1. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 1 ITMO Cancer From Precision to Personalised Medicine Brussels 24/09/2013 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX

2. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 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 2

3. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX How are we currently using genomics in patient management? 3 Single Gene AlterationMultiple 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Structures and Infrastructures: Molecular genetic centers 4 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX From genetic centers to biology driven therapy 5 F Nowak, JC Soria and F Calvo, Nat Rev Clin Oncol. 2012

6. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX An increasing number of actionable molecular alterations 6 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 7 New technologies… have resulted in > 100,000-fold decreases in sequencing costs: $1,000/genome will soon be achieved 200020102015 Single genes Gene panels Exomes Whole genomes Gene expression profiles Copy Number Variation

8. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX ICGC Map 8 64 projects launched

9. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX ICGC: Liver Cancer genome programme 9 Guichard et al. Nature Genetics, 2012

10. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Proof of concept for molecularly guided therapy: prospective trial for the future 10 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 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 11

12. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 12

13. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Rapid access to innovation 13 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Surveys of mutation databases indicate that most mutations are found in many tumour types 14 Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54 Release (Forbes et al., 2011).Forbes et al., 2011

15. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 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) Courtesy of Nault and Zucman, unpublished

16. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Putative targeted therapies: on-going pre-clinical analyses (level 2) 16 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

17. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 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. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX 2012 data 18

19. CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT MINES-TELECOMUNICANCERIRBAIRSNCIRADFONDATION MERIEUX Liver Cancer genome programme 19 Guichard et al. Nature Genetics, 2012