WINTHER: GUSTAVE ROUSSY GUSTAVE ROUSSY. NOM DU DOCUMENT / Date

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1 WINTHER Study Jean-Charles Soria, Razelle Kurzrock, Josep Tabernero, Apostolia Tsimberidou, Jordi Rodon, Raanan Berger, Amir Onn, Gerald Batist, Eitan Rubin, Yohann Loriot, Catherine Bresson, Vladimir Lazar

2 WINTHER: A study to select rational therapeutics based on the analysis of tumor and matched normal tissue biopsies in subjects with advanced malignancies

3 Position of the problem and clinical challenges to be addressed

4 Tumor Biopsy Today Standard Pathology DNA investigations Standard Protocols How can we improve cancer care for 60 to 70% of pts? Personalized Medicine Relevant DNA structural changes 30 to 40% of pts Match with targeted therapies

5 State of the Art

6 State of the Art Patient with metastatic cancer TUMOR BIOPSY Histology Control MOLECULAR PROFILING % of cancer cells Mutational aberrations CGH Deep sequencing TREATMENT BASED ON DNA NOM BIOLOGICAL DU DOCUMENT / Date INVESTIGATIONS OF THE TUMOR

7 WINTHER concept

8 WINTHER concept Patient with metastatic cancer TUMOR BIOPSY & MATCHED NORMAL TISSUE BIOPSY Histology Control MOLECULAR PROFILING % of cancer and normal cells Mutational aberrations CGH Transcriptomic Aberrations

9 WINTHER concept Patient with metastatic cancer TUMOR BIOPSY & MATCHED NORMAL TISSUE BIOPSY Histology Control MOLECULAR PROFILING % of cancer and normal cells Mutational aberrations CGH Transcriptomic Aberrations 1. Novelty: use of matched normal and tumoral biopsies from strictly the same patient. 2. Goal is to assess the genetic distance between tumor and normal by profiling of mrnas

10 WINTHER concept Computational tools Algorithm and genes_drugs database 3. Genetic distance converted into drugs scoring Individual Drug efficacy Scoring Statement Doctor s decision 2

11 WINTHER concept Computational tools Algorithm and genes_drugs database 3. Genetic distance converted into drugs scoring Individual Drug efficacy Scoring Statement Doctor s decision RATIONAL TREATMENT BASED NOM DU DOCUMENT ON HOLISTIC / Date BIOLOGICAL INVESTIGATIONS 2

12 Example of WINTHER predictive scoring, that ranks drugs depending on estimated efficacy 4

13 WINTHER Study Main components

14 WINTHER Participants Cancer Centers Gustave Roussy [France] Jean-Charles Soria, Coordinating PI MD Anderson Cancer Center [USA] Lia Tsimberidou, PI Technology Partners Foundation Medicine Gary Palmer NGS VHIO [Spain] Jordi Rodon, PI Chaim Sheba Medical Center [Israel] Rannan Berger, PI McGill Segal Cancer Center [Canada] Wilson Miller UCSD Moores Cancer Center [USA] Razelle Kurzrock Agilent Technologies V Lazar Gene Expression, mirna Ben Gurion University Eitan Rubin WINTHER Data Analysis

15 Recruitment goals Enroll 200 patients with metastatic cancer Tumor and matched normal tissue biopsies from each patient Histology Control Next Generation Sequencing (mutational and CNV aberrations) Actionable DNA aberrations Est % of patients NO Actionable DNA aberration Est % of patients WINTHER ARM A: Patient matched with existing targeted therapies or included in Phase 1 trials WINTHER ARM B: Choice of therapy guided by WINTHER drug efficacy predictive scoring derived from tumor vs. normal RNA investigations

16 Estimated repartition of patients Labeled Targeted Therapies: 20 patients 200 patients Arm A : 80 patients Targeted Therapies in Clinical Trials: 60 patients Arm B : 120 patients Standard of care: 20 patients Off label drugs (non clinical trials): 100 patients

17 WINTHER study main objectives WINTHER Arm A: Better identification of actionable DNA aberrations in patients (today limited to 30%), by using NGS PFS2/PFS1 > 1.5 in 50% of patients WINTHER ARM B: Offer a solution guided by each patient s individual biology to the vast majority of patients without actionable DNA aberrations Prove the efficacy of using alternative investigations based on functional genomics of the RNA on a dual biopsy of tumor and matched normal tissue to identify relevant aberrations in patients PFS2/PFS1 > 1.5 in 40% of patients RATIONAL TREATMENT BASED ON HOLISTIC BIOLOGICAL INVESTIGATIONS

18 Statistical design of the study Objective of WINTHER: achieve 1.5 ratio in 50% of patients in arm A achieve 1.5 ratio in 40% of patients in arm B 30 % being the average oncologist threshold PFS 1 PFS 2 Standard Therapy Tumor Progression Relevant Molecular Targeted Agent (WINTHER) Tumor Progression PFS 2 PFS1 > 1,5

19 WINTHER Workflow Multi-disciplinary trial BIOPSY FRESH TUMOR PATHOLOGICAL CONTROL MOLECULAR SCREENING NGS-CNV-CGH-gene expression CLINICAL DECISION TREATMENT Max 6 working weeks

20 WINTHER Study Initial achievments

21 Recruitment April May June July Rapid Accrual Currently 2-3 pts / week

22 WINTHER 1 pt included in another therapeutic clinical study 1 pt with rapid worsening condition 1 pt withdraw consent 2 pts with normal tissue not obtainable 5 Screening Fails 32 Consents From April 16 to July 2, biopsies yet to be performed 1 inappropiate choice of normal tissue 6 Tumor tissues < 60% of T cells IGR-1011 Breast cancer IGR-1012 Oral squamous cell carcinoma IGR-1013 Colon cancer IGR-1016 Lung ADK IGR-1019 Kidney cancer IGR-1027 Oral squamous cell carcinoma 7 Logistical Failures 19 Biopsies 9 Analyzed 3 biopsies July 2, 2013

23 Patients characteristics head and neck breast lung sarcoma kidney colon/rectum

24 Percentage of Cells WINTHER 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% NGS + CGH Not reliable 0%

25 WINTHER 9 sent 8 reports ARM A ARM B DNA structural alterations N=5 Transcriptomic alterations N=3

26 Target characteristics DNA alterations Transcriptome-based targets MET VEGFA HER3 Mutation Deletion Amplification Gene fusion

27 WINTHER 9 sent 8 reports ARM A ARM B DNA structural alterations N=5 transcriptomic alterations N=3 FGFR1 amp Included in EOS-3810 study Target MET On screening HER2 amp MET amp TSC1 mut Still on 1st line chemo On screening (MET inhibitor) On everolimus therapy Target VEGF-A Target HER-3 Still on treatment On screening RET gene fus On sorafenib therapy

28 TC IGR-1004 IGR-1007 IGR-1006 IGR-1010 WINTHER - Pr SORIA IGR-1004 Head & Neck SCC FM: MDM2 ampl, P53 mut BGU: MET ARM B 1/ SAR (Met inhibitor) 2/ cabozantinib IGR-1006 uterine Leiomyosarcoma FM: TSC1 mut ARM A: Everolimus IGR-1007 Lung ADK FM: KRAS G12D BGU: HER3, HER2 ARM B 1/ MM-141 phase I 2/ capecitabine + trastuzumab IGR-1010 Lung Carcinosarcoma FM: RET transl, MYC ampl ARM A 1/ sorafenib 2/ switch to another RET TKI with better IC50

29 TC IGR-1001 IGR-1002 WINTHER - Pr SORIA IGR-1001 Breast carcinoma FM: FGFR1 ampl, FGF3 ampl, FGF4ampl ARM A: lucitanib phase I IGR-1002 Head & Neck SCC FM: HER2 and EGFR ampl ARM A: Paclitaxel + Trastuzumab TC IGR-1005 IGR-1014 IGR-1005 Lung ADK FM: EGFR and MET amp ARM A: SAR-MET trial IGR-1014 Kidney cancer FM: VHL mut BGU: VEGFA ARM B: bevacizumab

30 Summary: Why is WINTHER different? Includes all patients, with or without actionable genetic aberrations Investigates both DNA and RNA Includes a variety of different technologies: Next Generation Sequencing, Copy Number Variations, gene expression, Comparative Genomic Hybridization Based on a dual biopsy of tumor and matched normal tissue of same histology, which enables: Evaluating the genetic distance between tumor and normal Disregarding variability factors between individuals Limiting the number of irrelevant aberrations and noise Increasing the statistical factor of the study by 16

31 Thank you Gustave Roussy: - Fabienne Dufour, Maud Ngo Camus - Aurélie Abou Lauverne - Catherine Richon - Nathalie Auger, Valerie Kouby, Ludovic Lacroix - Philippe Vielh - Thierry De Baere - Gilles Vassal