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The PREDICT Consortium
A Partnership Framework for Biomarker Discovery
James Whale Fund for Kidney Cancer Patient Day
17th
November 2010
James Larkin Royal Marsden Hospital /
Consultant Medical Oncologist Institute of Cancer Research
London
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Overview
Dramatic progress: kidney cancer 2005-10
New challenges 2010-15
Selection of patients for therapy
What are predictive biomarkers?
Why are they important? What is the PREDICT Consortium?
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Positive RCTs of Novel Agents in
Advanced Renal Cell Carcinoma
2003 &Bevacizumab NEJM
2007 &Sorafenib NEJM
2007 #Sunitinib NEJM
2007 #Temsirolimus NEJM
2007 #Bevacizumab + IFNE Lancet
2008 &Everolimus Lancet
2008#
Bevacizumab + IFNE JCO
2010 &Pazopanib JCO
& vs placebo
# vs IFNE
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Positive RCTs of Novel Agents in
Advanced Renal Cell Carcinoma
2003 &Bevacizumab NEJM
2007 &Sorafenib NEJM
2007 #Sunitinib NEJM
2007 #Temsirolimus NEJM
2007 #Bevacizumab + IFNE Lancet
2008 &Everolimus Lancet
2008#
Bevacizumab + IFNE JCO
2010 &Pazopanib JCO
& vs placebo
# vs IFNE
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Positive RCTs of Novel Agents in
Advanced Renal Cell Carcinoma
2003 &Bevacizumab NEJM
2007 &Sorafenib NEJM
2007 #Sunitinib NEJM
2007 #Temsirolimus NEJM
2007 #Bevacizumab + IFNE Lancet
2008 &Everolimus Lancet
2008#
Bevacizumab + IFNE JCO
2010 &Pazopanib JCO
& vs placebo
# vs IFNE
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VEGFR2
P
P P
P
Vascular permeability
Endothelial cellsurvival
Vascular endothelial cell
plasm
amem
br ane
VEGF
VEGF
Sor af enibSunitinib PazopanibAkt/PKB
PI3K
TemsirolimusEverolimus
Bevacizumab
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TRIAL
3rd-LineRelapse
2nd-LineRelapse
1st-LineRelapse
´Neoadjuvantµ(Pre-operative)
Adjuvant
SUNITINIB
PAZOPANIB
IFN- +BEVACIZUMAB
TEMSIROLIMUS
EVEROLIMUS(post²VEGFR-TKI)
SORAFENIB
(post-immunoRx)
SUNITINIB(post-immunoRx)
PAZOPANIB(post-immunoRx)
TRIALTRIAL
TRIAL
TRIAL(post²IFN- + BEV)
(post-TEMSIROLIMUS)
Options in Advanced RCC
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2005: Immunotherapy for advanced RCC
2010: Bevacizumab, sorafenib, sunitinib, pazopanib,
everolimus, temsirolimus and others
How should all these new (and old) agents be used?
How can outcomes in this disease further be improved?
What about the NHS?
Dramatic Progress 2005-2010
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1) Role of nephrectomy in µkinase inhibitor era¶?
2) New targets and new agents?
3) Combination«4) «or sequencing of agents?
5) Role of adjuvant therapy?
6) Selection of patients for therapy?
7) Mechanisms of resistance (and sensitivity) to therapy
8) Response assessment/clinical trial design
New Challenges 2010-2015
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1) Role of nephrectomy in µkinase inhibitor era¶?
2) New targets and new agents?
3) Combination«4) «or sequencing of agents?
5) Role of adjuvant therapy?
6) Selection of patients for therapy?
7) Mechanisms of resistance (and sensitivity) to therapy
8) Response assessment/clinical trial design
New Challenges 2010-2015
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Selection of patients for therapy
The problem in the treatment of advanced RCC
isn¶t the fact that there is a choice of active
agents supported by different levels of
evidence...
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Selection of patients for therapy
The problem in the treatment of advanced RCC
isn¶t the fact that there is a choice of active
agents supported by different levels of
evidence...
...the problem is the lack of factors allowing
selection of patients for therapy (VEGFR TKI or
mTORi or immunotherapy)
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Selection of patients for therapy
The problem in the treatment of advanced RCC
isn¶t the fact that there is a choice of active
agents supported by different levels of
evidence...
...the problem is the lack of factors allowing
selection of patients for therapy (VEGFR TKI or
mTORi or immunotherapy)
The cost of these drugs is also a related major
practical issue
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Selection of patients for therapy
Histology, performance status, prognostic factors,
previous therapy
No other proven factors
Hypertension is intriguing though*
µNeoadjuvant¶ studies provide a powerful way to
investigate molecular predictive factors
This is safe and feasible in advanced RCC and a
number of such studies are in progress
*Rini et al. ASCO 2008, Rini et al. GU ASCO 2010
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Targeted Agents to Treat Cancer 2010
ImatinibDasatinib
N ilotinib
Lapatinib
Er lotinib
Gefitinib
C etuxi mab
T r astuzumab
Bevacizumab
Sor afenib
Sunitinib
Pazopanib
Temsi r oli mus
E ver oli mus
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ImatinibDasatinib
N ilotinib
Lapatinib
Er lotinib
Gefitinib
C etuxi mab
T r astuzumab
Bevacizumab
Sor afenib
Sunitinib
Pazopanib
Temsi r oli mus
E ver oli mus
CML
GIST
Colorectal
Breast
Lung
RCC
Targeted Agents to Treat Cancer 2010
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ImatinibDasatinib
N ilotinib
Lapatinib
Er lotinib
Gefitinib
C etuxi mab
T r astuzumab
Bevacizumab
Sor afenib
Sunitinib
Pazopanib
Temsi r oli mus
E ver oli mus
Targeted Agents to Treat Cancer 2010
CML
GIST
Colorectal
Breast
Lung
RCC
Predictive
Biomar ker?
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ImatinibDasatinib
N ilotinib
Lapatinib
Er lotinib
Gefitinib
C etuxi mab
T r astuzumab
Bevacizumab
Sor afenib
Sunitinib
Pazopanib
Temsi r oli mus
E ver oli mus
Yes
No
Targeted Agents to Treat Cancer 2010
CML
GIST
Colorectal
Breast
Lung
RCC
Predictive
Biomar ker?
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RCC: No predictive biomar kers; treatment
according to histology, per f ormance status,
prognostic factors, previous ther apy
RCC: No Predictive Biomarkers
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RCC: No predictive biomar kers; treatment
according to histology, per f ormance status,
prognostic factors, previous ther apy
RCC: No Predictive Biomarkers
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RCC: Treatment according to molecular
predictive factors (already in routine pr actice in
NSCLC, breast, CRC, GIST and CML)
RCC: Predictive Biomarkers Found!
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High Dose IL-2
Anti- mTOR Rx
Anti-VEGF Rx
Unknown
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Predictive
Biomar kers
Advantages:
Larger benefits
Reduced side effects
QALYs cheaper (!)
Greater understandingof biology / resistance
Those not destined to
benefit from current
therapies can enter
trials sooner
Disadvantage:
Clinical trials to identify
predictive biomarkers
are difficult to do
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Predictive Biomarkers: The Problems
Most clinical trials not designed to discover biomarkers
Tissue collection often haphazard / not done,
minimising potential for retrospective genomic analysis
No significant tissue collection in pivotal RCTs in RCC
Cost pressures restrict access to new drugs
The PREDICT Consortium: coordinating clinical trials
with functional genomics to derive predictive biomarkers
of drug response
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Pan-European Multidisciplinary PREDICT Consortium
(Personalised RNA Interference to Enhance the Delivery
of Individualised Chemotherapeutics and Targeted
Therapies)
Scientific Lead: C Swanton; Clinical Lead: J Larkin
EU FP 7: 5.8 million euro grant awarded
Pre-nephrectomy everolimus (E-PREDICT) and sunitinib(S-PREDICT) in metastatic RCC
www.predictconsortium.eu
Swanton et al. Genome Medicine 2010
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siRNA screens
pshRNA screens
Tumour genetic analyses
Drug target identification
Functional analysis of drug
resistance genes
Bioinformatics
Project administration
Exon sequencing
Bioinformatics
Ex-vivo cell culture
pshRNA library technology
Biomarker validation
Clinical trials
Imaging data analysis
Drug target validation
Biomarker test development
Cell line engineering for
functional studies
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Strategy
Biopsies Nephrectomy
Patients with metastatic RCC planned for cytoreductive nephrectomy as part of routine care
Drug 6-8
weeksRestart drug until
disease progression
Functional genomics
Biopsies
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Post-treatment
functional MRI
Imaging: Mu Koh
Correlation of drug effects
with functional imaging,
tumour histology and genetics
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Functional Genomics Illuminates Common
Pathways of Drug Response
Gene Expression Pre-treatment Common pathways of drug response Predictive power
Juul, Szallasi and Swanton Lancet Oncol 2010, Swanton et al Cancer Cell 2007, Swanton et al PNAS 2009
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Identification/validation of predictive biomarkers
for everolimus/sunitinib response in RCC
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In the future, can mRCC become a
chronic disease?
Larkin and Gore Lancet 2010
Identifying and overcoming the mechanisms of resistance will
further improve patient outcomes
Drug BDrug A
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Conclusions
Unprecedented advances in the systemic
treatment of advanced RCC 2005-2010
Identification of predictors of response /resistance critical 2010-2015
This will lead to new targets and new agents...
...and have clinical, QoL and economic benefits
«and perhaps advanced RCC will become a
chronic disease?
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Thank you