JWF 17.11.10 LarkinSwanton

8/8/2019 JWF 17.11.10 LarkinSwanton

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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



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?



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











2008#


2010 &Pazopanib JCO

& vs placebo

# vs IFNE



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



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



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



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




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...







evidence...

...the problem is the lack of factors allowing

selection of patients for therapy (VEGFR TKI or

mTORi or immunotherapy)







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




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



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



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




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

Predictive

Biomar ker?



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


CML

GIST

Colorectal

Breast

Lung

RCC

Predictive

Biomar ker?



RCC: No predictive biomar kers; treatment

according to histology, per f ormance status,

prognostic factors, previous ther apy

RCC: No Predictive Biomarkers



RCC: Treatment according to molecular

predictive factors (already in routine pr actice in

NSCLC, breast, CRC, GIST and CML)

RCC: Predictive Biomarkers Found!



High Dose IL-2

Anti- mTOR Rx

Anti-VEGF Rx

Unknown



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



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



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



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



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



Post-treatment

functional MRI

Imaging: Mu Koh

Correlation of drug effects

with functional imaging,

tumour histology and genetics



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



Identification/validation of predictive biomarkers

for everolimus/sunitinib response in RCC



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



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?



Thank you

JWF 17.11.10 LarkinSwanton

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