Médecine de précision médecine personnalisée en Oncologie. Fabien Calvo, Directeur Recherche et Innovation, INCa, Directeur ITMO Cancer, AVIESAN

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1 Médecine de précision médecine personnalisée en Oncologie Fabien Calvo, Directeur Recherche et Innovation, INCa, Directeur ITMO Cancer, AVIESAN

2 Successful targeted drug development Rapid identification of potential targets For druggable targets Interval from target to clinical candidate is shorter FDA Approval 2011 For clinically important targets Interval from FIH to drug approval is short Chin L et al. Nature Medicine 17: , 2011

3 Using Genomics in Oncology: what for? 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

4 Using Genomics in Oncology: Questions Is it feasible? Anywhere? Is it useful for the patients? Is it associated with increased life expectancy? Has it an impact of how to conduct clinical research? Is it affordable? Research or health care in genomics? How could we work together: shared international databases, bioinfo treatment of data, clinical trials in collaborative international groups, rare tumors networks How Health industries participate to this effort?

5 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. 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?

6 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

7 From genetic centers to personalized therapy Patients tested 2011 (% positive) 6497 (18.9%) 944 (56%, 880 (13%) 8545 (21.3%) 443 (26%) (39%) (10%) F Nowak, JC Soria and F Calvo, Nat Rev Clin Oncol. 2012

8 Benefit for all patients For all patients free of charge for patients & hospitals compensation of local pathologists for sample shipments Ensure that all patients effectively benefit from molecular testing

9 Make the most of the generated data Molecular testing performed by the 28 platforms generates a highly valuable source for scientific knowledge Implementation of a lung cancer database : funded by the INCa coordinated by IFCT (Intergroupe Français de Cancérologie Thoracique) and platforms representatives collection of clinical, histological, molecular, therapeutical and patients follow up data => evaluate the adequation between molecular alteration and targeted therapy prescription => Assess the clinical significance of rare mutations This project will be expanded to other cancer localizations

10 Initiatives to anticipate the launch of new molecules For the 20,000 patients with non squamous NSCLC, EGFR screening and analysis of : KRAS, HER2, PI3KCA and BRAF mutations + ALK translocation. For the 17,000 patients with colorectal cancer, KRAS screening and analysis of : BRAF mutation and MSI test; BRAF and KIT mutations for patients with melanoma What s new in 2013? NSCLC : ROS1 translocation/crizotinib; MET translocation/vandetanib Squamous NSCLC : DDRE2 mutations/dasatinib Melanoma : NRAS mutations/ MEK inhibitor Breast cancer and other solid malignancies: FGFR1 amplification/fgfr inhibitors Papillary thyroid cancer: BRAF mutations/ vemurafenib RAI refractory thyroid cancer : BRAF mutations/ BRAF or MEK inihibitors for re acquisition of RAI uptake In the following years => an increasing repertoire of molecular tests in many cancer types : AKT1-2, CDK, CSR1R, CTNNB1, FGFR1-3, FLT3, HRAS, JAK2-3, KIT, MET, MLH1, MYC, NRAS, PDGFRA, PIK3CA, PTEN, RB1, RET, STK11, TP53

11 Single genes Gene panels Exomes Whole genomes Gene expression profiles Copy Number Variation New technologies have resulted in > 100,000-fold decreases in sequencing costs: $1,000/genome will soon be achieved

12 ICGC Map September projects launched

13 Liver Cancer genome programme Guichard et al. Nature Genetics, 2012

14 ICGC: Liver Cancer genome programme Guichard et al. Nature Genetics, 2012

15 Activation of AKT/mTor pathway (20 %) Activation of ras/raf/map kinase pathway (9 %) Cytokine and growth factor receptors (7 %) Targeted therapies with sufficient preclinical and clinical data (level 1) 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 %) Private mutations (2 %) MGMT HD (1%) Courtesy of Nault and Zucman, unpublished 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 preclinical analyses (level 2) Activation of NFE2L2/KEAP1 pathway (20 %) NFE2L2 mutation (5 %) KEAP1 mutation (3 %) Activation without known mutation (12 %) Targeted therapy HSP90 inhibitor (17-AAG and 17- DMAG) Activation of ras/raf/map kinase pathway (9 %) RPS6KA3 mutation (8 %) MEK 1/2 inhibitor (selumitinib) Cytokine and growth factor receptors (7 %) IL6ST mutation (2 %) JAK1/JAK2 inhibitor (ruxolitinib) Courtesy of Nault and Zucman, unpublished

17 Surveys of mutation databases indicate that most mutations are found in many tumour types 80,0% 70,0% 60,0% 50,0% 40,0% 30,0% 20,0% 10,0% Lung carcinoma (all subtypes) Prostate adenocarcinoma Breast carcinoma (all subtypes) Colon adenocarcinoma Pancreatic ductal adenocarcinoma Ovarian carcinoma (all subtypes) Hepatocellular carcinoma Gastric adenocarcinoma Renal cell carcinoma Malignant melanoma 0,0% APC BRAF CTNNB1 EGFR KRAS NRAS PIK3CA PTEN RB1 STK11 TP53 Sanger Institute: COSMIC v54 Release (Forbes et al., 2011).

18 Mutation databases need of facilitated and quick access to databases need to develop large databases recurent mutations in different tumors new mutations with unknown significance need of coordinated efforts for validation (annotated tumor banks and in vitro models) need of coordinated effort to set up animal models for drug testing need for health industry to participate to these efforts

19 3. 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

20 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 Druggable molecular alteration Chemotherapy: 6 8 cycles No alteration Or non druggable PR, SD PI: Fabrice André Sponsor: UNICANCER Funding partners INCa ARC N: 1000 for screening, 400 for therapeutic phase R Not included Arm A: targeted therapy According to the molecular alteration Arm B: best available therapy Based on available mono test

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23 Predictive tests for therapy Nowak, Soria and Calvo/ :Nat. Rev. Clin. Oncol. 2012

24 Tests performed in 2011 in the 28 platforms Nowak, Soria and Calvo Nat Rev. Clin. Oncol. 2012

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