EURURO Vol. 72 No. 6

979 1030

PFS (12.9 vs 1.9 mo) . Unfortunately, a phase Ib study of
a dual PI3K–mTOR inhibitor in patients with advanced RCC
of any subtype revealed significant toxicity without
objective responses Collectively, data support
the notion that pRCC should be stratified according to
MET alteration status. A randomized phase II study
projected to accrue 180 patients will perform comprehen-
sive genomic profiling and measure efficacy of MET kinase
inhibitors (cabozantinib, crizotinib, and savolitinib), each
compared with sunitinib in metastatic pRCC (PAPMET;
NCT02761057). Owing to its sample size, PAPMET will
establish a prognostic and predictive value of designation of
papillary subtype and markers of dysregulated MET
signaling. Similarly, gene expression studies revealed
MYC pathway activation in high-grade type 2 pRCCs,
suggesting that the aggressive phenotype of type 2 pRCCs
may be influenced by inhibition of components of the MYC
signaling pathway .
In patients with HLRCC (with a distinct RCC entity
resembling pRCC type 2; pathological hallmark is large
nuclei with prominent orangeophilic nucleoli), a defect in
the gene encoding the Krebs cycle enzyme fumarate
hydratase FH , generates a pseudohypoxic state and
upregulation of hypoxia-inducible factor target genes,
similar to ccRCCs. Germline mutations in succinate
dehydrogenase B are likewise associated with nonsyndro-
mic RCCs . Dual VEGF/epidermal growth factor receptor
blockade with bevacizumab and erlotinib in patients with
advanced HLRCC-associated RCC or sporadic pRCC is
currently being tested in a phase II trial (NCT01130519;
). Data from the first 41 patients enrolled were
recently presented, including 20 with HLRCC-associated
kidney cancer and 21 with sporadic forms of pRCCs. In
the HLRCC cohort, an overall response rate of 65% was
noted, while the response rate in the sporadic population
was 29%.
Further evidence has been gathered for chRCC and
translocation tumors. Pathway analysis highlighted clinical-
ly relevant dysregulated pathways of c-erbB2 and mTOR
signaling in chRCCs . The chRCCs are associated with
germline FLCN loss in BHD syndrome and germline mutation
of PTEN in Cowden syndrome An FLCN-interacting
protein, FNIP1, interacts with 5 0 AMP-activated protein
kinase, a molecule for energy sensing that negatively
regulates mTOR activity . In vivo BHD murine models
treated with rapamycin validate the potential of mTOR
inhibitors for treating patients with BHD syndrome,
although it is unclear whether this strategy is relevant for
the more common sporadic chRCCs As mentioned
above, molecular analysis of 66 sporadic chRCCs implicated
changes in mitochondrial function and elevated TERT
expression in chRCCs. Only two significant genes were
found to be mutated in this cohort: TP53 (32%) and PTEN(9%)
. In RCCs of all subtypes with sarcomatoid dedifferen-
tiation, TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2
(19.2%) were the most frequently altered genes Since
TP53 is relatively rarelymutated in ccRCCs the presence
of such frequent mutations may suggest alternative
treatment pathways similar to other TP53-mutated tumors.
FLCN inactivation and upregulation of KIT are also
associated with chRCCs . KIT-targeting drugs, including
sorafenib, are not being currently tested in clinical trials
specifically involving chRCCs. In a phase II trial involving
14 patients with advanced RCC treated with imatinib, only
one patient had chRCC. This was the only KIT-positive
tumor, and treatment with imatinib resulted in SD for 6 mo
. An exploratory analysis in the ESPN trial showed that
median OS was longer with both sunitinib and everolimus
for patients with chRCCs. In one patient with chRCC, a
58% decrease in tumor diameter with everolimus appeared
to be associated with a TSC2 mutation, which underscores
the need for molecular characterization of each tumor
. In the ASPEN study, a median PFS of 11.4 mo was
reported for chRCCs with everolimus versus 5.5 mo with
sunitinib
Translocation RCCs (TRCCs) are characterized by trans-
locations resulting in gene fusions involving the TFE3
transcription factor gene (Xp11.2) , TFEB (6p21), or MITF
(3p13) with other genes. TRCCs display a distinctive gene
expression signature as compared with other RCC types and
harbor activation of MITF, transforming growth factor b1,
and PI3K complex targets . Tissue microarrays from
21 Xp11.2TRCCs, seven ccRCCs, and six pRCCs revealed
elevated expression of phosphorylated S6 in TRCCs,
suggesting that the mTOR pathway may be a potential
therapeutic target Furthermore, induction of MET by
translocation fusion gene products involved in TRCC results
in strong MET autophosphorylation and activation of
downstream signaling in the presence of HGF. In malignant
cell lines containing endogenous TFE3 fusion proteins,
inhibiting MET by RNA interference or by the inhibitor
PHA665752 abolishes HGF-dependent MET activation,
causing decreased cell growth. MET is thought to possibly
be an additional potential therapeutic target for this tumor
subtype Adult TRCCs appear to be different genetically
from pediatric TRCCs and are characterized genomically by
17q gain in addition to MITF-family translocation
. Choueiri et al analyzed 15 adults with advanced
TRCCs of whom 10, three, and two received sunitinib,
sorafenib, and monoclonal anti-VEGF antibodies, respec-
tively. Three patients had a partial response (PR), seven SD,
and five progressive disease. The median tumor reduction
was 4.5% (range: 48% shrinkage to 67% growth). Median PFS
and OS of the entire cohort were 7.13 and 14.3 mo,
respectively. Malouf et al reported on 21 patients with
metastatic TRCCs who received systemic therapy. Seven
patients achieved an objective response. In first line, median
PFS was 8.2 mo for sunitinib (n = 11) versus 2 mo for
cytokines ( n = 9). In second line, three patients receiving
sunitinib had a PR (median PFS 11 mo), seven of eight
patients receiving sorafenib had SD (median PFS 6 mo), and
of seven patients receiving mTOR inhibitors one had a PR
and six SD. Median OS was 27 mo with a 19-mo median
follow-up . Currently, patients of all age groups with
TRCCs are being enrolled in a randomized phase II trial of
axitinib with pembrolizumab versus single-agent axitinib
or pembrolizumab in a children’s oncology group study for
the treatment of TFE/TRCCs (AREN 1621) .
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 7 4 – 9 8 3 979