From Precision to Personalised Medicine

(1)

CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER

ITMO Cancer

From Precision to Personalised Medicine

Brussels 24/09/2013

(2)

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

(3)

How are we currently using

genomics in patient management?

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?

(4)

Structures and Infrastructures:

Molecular genetic centers

 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

(5)

From genetic centers to biology driven therapy

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

(6)

An increasing number of actionable molecular alterations

 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

(7)

New technologies… have resulted in > 100,000-fold decreases in sequencing costs:

• $1,000/genome will soon be achieved

2000 2010 2015

Single genes

Gene panels

Exomes

Whole genomes

 Gene expression profiles

 Copy Number Variation

(8)

ICGC Map

64 projects launched

(9)

ICGC: Liver Cancer genome programme

Guichard et al. Nature Genetics, 2012

(10)

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

 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 CLIP ² (INCa- Fondation ARC- Unicancer)

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

trials

(11)

Conclusions and perspectives

The 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

(12)

(13)

Rapid access to innovation

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

(14)

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

tumour types

Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54

Release (Forbes et al., 2011).

(15)

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

15 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)

(16)

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

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)

Targeted

therapy

(17)

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 alteration Or non

druggable Druggable molecular alteration

Not included R

Arm A: targeted therapy According to the molecular alteration

Arm B: best available therapy

Based on available mono-test

PR,

SD PI: Fabrice André

Sponsor: UNICANCER- Funding partners INCa- ARC

N: 1000 for screening, 400

for therapeutic phase

(18)

2012 2012

data data

(19)

Liver Cancer genome programme

Guichard et al. Nature Genetics, 2012

From Precision to Personalised Medicine

ITMO Cancer

From Precision to Personalised Medicine

Brussels 24/09/2013

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

How are we currently using

genomics in patient management?

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?

Structures and Infrastructures:

Molecular genetic centers

 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

From genetic centers to biology driven therapy

An increasing number of actionable molecular alterations

 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

New technologies… have resulted in > 100,000-fold decreases in sequencing costs:

• $1,000/genome will soon be achieved

2000 2010 2015

Single genes

Gene panels

Exomes

Whole genomes

 Gene expression profiles

 Copy Number Variation

ICGC Map

64 projects launched

ICGC: Liver Cancer genome programme

Guichard et al. Nature Genetics, 2012

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

 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 CLIP 2 (INCa- Fondation ARC- Unicancer)

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

trials

Conclusions and perspectives

The 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

Rapid access to innovation

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

 To be performed in the CLIP ² (INCa- Fondation ARC- Unicancer)