patients.
Patients for whom there was a question of tumor progression versus inflammatory response on MRI, were continued on anti-PD1 therapy until either clinical deterioration;
appearance of new lesions; or tumor growth of greater than
25 % on a subsequent scan.
The study was approved by all centers’ institutional
review boards. Two patients had tumors resected at the
time of recurrence following treatment with PBL. These
two samples were examined for lymphocyte staining and
PD-L1. We utilized an FDA-approved 22C3 PD-L1 staining
technique (DAKO) [11]. Five patients had tumors analyzed
molecularly for microsatellite instability (MSI) and mutational load.
Results
Patient characteristics and results (Table 1)
Our series of 22 patients included seventeen adults with
10 (G Bs), 2 anaplastic astrocytomas (AA), 2 anaplastic
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oligodendrogliomas, 2 patients with (transformed) low
grade gliomas, and one brain stem glioma (BSG ); and
5 children: 2 BSG ; and 1 each of G B, atypical teratoid/
rhabdoid tumor, and medulloblastoma. Most adult patients
were heavily pretreated: mean number of previous treatment lines in adults was 2 (range 1–6); 8/17 adults
(47.1 %) received 2 treatment lines and 5/17 patients
(29.4 %) received three and more treatment lines. In children, median number of treatment lines was 1 (range 1–2).
The median dose of PBL was 150 mg administered every
3 weeks (range 100–200) in adults. All pediatric patients
received PBL at the flat dose of 50 mg every 3 weeks.
Twelve patients started PBL while on steroids (median
dose in adults 4 mg [range 0.5–8 mg] and median dose
in children 1.5 mg [range 0.5–4]), and 5 patients (3 adults
and 2 children) received steroids later during PBL treatment due to clinical deterioration. Twelve patients (10
adults and 2 children) received concomitant bevacizumab
(BVZ) with PBL. Patients who received therapy with BVZ
and PBL were weaned off steroids or tapered to a minimal dose of 2 mg. All patients showed progressive tumor
growth during therapy. Median number of PBL infusions
was 3 (range 1–7) in adults and 4 (range 2–10) in children.
Median overall survival (OS) from the initiation of treatment with PBL was 2.6 months (range 0.4–11.6) in adults
and 3.2 months (range 2.3–7.9) in children.
There were two cases of side effects which may have
possibly been related to PBL treatment: one patient suffered a mild rash and increased liver enzymes; and a second
patient experienced protracted diarrhea.
Two G B patients underwent resection of recurrent
tumor following treatment with four and two cycles,
respectively, of PBL. Hematoxylin & eosin (H&E) and
immunohistochemistry stains, including stains for lymphocytes and PD-L1 are shown in Fig. 1 for these two
patients. Immunohistologic examination showed no evidence of local tumor-lymphocytic response in these two
cases. Programmed death-ligand 1 (PD-L1) immune-staining following resection for recurrent tumor was as well
negative in both cases.
Five of our adult patients had sent tissue during the course
of their treatment to FoundationOne (FoundationOne™,
Foundation Medicine Inc., Cambridge, MA) for genomic
sequencing of their tumor samples [12]. We retrospectively
reviewed these cases for mutational load and microsatellite
MSI. Analysis of these samples showed stable MSI with
low mutation burden in four of the five cases (3–5 mutations per megabase [Mb]); these four cases involved tissue
from the time of tumor diagnosis/initial surgery. However,
one case (depicted in Fig. 1a–c) whose tumor sample was
examined at the time of recurrence, showed stable MSI with
a very high mutation rate of 75 per Mb.
J Neurooncol
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Table 1 Patient characteristics
(n = 22)
Total number
Sex (f/m)
Median age
Pathology
Glioblastoma
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Low grade glioma (probably transformed)
Diffuse brainstem glioma
Medulloblastoma
Atypical rhabdoid-teratoid tumor
No of previous treatment lines
One
Two
Three and more
Median
Radiation treatment in the past
Median dose of PBZ, mg
Median number of PBZ cycles
No of patients treated concomitantly with bevacizumab
Steroids
No of patients starting PBZ without steroids
No of patients starting PBZ while on steroids
No of patients starting steroids later on
Median dose of dexamethasone (mg)
Treatment response
Median OS from start of PBZ, months [range]
Discussion
Immune-based, “checkpoint” therapies have created a
revolution in the field of oncology over the recent years.
With justification, these therapies have produced previously
unbelievable results in patients with advanced metastatic
melanoma and other cancers [7, 10, 11, 13–17]. The efficacy of anti-PD1 therapy in a variety of other tumor types is
currently under investigation [18, 19].
Therapies targeting programmed cell death protein 1
(PD-1) work by facilitating the body’s innate immune
defenses to work against the tumor. To evade immune recognition, tumors utilize various mechanisms. One of the key
interactions between the tumor and the host immune system involves the signaling of PD-1 after binding to PD-L1.
This happens when activated B and T-cells expressing the
PD-1 receptor encounter tumor cells expressing PD-L1 on
their surface [20]. The binding of PD-1 to PD-L1 generates an immunosuppressive cascade which allows the tumor
cell to evade destruction by the innate immune system [21].
Anti-PD-1 and PD-L1 therapies prevent the tumor cell from
Adults
Children
17
3/14
38.5 [25–71]
5
All males
5 [3–7]
10
2
2
2
1
–
–
1
–
–
–
2
1
1
4
8
5
2 [1–6]
All
150 [100–200]
3 [1–7]
10
4
1
–
1 [1, 2]
All
50 (all)
4 [2–10]
2
8
9
3
4 [2–8]
PD—all
2.6 [0.4–11.6]
2
3
2
1.5 [0.5–4]
PD—all
3.2 [2.3–7.9]
masking itself from the immune system, and allow the lymphocytes to target the foreign cancer cell invader.
Anti-PD1 and immunotherapy in primary brain tumors
Pre-clinical data
Pre-clinical data suggests a role for anti-PD1 therapy in glioma, specifically with synergistic radiation. Radiation has
been shown to increase antigen presentation and promote
a pro-inflammatory tumor microenvironment which could
work synergistically to complement anti-PD1 therapy. A
mouse glioma line was treated with anti-PD1 and stereotactic radiosurgery, as single or combined modalities, to
test this theory. Results of this study showed a significant
increase in survival in the combined modality group, with
long term survivors seen in the combined modality cohort
alone. Moreover, a correlating immune response was seen
in the orthotopic tumor with cytotoxic T cell infiltration
(increased CD8/CD4 ratio) in the combined therapy cohort
[22].
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J Neurooncol
Fig. 1 a–f Two patients with recurrent GB tumor samples following
treatment with pembrolizumab (PBL). a–c CD8 (lymphocyte), Hematoxylin & Eosin (H&E), and PD-L1 immunohistochemistry stains
respectively, in a patient treated with four cycles of PBL. HE shows an
active glioblastoma with regions of pseudopallisading necrosis. Stains
for CD8 lymphocytic infiltrate as well as PD-L1 are negative. This
same patient showed a very high mutational load on genomic analysis.
d–f Similar staining in a patient who underwent resection following
treatment with two cycles of PBL. Both cases are notable for viable
glioblastoma tumor on HE with scant to no lymphocytic infiltration;
PD-L1 staining is negative. g Positive control slide (tonsil) for PD-L1
Clinical data
in combination with ipilimumab, versus bevacizumab. The
primary endpoint will be overall survival, with secondary
endpoints of safety, PFS and ORR [24].
There is limited clinical data for anti-PD1 therapies in the
context of PBT. Recent presentations from the American
Society of Clinical Oncology (ASCO) 2015 annual meeting
reported primarily safety data from an ongoing prospective
study of nivolumab for recurrent GB patients.
Twenty patients (ten per arm) were treated with either human
IgG 4 PD1 antibody nivolumab alone or in combination with
ipilimumab in a small randomized trial for GB at first recurrence. The study endpoints were tolerability and safety. Side
effects were more severe and more common in the combination
arm. Overall survival at 6 months was 75 % for the two groups,
similar to historical standards. Final data are pending [23].
An ongoing phase IIB study for patients with first recurrence of GB will treat 240 patients with nivolumab alone or
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Our cohort
Responses in other settings of once thought “intractable disease” have proven the worth of anti-PD1 treatment. However, the efficacy of these therapies has not been proven in
all oncologic settings, and many tumor types have not been
shown to benefit from the anti-PD1 mechanism. The logic
supporting PBT as an appropriate target for anti-PD1 therapy is theoretically sound for some cases of primary brain
tumors; however, the clinical data for efficacy is lacking,
and certainly not expected to be as dramatic as in the case of
metastatic melanoma, if at all.
J Neurooncol
None of our 22 patients with recurrent PBT showed
radiologic, clinical, or immune-histologic response to treatment with PBL. There are several possible explanations for
the lack of response in our cohort.
First, is the issue of molecule size and blood brain barrier (BBB) penetration. The BBB may mechanically prevent
the large PBL molecule (146 kDa) from entering the CNS
and approaching the target cells. Most molecules which permeate by transmembrane diffusion are close to 1000 times
smaller than the PBL antibody [25].
Despite this theoretical concern of BBB penetration,
anecdotal reports of patients with brain metastases report
robust reactions of their central nervous system tumors
to treatment with PBL, including histologic evidence of
inflammation and microglial response [26]. As such, it is
likely that the BBB concern is not the primary reason for
lack of a clinical response to anti-PD-1 treatment.
Secondly, the innate immune system and anti-tumor
immune response which the anti-PD1 therapy potentiates, is
not the same in the CNS as in the systemic periphery [22].
Systemic melanoma has long been addressed by immune
therapies (alpha interferon, IL) and may be as such the ideal
target for anti-PD1 therapy. The presence of CD8 + T-cells
in tumor tissue has been associated with successful tumor
response to anti-PD1 therapy in melanoma [27, 28]. We did
not see evidence of T-cell infiltration in the two tumor cases
in our cohort sampled after treatment with PBL. Furthermore, tumors which are more immunogenic (i.e., melanoma)
have a higher MSI. Compared to other human cancers, the
prevalence of somatic mutations in GB (and medulloblastoma) is on the lower end of the spectrum, certainly much
lower than in tumors with high MSI such as melanoma or
lung adenocarcinoma [29]. As such, these PBT would be
expected to be less responsive to anti-PD1 therapies than
tumors with higher scores. There may be selected subgroups
of gliomas which may have higher MSI scores, perhaps due
to mismatch repair mechanisms (MMR). A cohort of consanguineous pediatric gliomas has been reported, with an
MMR mutation which may render them an ideal population for treatment with anti-PD1 therapy [30]. Mutational
load has also been recognized as a predictor of response to
anti-PD1 therapy. A recent report revealed a high mutational
load in 37 pediatric patients (including GB) with a hereditary mismatch repair deficiency syndrome, who underwent
exome sequencing; two siblings in this cohort were treated
with anti-PD1 therapy with excellent clinical and imaging
responses [31].
Mutations in the tumor can produce specific neoantigens which can elicit T cell responses to immunotherapy
[32]. Despite a very high mutational burden (as might be
expected in a recurrent tumor post-exposure to temozolomide) [33, 34] seen in one of the GBM tumor samples in
our series that was examined at re-operation, this patient did
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not respond clinically or radiographically to treatment with
PBL. In the case of primary brain tumors, a “stable” MSI
score may be a more significant negative predictive factor
to anti-PD1 therapy than an increased mutational load of the
tumor is a positive predictive factor.
Thirdly, our patients were almost all heavily pre-treated,
at an advanced and refractory stage of disease. Treating at
an early stage of disease, and more specifically with synergistic radiation, has been shown to optimize effect of the
anti-PD1 therapy in pre-clinical models [22, 35], and may
be a superior strategy.
Fourth, the use of corticosteroids, typically dexamethasone, is widespread in patients with advanced PBT for
control of tumor-associated edema and preservation of
neurologic functional status. Although there are reports of
successful treatment with PBL during treatment of dexamethasone at a dose of 4 mg a day [36], it is still not known
if steroid use may antagonize and diminish, if not nullify,
the desired immune-enhancing effect of the anti-PD1 therapies. Some of our patients avoided or minimized steroid use
by concurrent therapy with bevacizumab, to control tumor
edema. The relatively high number of patients who were
treated with dexamethasone during therapy with PBL may
explain the low incidence of side effects we observed in this
cohort; steroids may have prevented unwanted inflammatory responses in other organs.
Lastly, we did not see expression of PD-L1 staining in the
cases examined post-treatment, contrary to other reports. An
analysis of PD-L1 gene expression in 446 GB cases from
the Cancer G enome Atlas reported immunohistochemistry
staining for PD-L1 expression in 70–90 % of GB cases, less
in proneural and higher in mesenchymal subtypes. PD-L1
expression did not appear to correspond with age or prognosis, nor did it seem to change from initial diagnosis to recurrence [37]. A recent smaller study of 94 GB tumors showed
PD-L1 positive staining in greater than 60 % of tumors, but
most with a small percentage of cell surface expression.
Expression of PD1 and PD-L1 in this study was found to be
a negative prognostic factor for survival [28].
This discrepancy in the low incidence of PD-L1 expression in our cohort may be related to the small number of
patients who underwent immunostaining, or it could be
indicative of differences between our PD-L1 staining technique and others cited in the literature.
Even if there had been PD-L1 expression in the tumors
of our patients prior to treatment, we would expect to have
seen some remnant of reactivity or inflammation at the time
of reoperation following immunotherapy.
Ethical viewpoint
Patients with progressive GB who have exhausted the standard treatment options and for whom no feasible clinical
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trials are available are desperate for a “life-line”. The ethics
of providing unproven therapy to this population is wrought
with controversy. Treatments may be potentially toxic,
without the promise of proven benefit; possible toxic effects
associated with treating with a developing drug off-label can
deter the development of the product to make it available to
the public who could benefit from it. The physician may
find her/himself unduly pressured by the patient and family
to prescribe an unproven therapy against better judgment,
which begs the question of the need for increased institutional regulation. A modicum of skepticism regarding a new
product is advised when data are sparse. However, physicians may differ in practice styles: while some practitioners
do not treat in the absence of convincing evidence, certain
physicians may feel uncomfortable denying a patient’s or
family’s requests for off-label medications and are more
influenced by the arguments of the patient or by unsubstantiated anecdotes, and acquiesce to these requests. Yet others
seek to practice on the “cutting edge” and are more willing
to pursue new therapies, even when data are lacking [38].
What is the accountability of the pharmaceutical companies to provide commercial medications if used off-label;
is the physician, the hospital or health authorities or ultimately the “informed”, but far from objective patient culpable for the ultimate treatment decision? Some individuals
turn to social media and groups of patients may petition for
expanded access of new medications. It is not always clear
if these requests come from adequately informed sources
[39]. On the one hand, it is not always feasible to wait for
level I evidence (phase III randomized trials) to gain access
to new drugs for an “orphan” population; by waiting, lives
may be compromised. However, on the other hand, there
needs to be a mechanism to offer patients such vanguard
treatments, requiring at least minimal clinical (even anecdotal) evidence for response, with acceptable toxicity data.
Conclusion
PBL is well-tolerated in patients with recurrent primary
brain tumors, both in adults and in children. However, we
did not observe a signal of efficacy for treatment with the
anti-PD1 therapy in our patient population. High mutational
load was not associated with response to PBL in our limited
experience. We do not recommend further use of PBL for
recurrent PBT unless convincing prospective clinical trial
data is published.
Acknowledgments We thank Phil Stephens, PhD and Joana Buxhaku from Foundation Medicine who assisted with the analysis of MSI
and mutational number on available patient samples. Thank you to Jay
A. Jacobson, M.D. of the University of Utah School of Medicine for
medical ethics advice. We thank Anat Mordechai, RN from Hadassah
Medical Organization for her assistance with clinical data retrieval.
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Funding This research was not funded by outside sources.
Compliance with ethical standards
Conflict of interest Gilad W. Vainer, MD, PhD served on advisory
committees for Pfizer, Roche, and Merck (MSD) regarding immunologic and molecular testing.
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J Neurooncol