CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 1 ITMO Cancer.

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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD

FONDATION MERIEUX

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ITMO Cancer

From Precision to Personalised Medicine

Brussels 24/09/2013

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Genomics in Oncology: from biology to care

Generating information about cancer development and metastasis

Identifying new genes susceptible to induce « addiction », thus « targetable »

Helping to develop new therapies Helping to accelerate new drug approval: new

early phase trials, shortening time to MA

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How are we currently using genomics in patient management?

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Single Gene Alteration Multiple gene alterations

Already incorporated in patient management

Impacts the following decisions :

• Selection of agents:− Positive effect− Negative effect

• Prediction of toxicity• Treatment changes in

case of resistance

Under investigation at many institutions

Should it be incorporated in routine care (when?) or remain a research tool?

Is it practical?What is the cost/benefit?

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Structures and Infrastructures: Molecular genetic centers

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High quality molecular testing, all patients, anywhere in France

Partnerships between University hospitals and cancer centers

Regional organization

PPPs with Roche,

Amgen, Pfizer, GSK, AZ

High quality molecular testing, all patients, anywhere in France

Partnerships between University hospitals and cancer centers

Regional organization

PPPs with Roche,

Amgen, Pfizer, GSK, AZ

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From genetic centers to biology driven therapy

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F Nowak, JC Soria and F Calvo, Nat Rev Clin Oncol. 2012

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An increasing number of actionable molecular alterations

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PF 02341066MetiALK

CC-223LKB1iLKB1 or STK11

BKM120Pi3KiPTEN

ARQ197Crizotinib

METiMET mut/ampl

FGFR mut/ampl

PI3KCA1 or PDPK1

NRAS

HER2 mut/ampl

BRAF V600E

KRAS mut

Druggable Target

AZD4547FGFRi

PF-04691502BKM120

Pi3KiPi3Ki

PF-04691502 GSK1120212

Pi3KiMEKi

PF-00299804BIBW2992

HER2i

GSK2118436 PF-04691502

RAFiPi3Ki

GSK1120212 PF-04691502

MEKiPi3Ki

DrugClass

PF 02341066MetiALK

CC-223LKB1iLKB1 or STK11

BKM120Pi3KiPTEN

ARQ197Crizotinib

METiMET mut/ampl

FGFR mut/ampl

PI3KCA1 or PDPK1

NRAS

HER2 mut/ampl

BRAF V600E

KRAS mut

Druggable Target

AZD4547FGFRi

PF-04691502BKM120

Pi3KiPi3Ki

PF-04691502 GSK1120212

Pi3KiMEKi

PF-00299804BIBW2992

HER2i

GSK2118436 PF-04691502

RAFiPi3Ki

GSK1120212 PF-04691502

MEKiPi3Ki

DrugClass

Implementation of Next Generation Sequencing (NGS) for clinical use Development of pharmacogenetics for reducing toxicities and improving efficacy

Implementation ongoing for the investigation of a panel of genes Next years : analysis of whole exome or genome

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New technologies… have resulted in > 100,000-fold decreases in sequencing costs:• $1,000/genome will soon be achieved

2000 2010 2015

Single genesGene panels

ExomesWhole genomes

Gene expression profiles Copy Number Variation

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ICGC Map

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64 projects launched

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ICGC: Liver Cancer genome programme

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Guichard et al. Nature Genetics, 2012

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Proof of concept for molecularly guided therapy: prospective trial for the future

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Need to demonstrate that sequencing tumours (Exome-Whole GS) is of interest for treatment decision

A national cooperative randomized study in early metastatic patient in some tumour types

Comparing therapeutic decision based on NGS to current diagnostic procedures including defined genetic tests

To be performed in the CLIP2 (INCa- Fondation ARC- Unicancer)

With the help of Pharmas to provide drugs already in phase 2 trials

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Conclusions and perspectivesThe French molecular screening initiative :

has been operational for 5 years for access to targeted therapies

Opens the path to switch to complete genomics and personalized

therapy

is an opportunity to improve patient accrual into clinical trials

Current research on genomics of cancer

is the basis to understand the steps of cancer development,

identify new targets and develop new therapies through the

synergy between fundamental, translational and clinical sciences

Allows to foster on innovation through bioinformatics, biomarkers

and drug development

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Rapid access to innovation

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Mid 2008 : EMA approvals for panitumumab and

cetuximab for patients with wild type KRAS

tumours

Allocation of €2.5M to the 28 centres at the end of

2008

June 2009 : gefitinib approvals by EMA for

patients with activating mutations of EGFR in

their tumors

Allocation of €1.7M to the 28 centres at the

end of 2009

Offer each patient in France an equal access to molecular tests as soon as a new targeted therapy is available

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Surveys of mutation databases indicate that most mutations are found in many

tumour types

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Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54 Release (Forbes et al., 2011).

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Targeted therapies with sufficient preclinical and clinical data (level 1)

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Activation of AKT/mTor pathway (20%)

Private mutations (2%)

Activation of ras/raf/MAP kinase

pathway (9 %)

Cytokine and growth factor receptors (7%)

PIK3CA mutations (1%)TSC1 and TSC2 mutations (7%)

PTEN HD (2%)Activation without

known mutation (10%)

BRAF mutation (1%)

FGF19 amplification (1%)

EGFR overexpression (1%)

HER2neu overexpression (1%)

SUFU mutation (1 %)

MGMT HD (1%)

Targeted therapy

mTor inhibitor (everolimus, sirolimus)

BRAF V600 inhibitor (vemurafenib)

FGFR inhibitor(pazopanib)

Antibody anti-EGFR (cetuximab)

Antibody anti-HER2(trastuzumab)

Inhibitor of sonic hedgehog (vismodegib)

Oral alkylating agent (temozolomid)

Courtesy of Nault and Zucman, unpublished

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Putative targeted therapies: on-going pre-clinical analyses (level 2)

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Activation of NFE2L2/KEAP1 pathway

(20 %)

Activation of ras/raf/MAP kinase pathway (9 %)

Cytokine and growth factor receptors (7 %)

NFE2L2 mutation (5%)KEAP1 mutation (3%)

Activation without known mutation (12%)

RPS6KA3 mutation (8%)

IL6ST mutation (2%)

HSP90 inhibitor (17-AAG and 17-

DMAG)

MEK 1/2 inhibitor

(selumitinib)

JAK1/JAK2 inhibitor (ruxolitinib)

Courtesy of Nault and Zucman, unpublished

Targeted therapy

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SAFIR02

Metastatic Her2-neg breast cancer

pretreated with 1 line chemotherapy

Metastatic EGFR / ALK wt lung cancer not pretreated with

chemotherapy

Biopsy Metastatic Site:NGS target gene

sequencing

Chemotherapy:

6-8 cycles

No alterationOr non druggable

Druggablemolecularalteration

Not included

R

Arm A: targeted therapyAccording to the

molecular alteration

Arm B: best available therapy

Based on available mono-test

PR, SD

PI: Fabrice AndréSponsor: UNICANCER- Funding partners INCa-ARC N: 1000 for screening, 400 for therapeutic phase

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2012 2012 datadata

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Liver Cancer genome programme

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Guichard et al. Nature Genetics, 2012

CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 1 ITMO Cancer.

Documents

az slide

genome slide

number variation slide

molecular genetic centers

cancer development

new therapies

new genes susceptible

new technologies