Kidney Cancer Journal 51
with brain metastases in the NIVOREN trial (Nivolumab
in Patients With Metastatic Renal Cell Carcinoma Who
Have Progresses During or After Prior Systemic Anti-angiogenic
Regimen), also called GETUG-AFU 26. NIVOREN
was a phase 2 study examining the efficacy of nivolumab
in the systemic therapy of mRCC after the failure of at
least 1 or 2 previous systemic treatments.16 Of the 588 patients
enrolled, 55 had asymptomatic brain metastases,
including 67%, 12%, and 21% with 1, 2, or more than 2
brain metastases, respectively. Of the 55 patients, 37
(67%) had had no previous treatment for brain metastases,
5 (9%) had undergone brain surgery, and 17 (31%)
had received radiation therapy. The median duration of
therapy in the patients with brain metastases was 2.4
months (range, 0-9 months). Of 44 patients with BM who
were assessed for response, 10 (23%) had an objective response
and 21 (48%) had progressive disease. (16) Neurologic
decline requiring corticosteroid treatment de-
veloped in 15 patients (34%).
Although this study was small, it did show a potential
response that requires further exploration. Prospective
clinical trials, including approaches combining radiotherapy
with immune-oncology, are under way (NCT02978-
404).
Rothermundt et al17 presented the case of a 54-yearold
woman with clear-cell renal cell cancer, who developed
metastases in multiple organs including one brain
metastasis (gyrus cinguli). She was treated with pazopanib
and the solitary brain metastasis was irradiated with 30
Gy. After 8 months of treatment with pazopanib, there
was progression in the brain metastasis as well as development
of two new brain metastases. Whole brain radiotherapy
was performed leading to a cumulative dose of
52.5 Gy at the site of the gyrus cinguli metastasis.
The patient was subsequently treated with bevacizumab
for progressive cerebral edema interpreted as radiation
induced brain necrosis. Upon systemic and cen-
tral nervous system (CNS) progression 5 months later
treatment with axitinib was started—achieving a partial
response (PR) However, after 4 months, in March 2015,
further systemic and CNS progression was documented
Treatment with pembrolizumab, a novel human programmed
death receptor-1 (PD-1)-blocking antibody, was
initiated. Pembrolizumab was chosen due to off-label
availability at a time when no anti-PD-1 or anti-PD-ligand
(L)1 antibody was licensed in Europe. After four infusions,
the patient experienced complete resolution of lung
metastases, stabilization of other metastases. Importantly,
regression of all brain metastases was documented on
magnetic resonance imaging. This excellent response
was seen despite continued steroid use of 4 mg dexamethasone/
day and is still ongoing after 7 months of treatment.17
Future Directions, Unresolved Issues and Hypotheses
The next generation of studies will need to address a
broad spectrum of issues as they seek to resolve many unresolved
questions in this important subset of RCC patients.
As Brastianos et al noted in their report18 on the
genomic characterization of BM, it is still unknown
whether BM harbor distinct genetic alterations beyond
those observed in primary tumors. Currently, decisions
for individualized systemic therapies in those with BM
are lacking and the conventional treatment approach incorporates
systemic agents that are routinely used for
mRCC patients with extracranial disease. This is just one
conundrum among many that need to be considered as
studies explore new targets to improve the dismal prognosis
for RCC patients with BM.
Genomically guided clinical trials have been successful
at matching patients to novel targeted agents in patients
with advanced cancer; however, patients with active BM
are routinely excluded from these trials in part due to the
poor correlation between systemic response and brain response.
Patients will often develop progressive BM in the
setting of extracranial disease that is adequately controlled
with existing chemotherapies or targeted therapies.
18 Historically, this clinical divergence has been
ascribed to inadequate systemic therapeutic penetration
of the blood–brain barrier. Aside from need for better CNS
penetrance of therapeutic agents in mRCC, further understanding
of potentially oncogenic alterations unique
in RCC brain metastases may offer novel treatment strategies
that are desperately needed in this subset.
Brastianos et al, for example, detected alterations associated
with sensitivity to P13K/AKT/mTOR, CDK, and
HER2/EGFR inhibitors in brain metastases.18 Additional
studies are needed to clarify the extent to which such genomic
analyses can expand our awareness of potential
therapeutic targets in mRCC patients. Only limited data
are available on whether checkpoint inhibitors could play
a larger role in treatment. It appears, from studies like one
from Harter et al,19 that RCC is one of the most immunogenic
entities. Their study focused on characterizing
tumor-infiltrating lymphocytes and expression of immune
checkpoints in respective tumors. One of the future
directions will include efforts to further characterize differences
in immunotherapeutic responses for BM according
to primary tumor site.
Brain Barrier Penetration Remains Unresolved Issue
We recommend that the current management approach
for patients with RCC and BM be multidisciplinary with
incorporation of treatment strategies such as surgery
and/or radiation therapy, when feasible. The ability of
cabozantinib to penetrate the CNS is promising and has
recently been supported in several tumor types including
glioblastoma, RCC metastatic to the brain, and nonsmall
cell lung cancer metastatic to the brain where
cabozantinib demonstrated therapeutic efficacy.20-22
Based on evidence available to date and our experience,
cabozantinib may represent the ideal systemic agent of
choice in mRCC patients with BM. Evidence is increasing
to suggest that immune checkpoint inhibitors may additionally
represent attractive systemic agents in treating
this RCC patient subset. Although the majority of clinical
trials in mRCC have historically excluded patients with
BM, a growing number of trials investigating systemic
agents in mRCC subjects are now permitting inclusion of
this high-risk subgroup. These studies will provide important
knowledge on identifying effective agents and disease
characteristics that may inform further treatment
selection tailored to the individual with RCC metastatic
to the brain. In mouse models exploring the ability of
pazopanib to penetrate the CNS, only 1.5% of the con