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
Sysmex Corporation Kobe 2
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
Sysmex Corporation Marketing Business Development Quality Sales R&D Regulatory Operations Market Access Medical Affairs GLOBAL INTEGRATED NETWORK
Sysmex Corporation 43 PRODUCTS WITH FDA CLEARANCE (510K) 181 PRODUCTS CE-IVD 307 PRODUCTS WITH PMDA 191 PRODUCTS CFDA GLOBAL REGULATORY EXPERTISE
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
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
Detection of Cell-Free Tumor DNA Localized vs Metastatic Disease Bettegowda et al, Sci Tran Med Feb 2014 8
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
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% - 0.04%)» 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
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
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
# cumulative publications Publications 60 50 40 Van Cutsem et al. 2015 Journal of Clinical Oncology Sorich et al. 2015 Annals of Oncology Thress et al. 2015 Lung Cancer Diaz et al. 2012 Nature Karlovich et al. 2016 Clinical Cancer Research Tabernero et al. 2015 Lancet Oncology Oxnard et al. 2016 JCO Spoerke et al. 2016 Nat Comun. Toledo et al. 2016 Oncotarget 30 Misale et al. 2012 Nature Morelli et al. 2015 Annals of Oncology 20 10 Dawson et al. 2013 New England Journal of Medicine Cardiallo et al. 2014 Journal of Clinical Oncology 0 2009 2010 2011 2012 2013 2014 2015 2016 13
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) : 509 15.; Jones et al. (2016): J Clin Oncol 34 (suppl; Abstract 11538); Higgins et al. (2012): Clin Cancer Res. 18(12) : 3462-9; Schadendorf, et al. (2015): Eur J Cancer. 51 : S685. 14
The OncoBEAM RAS CRC Kit Bringing Service based Assays to Hospitals Globally LDT to IVD
RAS Tissue Testing From Physician Order to Test Results USA 3 Median 27 days Range: 14-77 days UK 2 14-30 days FRANCE 4,5 21-28 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, 631 636; 4 INCa 2012 Survey, 5 Etude FLASH RAS 2014 16
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 2016 2014 2015 2016 2017 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
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
Concordance Study Results Tissue SOC RAS result OncoBEAM RAS CRC Plasma RAS Result Mutation detected No mutation detected Total Mutation detected 112 7 119 No mutation detected 9 110 119 Total 121 117 238 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
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 7.7-25) 10.3m (95% CI 7.7-19.8) Vidal et al., submitted for publication 20
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- 024. 21
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
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% 0.02-0.1% >0.1-1% >1% >5% 0.02-0.1% 0.1-1% >1% >5% 0.02-0.1% 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) : 208 219; Saunders et al. (2016): Annals of Oncology 27 (6) : 149 206; Vidal et al. (2017): J Clin Oncol 35 (suppl 4S; Abstract 607); Oxnard et al. (2016) J Clin Oncol 34(28):3375-3382; Baselga et al. (2015): Oral presentation. SABCS, Abstract S 6 01 23
Next Steps: Monitoring 1. Is the therapy working? 2. Is the cancer progressing? 24
RAS Mutant Clones Dynamically Evolve in Response to Pulsatile anti-egfr Therapy Siravegna et al. (2015) Nature Medicine 21, 795 801 (2015) 25
OncoBEAM RAS testing in RAS mutant patients Siravegna et al. (2015) Nature Medicine 21, 795 801 (2015) 26
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
Breast Cancer Panel (AKT1/PIK3CA/ESR1) Baselga et al. SABS 2015 28
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
Applications in Lung Cancer EGFR Deletion 19 L858R T790M C797S» 11 different mutations multiplexed to run with 2 ml of plasma 30
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 2015 31
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 40 20 * * Plasma T790M negative Plasma T790M unknown 40 20 * Tumour T790M negative Tumour unknown 0 0 20 20 40 40 60 60 80 80 100 100 Oxnard et al. JCO 2015 32
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
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