The OncoBEAM Platform: The Use of a High Sensitive Technology for Liquid Biopsies in Clinical Practice

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1 The OncoBEAM Platform: The Use of a High Sensitive Technology for Liquid Biopsies in Clinical Practice Sysmex Inostics Dr. Friederike Lehmann Head of CRO Marketing

2 Sysmex Corporation Kobe 2

3 Sysmex Corporation 190+ COUNTRIES SUPPLIED >10% R&D EXPENDITURE $2.3B FY2015 NET TOTAL SALES SUBSIDIARIES & AFFILIATES 66 locations in 41 countries NUMBER OF EMPLOYEES >7,500 TOP 10 LEADING IVD COMPANIES WORLDWIDE

4 Sysmex Corporation Marketing Business Development Quality Sales R&D Regulatory Operations Market Access Medical Affairs GLOBAL INTEGRATED NETWORK

5 Sysmex Corporation 43 PRODUCTS WITH FDA CLEARANCE (510K) 181 PRODUCTS CE-IVD 307 PRODUCTS WITH PMDA 191 PRODUCTS CFDA GLOBAL REGULATORY EXPERTISE

6 What Does Sysmex Inostics Do? Pharma/CRO Services Clinical Products and Services Assist in Therapy Selection Assessment of Drug Response Resistance and Recurrence Monitoring Biomarker Assay Development CDx Kit Development Regulatory Registration & Approval cgmp Manufacturing Commercialization 6

7 Advantages of Plasma DNA Testing» High compliance Minimally invasive, few risks Patient / Oncologist» Accessible Tissue not always accessible; e.g. NSCLC» Fresh DNA Archival tissue can be degraded & have different mutation profile» No selection bias Assess primary tumor and metastases w/ one sample Tumor intra/inter-heterogeneity not a problem Direct Plasma Testing Physician Specialist (i.e. Surgeon) Pathology Tissue Testing» Shorter TAT Shorter clinical TAT from physician order to test results Clinical Laboratory» Monitoring possible Allows monitoring for drug response and resistance 7

8 Detection of Cell-Free Tumor DNA Localized vs Metastatic Disease Bettegowda et al, Sci Tran Med Feb

9 BEAMing Digital PCR Pre-Amplification Emulsion PCR Hybridization Flow Cytometry Flow Cytometry Wild-type Mutant» BEAMing (Beads, Emulsions, Amplification, Magnetics) has shown efficacy in several therapeutic clinical trials as well as in oncology patient testing applications. 9

10 Sysmex Inostics OncoBEAM TM Assays for Therapy Selection and Monitoring» A wide variety of assays available multiplexed to run with 2 ml of plasma or FFPE/frozen tissue (single gene as well as multigene)» Consistent high sensitivity (most assays with analytical sensitivities of 0.02% %)» Different validation status: GCP/CLIA» Validated for samples collected in BD Vacutainer K2EDTA tubes as well as Streck Cell-Free DNA BCT» All OncoBEAM tests can also be customized as a subset of listed genes and mutations 10

11 Sysmex Inostics CLIA & GCP Labs USA GCP, CLIA testing facility Baltimore JAPAN GCP testing facility, Kobe GERMANY GCP testing facility Hamburg USA Partnership with CHINA GCP testing facility Covance, Shanghai

12 CRO Partner to Pharmaceutical Companies > 100 clinical trials; > 40,000 samples total Pancreas, 3% Prostate, 2% Ovarian, 1% Various, 9% Thyroid, 1% Breast, 15% Endomedrium, 3% Gastric (GIST), 6% Liver, 2% Colon, 6% Lung, 31% Skin, 22% 12

13 # cumulative publications Publications Van Cutsem et al Journal of Clinical Oncology Sorich et al Annals of Oncology Thress et al Lung Cancer Diaz et al Nature Karlovich et al Clinical Cancer Research Tabernero et al Lancet Oncology Oxnard et al JCO Spoerke et al Nat Comun. Toledo et al Oncotarget 30 Misale et al Nature Morelli et al Annals of Oncology Dawson et al New England Journal of Medicine Cardiallo et al Journal of Clinical Oncology

14 Concordance Between Tissue and Cell-Free DNA on Clinically Actionable Mutations OncoBEAM Clinical Snapshot: Published Performance Sources: Jeffers et al. (2013): Cancer Res. 73. SY 11 02; Thress et al. (2015): Lung Cancer. 90(3) : ; Jones et al. (2016): J Clin Oncol 34 (suppl; Abstract 11538); Higgins et al. (2012): Clin Cancer Res. 18(12) : ; Schadendorf, et al. (2015): Eur J Cancer. 51 : S

15 The OncoBEAM RAS CRC Kit Bringing Service based Assays to Hospitals Globally LDT to IVD

16 RAS Tissue Testing From Physician Order to Test Results USA 3 Median 27 days Range: days UK days FRANCE 4, days 26% more than 4 weeks AUSTRALIA 1 Median 17 days 20% more than 4 weeks 1 Scott et al. (2014) Asia Pac J Clin Oncol. 10(3):261-5; 2 Saunders et al. ESMO 2016, Abstract #526P; 3 Schwaederle et al. (2014) Oncologist 19, ; 4 INCa 2012 Survey, 5 Etude FLASH RAS

17 The OncoBEAM RAS CRC Kit Deal signed in April 2014 to develop a CE marked RAS liquid biopsy mutation test (IVD) based on the BEAMing technology CE marked April RUO kit launched at ASCO 2015 allowed for COE set-up and training as well as concordance studies Target: 40 sites certified end of FY2016

18 RAS CRC Kit Target Markets EMEA EMEA 32 IVD testing centers CHINA 1 IVD testing center Asia/Pacific Latin America JAPAN 1 IVD testing center LATIN AMERICA 2 IVD testing centers ASIA PACIFIC 4 IVD testing centers OncoBEAM TM COE Program Update CONFIDENTIAL Not For Distribution

19 Concordance Study Results Tissue SOC RAS result OncoBEAM RAS CRC Plasma RAS Result Mutation detected No mutation detected Total Mutation detected No mutation detected Total Overall Agreement = 93.3% Positive Percent Agreement = 92.6% Negative Percent Agreement = 94.0% Cutoff Setting» RAS Tissue Mutation Rate: 50.8%» RAS OncoBEAM TM Blood Mutation Rate: 50.0% 19

20 High Sensitivity is Required for Reliable cfdna Profiling Clinical Relevance: PFS in RAS wild-type population (N=34) PFS RAS WT by tissue testing PFS RAS WT by BEAMing plasma 10.3m (95% CI ) 10.3m (95% CI ) Vidal et al., submitted for publication 20

21 Clinical Performance: Blood versus Tissue Clinical Relevance: PFS and OS in RAS wild-type RAS population Graselli et al. (2016): Oral presentation. ESMO GI, abstr O

22 Value of Sensitivity of OncoBEAM TM RAS CRC Kit Offers the sensitivity NEEDED to detect mutations at low levels in recurrent patients» HIGH Sensitivity Matters 22

23 High Sensitivity Matters Distribution of RAS of RAS MAFs in mcrc MAFs patients in mcrc patients Distribution of EGFR MAFs in EGFR-mutant NSCLC patients with T790M+ resistance Distribution of PIK3CA MAFs in HR+/HER- recurrent breast cancer patients 38% 13% 36% 15% 32% 22% 35% 27% 23% 14% 22% 23% % >0.1-1% >1% >5% % 0.1-1% >1% >5% % 0.1-1% >1% >5% 48% of patients with MAFs <1% 42% of patients with MAFs <1% 45% of patients with MAFs <1% Sources: Schmiegel et al. (2017): Mol Oncol. 11(2) : ; Saunders et al. (2016): Annals of Oncology 27 (6) : ; Vidal et al. (2017): J Clin Oncol 35 (suppl 4S; Abstract 607); Oxnard et al. (2016) J Clin Oncol 34(28): ; Baselga et al. (2015): Oral presentation. SABCS, Abstract S

24 Next Steps: Monitoring 1. Is the therapy working? 2. Is the cancer progressing? 24

25 RAS Mutant Clones Dynamically Evolve in Response to Pulsatile anti-egfr Therapy Siravegna et al. (2015) Nature Medicine 21, (2015) 25

26 OncoBEAM RAS testing in RAS mutant patients Siravegna et al. (2015) Nature Medicine 21, (2015) 26

27 Applications in Breast Cancer ESR1 E380Q S463P V534E P535H PIK3CA C420R E542K E545G AKT1 E17K L536H L536P L536R L536Q E545K Q546K M1043I Y537N Y537S Y537C D538G H1047R H1047L H1047Y» 22 different mutations multiplexed to run with 2 ml of plasma 27

28 Breast Cancer Panel (AKT1/PIK3CA/ESR1) Baselga et al. SABS

29 OncoBEAM TM BCP BELLE2 Clinical Trial Critical Results:» When PIK3CA mutation status was analyzed with archival tissue, no statistically significant difference in overall response was seen» When PIK3CA mutation status was analyzed using the OncoBEAM BCP assay from blood samples, PIK3CA mutant patients demonstrated a significant OR benefit (18.4 vs. 3.5 months) with the addition Buparlisib 29

30 Applications in Lung Cancer EGFR Deletion 19 L858R T790M C797S» 11 different mutations multiplexed to run with 2 ml of plasma 30

31 Performance of different EGFR plasma assays Cobas Therascreen ddpcr OncoBEAM Exon 19 deletion Sensitivity 86% 82% - 93% Concordance 89% 87% - 95% L858R Sensitivity 90% 78% 90% 100% Concordance 97% 95% 97% 95% T790M Sensitivity 41% 29% 71% 71% Concordance 57% 48% 74% 70% Source: Thress et al, Lung Cancer

32 Clinical Performance: AZN AURA Trials High ORR in Patients with Tumor or Plasma Positive T790M with AZD9291/Tagrisso 100 Tumour T790M positive (n=173) 100 Plasma T790M positive (n=164) 80 ORR (95% CI): 62% (54, 70) 80 ORR (95% CI): 63% (55, 70) 60 Plasma T790M positive 60 Tumour T790M positive * * Plasma T790M negative Plasma T790M unknown * Tumour T790M negative Tumour unknown Oxnard et al. JCO

33 Paradigm Shift is Occurring Blood based testing first A. Conventional paradigm FFPE, formalin-fixed paraffinembedded Acquired resistance to EGFR-TKI All patients undergo biopsy, FDA approved FFPE assay for T790M T790M positive T790M negative Third gen. EGFR-TKI Chemotherapy B. Proposed paradigm for use of plasma diagnostics Acquired resistance to EGFR-TKI T790M positive Skip biopsy, start 3 rd gen. EGFR-TKI FDA approved plasma assay for T790M and sensitising mutations T790M negative Biopsy, FDA approved FFPE assay for T790M T790M positive T790M negative 3 rd gen. EGFR-TKI Chemotherapy 33

34 Thank you