NIVO+IPI NR (28.2–NR)
SUN 26.0 (22.1–NE)
Figure 4. OS: IMDC intermediate/poor risk. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab
vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma (RCC): results from CheckMate214,
including overall survival by subgroups. Society for Immunotherapy for Cancer 2017 meeting; Abstract 038.
Kidney Cancer Journal 99
mutations exhibit only kidney cancer.13 These studies also
demonstrated that mutated MET might be more easily activated
than wild-type MET and more likely to remain activated
for longer periods after stimulation. Although the
role of MET expression in tumors was investigated in the
METEOR trial it does not appear to be to be predictive of
the clinical activity of cabozantinib over everolimus, there
is still widespread interest in this possible connection and
other blood and tissue biomarkers that could yield clues
as to the activity of cabozantinib.14
The AXL Pathway and Its Role in RCC
AXL signaling is also implicated in tumor growth and survival.
Activation of AXL by its cognate ligand GAS6 promotes
cell proliferation, migration, and protection from
apoptosis; in many contexts, AXL functions in concert
with other receptors to amplify downstream signaling
pathways.15 Despite the success of anti-angiogenic agents
in treating RCC, a fraction of patients do not respond to
systemic therapy, and responding patients eventually
progress and succumb to their disease. Resistance to
VEGF-targeted therapy is mediated by upregulation of alternative
angiogenic and invasive pathways, including
MET and AXL.
Zhou et al hypothesized that sunitinib-induced upregulation
of the prometastatic MET and AXL receptors
is associated with resistance to sunitinib and with
more aggressive tumor behavior.16 In their study, tissue
microarrays containing sunitinib-treated and untreated
RCC tissues were stained with MET and AXL
antibodies. The low malignant RCC cell line 786-O was
chronically treated with sunitinib and assayed for AXL,
MET, epithelial-mesenchymal transition (EMT) protein
expression and activation. Co-culture experiments
were used to examine the effect of sunitinib pretreatment
on endothelial cell growth. The effects of AXL
and MET were eval- uated in various cell-based models
by short hairpin RNA or inhibition by cabozantinib,
which targets VEGF, MET and AXL.
Xenograft mouse models tested the ability of cabozantinib
to rescue sunitinib resistance. Zhou et al demonstrated
that increased AXL and MET expression was
associated with inferior clinical outcome in patients.
Chronic sunitinib treatment of RCC cell lines activated
both AXL and MET, induced EMT-associated gene expression
changes, including upregulation of Snail and
catenin, and increased cell migration and invasion. Pretreatment
with sunitinib enhanced angiogenesis in 786-
0/human umbilical vein endothelial cell co-culture
models.
The suppression of AXL or MET expression and the inhibition
of AXL and MET activation using cabozantinib
both impaired chronic sunitinib treatment-induced
prometastatic behavior in cell culture and rescued acquired
resistance to sunitinib in xenograft models. In
summary, chronic sunitinib treatment induces the activation
of AXL and MET signaling and promotes prometastatic
behavior and angiogenesis. The inhibition of
AXL and MET activity may overcome resistance induced
by prolonged sunitinib therapy in metastatic RCC. These
findings need to be confirmed in further studies elucidating
the role of biomarkers in resistance to sunitinib.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33
Months
Overall Survival (Probability)
No. at Risk
425 399 372 348 332 318 300 241 119 44 2
422 387 352 315 288 253 225 179 89 34 3
0
0
NIVO + IPI
Sun
Median OS (95% CI), months
HR (99.8% CI), 0.63 (0.44–0.89)
P = 0.0001