ITMO Cancer From Precision to Personalised Medicine Brussels

ITMO Cancer From Precision to Personalised Medicine Brussels 24/09/2013 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 1

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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 2

How are we currently using genomics in patient management? Single Gene Alteration 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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX Multiple gene alterations 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? CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 3

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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 4

From genetic centers to biology driven therapy CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR ARIIS JCCIRAD EFS FONDATION INSTITUT CURIE INSTITUT MINES-TELECOM F Nowak, Soria and F Calvo, Nat Rev. MERIEUX Clin Oncol. INERIS 2012 IRD IRBA IRSN UNICANCER 5

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 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER § Next years : analysis of whole exome or genome 6

Single genes Gene panels Exomes Whole genomes Gene expression profiles Copy Number Variation 2000 2015 New technologies… have resulted in > 100, 000 -fold decreases in sequencing costs: • $1, 000/genome will soon be achieved ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 7

ICGC Map 64 projects launched ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 8

ICGC: Liver Cancer genome programme Guichard et al. Nature Genetics, 2012 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 9

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 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER 10

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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 11

ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 12

Rapid access to innovation Offer each patient in France an equal access to molecular tests as soon as a new targeted therapy is available Mid 2008 : EMA approvals for panitumumab and cetuximab for patients with wild type KRAS tumours June 2009 : gefitinib approvals by EMA for patients with activating mutations of EGFR in their tumors Allocation of € 2. 5 M to the 28 centres at the end of 2008 Allocation of € 1. 7 M to the 28 centres at the end of 2009 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 13

Surveys of mutation databases indicate that most mutations are found in many tumour types 80. 0% 70. 0% Lung carcinoma (all subtypes) 60. 0% Prostate adenocarcinoma 50. 0% Breast carcinoma (all subtypes) Colon adenocarcinoma 40. 0% Pancreatic ductal adenocarcinoma Ovarian carcinoma (all subtypes) 30. 0% Hepatocellular carcinoma 20. 0% Gastric adenocarcinoma Renal cell carcinoma 10. 0% Malignant melanoma 53 TP 1 K 1 ST 1 RB EN PT 3 C A PI K S RA N FR AS KR N N CT EG B 1 AF BR AP C 0. 0% Sanger Institute: http: //www. sanger. ac. uk/cosmic, COSMIC v 54 Release (Forbes et al. , 2011). ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 14

Targeted therapies with sufficient preclinical and clinical data (level 1) Activation of AKT/m. Tor pathway (20%) PIK 3 CA mutations (1%) TSC 1 and TSC 2 mutations (7%) PTEN HD (2%) Activation without known mutation (10%) Activation of ras/raf/MAP kinase pathway (9 %) Targeted therapy m. Tor inhibitor (everolimus, sirolimus) BRAF V 600 inhibitor (vemurafenib) BRAF mutation (1%) FGFR inhibitor FGF 19 amplification (1%) Cytokine and growth factor receptors (7%) EGFR overexpression (1%) (pazopanib) Antibody anti-EGFR (cetuximab) HER 2 neu overexpression (1%) Antibody anti-HER 2 (trastuzumab) SUFU mutation (1 %) Private mutations (2%) ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX MGMT HD (1%) CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM Courtesy of Nault and Zucman, unpublished Inhibitor of sonic hedgehog (vismodegib) Oral alkylating agent IRD IRBA (temozolomid) IRSN UNICANCER 15

Putative targeted therapies: on-going pre-clinical analyses (level 2) NFE 2 L 2 mutation (5%) KEAP 1 mutation (3%) Activation without known mutation (12%) Activation of NFE 2 L 2/KEAP 1 pathway (20 %) Activation of ras/raf/MAP kinase pathway (9 %) CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX HSP 90 inhibitor (17 -AAG and 17 DMAG) MEK 1/2 inhibitor RPS 6 KA 3 mutation (8%) (selumitinib) Cytokine and growth factor receptors (7 %) ARIIS Targeted therapy JAK 1/JAK 2 inhibitor IL 6 ST mutation (2%) (ruxolitinib) CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM Courtesy of Nault and Zucman, unpublished IRD IRBA IRSN UNICANCER 16

SAFIR 02 Biopsy Metastatic Site: NGS target gene sequencing Metastatic Her 2 -neg breast cancer pretreated with 1 line chemotherapy Metastatic EGFR / ALK wt lung cancer not pretreated with chemotherapy ARIIS CIRAD EFS Arm A: targeted therapy According to the molecular alteration Druggable molecular alteration Chemotherapy: 6 -8 cycles No alteration Or non druggable CEA CHRU CNRS FONDATION MERIEUX PR, SD R Arm B: best available therapy Based on available mono-test PI: Fabrice André Sponsor: UNICANCER- Funding partners INCa. ARC N: 1000 for screening, 400 for therapeutic phase Not included CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 17

2012 data ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 18

Liver Cancer genome programme Guichard et al. Nature Genetics, 2012 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA IRSN UNICANCER 19