RCC The Met Pathway as a Target in - Harriet Kluger, M.D. Associate Professor Yale Cancer Center Disclosures pertinent to this presentation - none
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The Met Pathway as a Target in
RCC
Harriet Kluger, M.D.
Associate Professor
Yale Cancer Center
Disclosures pertinent to this
presentation - none
c-Met Pathway (Biocarta)
Rationale for c-Met targeting in ccRCC • Resistance to VEGF-R inhibitors and/or mTOR inhibitors develops with time, and additional targets and/or co-targets are needed • Addition of mTOR inhibitors to VEGF/VEGFR inhibitors has proven to be toxic • c-Met is rarely mutated in >400 clear cell RCCs sequenced by TCGA, yet it might be activated by other mechanisms • Loss of VHL results in increases in c-Met expression and normal kidney secretes HGF • Some renal tumors have gain of chromosome 7 or c-Met gene amplification in the absence of a mutation
Is c-Met over-expressed and active in
RCC?
• Gibney et al, Annals of Oncology 2013
• Expression measured by quantitative
immunofluorescence in 330 nephrectomy cases
• 300 cases had matched normal kidney tumor
• Clinical and pathological data (age, gender, size,
grade, histologic subtype, survival) availableCharacteristic Number
(N=317 total)
Median Patient Age 64 years
(range 25-87 years)
Male Gender 197 (62%)
RCC Tumor Subtype
Clear Cell 222 (70.0%)
Papillary 45 (14.2%)
Oncocytoma 20 (6.3%)
Mixed Histology 12 (3.8%)
Sarcomatoid 11 (3.5%)
Chromophobe 7 (2.2%)
Nuclear Grade
I 41 (12.9%)
II 161 (50.8%)
III 84 (26.5%)
IV 31 (9.5%)
Stage
I 179 (56.5%)
II 26 (8.2%)
III 9 (27.8%)
IV 24 (7.6%)Quantitative Immunofluorescence method developed by David Rimm and Robert Camp, adapted for renal cell carcinoma
Technical reproducibility and intra-tumor
homogeneity using matched cores
Bivariate Fit of 166-1 P/M By 166-2 P/M
90
80
70 R=0.92, MET4
60 antibody from
166-1 P/M
50 George Vande Woude
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
166-2 P/M
Linear Fit
Linear FitAssociation between c-Met levels and RCC specific survival c-Met scores divided into quartiles for purposes of depiction
Multivariable survival analysis
(continuous scores)
All cases
Variable Risk Ratio 95% CI P value
c-Met
1.013 1.002 - 1.023 0.015
AQUA score
Fuhrman grade III/IV
3.202 1.904 - 5.385 < 0.001
vs. I/II
Stage
5.304 3.083 - 9.126 < 0.001
III/IV vs. I/II
Clear cell cases only
c-Met
1.017 1.003 – 1.032 0.018
AQUA score
Fuhrman grade III/IV
2.337 1.284 – 4.256 0.005
vs. I/II
Stage
4.321 2.260 – 8.264 < 0.001
III/IV vs. I/IIIs c-Met expression comparable in
primary and metastatic specimens?
• Indications for systemic therapy in RCC include both
neoadjuvant for nephron sparing prior to nephrectomy and
therapy for metastatic disease
• c-Met pathway might not be equally up-regulated in primary
and metastatic sites
Oneway Analysis of Mean Scores By Status Bivariate Fit of Mean Scores P By Mean Scores M
90 90
80 80
P=0.1 70
R=0.5
70
from
P
60 60
Mean Scores
Scores
MeanScore
50 50
Primary
40 40
AQUA
30 30
20 20
10 10
0 0
Metastatic Primary 10 20 30 40 50
AQUA Score
Mean from
Scores M
Status MetastasisIs c-Met active in RCC cells in culture, and
can it be inhibited pharmacologically?
Cell Line SU11274 ARQ 197
(μM) (μM)
769P 8.39 0.68
A498 6.11 0.58
786-O 7.56 0.67
ACHN 5.81 0.53
Caki-1 8.22 0.35Examples of other studies supporting c-
Met targeting in RCC
• Bommi-Reddy A, Almeciga I,
Sawyer J et al, PNAS 2008:
screened 100 shRNA vectors
against 88 kinases, for ability
to inhibit viability of RCC cells
with VHL loss compared with
isogenic cells with restored
VHL function. “Hits” were
CDK6, MET, and MEK1
• Peruzzi B, Athauda G, Bottaro
DP., PNAS 2006 showed that
VHL loss results in increased
beta-catenin signaling in RCC,
partially mediated by c-MetClinical grade c-Met inhibitors in RCC • Chouerri et al, ASCO 2012, XL-184 (cabozantinib) given to 25 patients with ccRCC, 88% had prior VEGFRis and 60% prior mTORis, 52% had both. Median PFS - 14.7 months, ORR - 28% • Foretinib (XL-880) active in papillary RCC, other met inhibitors, such as INC280, being studied • ARQ-197 (tivantinib) alone or with sunitinib in advanced RCC (accrual complete)
Rationale behind co-targeting VEGF-R2
and c-MET in RCC
• Resistance to VEGF-R2-targeted therapies may
arise from up-regulation of alternative pro-
angiogenic and pro-invasive signaling pathways,
including the MET pathway (Sennino and
McDonald, Nat Rev, 2012).
• Combined VEGFR and MET inhibition is more
effective than either pathway alone in a prostate
and pancreatic carcinoma tumor model (Aftab et
al, Clin Trans Onc, 2011, Sennino et al, Cancer
Discovery, 2012).XL-184-308 study • A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell RCC that has Progressed after Prior VEGFR Inhibitor • 375 patients, accrual almost complete • Primary endpoint is PFS
Conclusions • c-Met is rarely mutated in clear cell RCC, but is often over-expressed • High c-Met expression is associated with advanced stage and decreased survival in clear cell RCC • c-Met inhibition in RCC cells, particularly with VHL silencing, inhibits cell proliferation and decreases pAkt and pS6 • co-Inhibition of c-Met and VEGFR2 might be more effective than either one alone; the current randomized trial is not designed to prove this • Activity of the dual c-Met/VEGFR2 inhibitor, XL-184 is being studied in an ongoing phase III trial • The role of drugs such as XL-184 in future treatment paradigms, including PD-1/PD-L1 inhibitors will need to be examined
Acknowledgements Kluger Lab Members • Geoffrey Gibney • Lucia Jilaveanu • Patricia Conrad • Saadia Aziz Collaborators • Brian Shuch • Adebowale Adeniran • Brian Schwartz • Chang-Rung Chen • Robert Camp Funding sources: NCI, ACS
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