Biomarker & Companion Diagnostics

Transcription

1 Biomarker & Companion Diagnostics The First Half of Precision Medicine Dr. Nick Zhang Chairman and CEO Qiagen Suzhou Translational Medicine

2 Understanding of diseases has significantly advanced Cells Genes Pathways Single (Onco)gene Normal cell growth Transfection * Cells Permanent = uncontrolled cell growth Uncontrolled cell growth *

3 Molecular pathway is unveiling the mystery of cancer 1850s Molecular Dx Patient clinical signs / symptoms Cellular Morphology Molecular mechanism White Blood Disease Leukemia Lymphoma Chronic Leukemia Acute Leukemia Preleukemia Indolent Lymphoma Aggressive Lymphoma Acute myeloid leukemia Acute lymphoblastic leukemia Acute promyelocytic leukemia Chronic myeloid leukemia Chronic myeloproliferative disorders Myelodysplastic syndromes Mixed myeloproliferative / myelodysplastic syndromes And associated sub-types (~40 total) Mature B-cell lymphomas Mature T-cell lymphomas Plasma cell neoplasm Immature (precursor) lymphomas Hodgkin s lymphoma Immunodeficiency associated lymphomas Other hematolymphoid neoplasms And associated sub-types (~50 total) Disease and treatment by molecular mechanism 5YR Survival rate: <10% ~20% ~50% ~65% Significantly improved outcomes Source: WHO classification criteria; SEER Cancer Statistics Review

4 Decreasing Mortality Rates over Time Globally

5 Precision Medicine = Effectiveness & Efficiency Stratification with diagnostic tools the right patients do get the right drugs and at the right time with increased efficacy and safety Biomarker is the key indicator

6 What is Biomarker and How Biomarker = Any biological parameter(s) that is indicator of disease process or drug response Clinical Validation Example = - Body temperature for Fever - Sugar in urine for Diabetes s.10 s Human Papilloma Virus for Cervical Cancer - EGFR, KRAS Mutation Exploratory Potentially valuable Early stage use Biomarker for clinical use Biomarker development based on huge clinical date

7 Biomarker and CDx in Precision Medicine Future 2020s Now Precision medicine healthcare system Regulatory bodies worldwide requires >75% responder rate for approval of any innovative drug with CDx cfda release CDx guidance No approval of new drugs without CDx in major markets Subgroup definition by molecular diagnostics will segregate syndromes into distinct diseases FDA released the CDx guidance In Aug, 5 th, 2016, BMS s Opdivo 1 st line treatment for NSCLC trial failed The possible reason is that the stratification criteria of biomarker PD-L1 was too low which is different from Merck s. BMS used 5% while Merck use 50% for their successful keytruda s trial. BMS s stock fall 23% on that day!

8 The Uses of Biomarker in Drug R&D Prognostic/Diagnostic Safety/Toxicity Respond/Non-Responder Disease Progression Efficacy Safety/Efficacy Discovery Pre-Clinical Development Clinical Development Pathway Elucidation Animal Model Validation Mechanism of Action Product Decision Target Identification/Characterization/Prioritization Biomarkers 8

9 Precision Medicine Requires Collaboration between Rx and Dx Collaboration: Validation of biomarkers and target pathways Understanding of translational science. Stratification of patients for clinical trials Commercialization of CDx and targeted drugs Recent collaboration between Biodesix (CDx) and Aveo(Rx) showed they share the R&D cost of drug and CDx and also share 50% of drug sale profit, which is a milestone of new business model, representing a new trend of Rx and CDx collaboration.

10 Clinically Relevant Biomarkers From Pathway Knowledge To Biomarkers Predictors of response or resistance or therapy ABL FGFR3 MAP2K2 PTEN NRAS BRAFT FGFR4 MAP2K4 RETT HRAS FGFR1 FLT3 MET SRC AR FGFR2 MAP2K1 PIK3CA MCL1 ERBB3 AKT1 AKT2 AKT3 ERCC1 ERBB4 ESR1 EGFR KRAS RARAT KIT CEBPA JAK2 NMP1 PDGFR BRCA Indicators of Prognosis APC CCND1 MLH1 MSH2 MSH6 MYC TP53 MCL1 CDKN2A MGMT1T Markers for Toxicity or Pharmacokinetics CYP2D6 UGT1A1 TMPT DPYD CYP1B1 ESR2 MTHFR S0D2 CYP2C19 FGGR3A NQ01 SULT1A1 CYP2C8 GSTP1 NRP2 TYMS CYP3A4 ITPA SLC19A1 UMPS CYP3A5 ERCC2 MAN1B1 SLC22A2 SLC01B3

11 Targeted Therapy Based on Pathways and Biomarkers Molecular mechanisms in drug development Biomarker UGTIA1 PIK3CA HLA-B*5701 C-KIT HLA-B*1502 PTEN UGT1A1 CYP2C9 EML4-ALK PDGFR Cytogenetics HER2 BCR-ABL EGFR KRAS BRAF MET Herceptin Gleevec Iressa Vectibix Tomtovok Tykerb Warfarin Erbitux Nexavar Tegetrol Celebrex Ziagen Tarceva Drugs Camptosar Avastin

12 Biomarkers To Companion Diagnostics (CDx) Majewski IJ, Bernards R. Taming the dragon: genomic biomarkers to individualize the treatment of cancer. Nat Med. 2011; 17(3):

13 CDx Considerably Improves Clinical Success Rate 70% 60% 50% Success rate 62% 40% 30% 20% 10% 28% 31% 0% Overall Targeted Therapy CDx Guided Targeted Drug Success rate for NSCLC drugs in Phase III trials Source: Dana Olsen, Jan Trøst Jørgensen. Frontiers in Oncology 2014, 4: 105.

14 CDx Development Across Therapeutic Areas Scientific potential and economic attractiveness for companion diagnostics development across therapeutic areas companion diagnostics can improve R&D productivity by decreasing trial size, reducing attrition rates and/or increasing speed to market, and can improve commercial performance by improving market share and/or supporting higher drug prices. Davis JC, et al. The microeconomics of personalized medicine: today's challenge and tomorrow's promise. Nat Rev Drug Discov. 2009; 8(4):

15 Collaborations Between Rx and Dx Rx Pathway Drug Development Pre-clinical and Phase I Dx Pathway Biomarker Development and Validation Drug Development Phase II and III CDx Development FDA/CFDA Approval & Marketing CDx Approval Preclinical Studies Clinical Trials Patients Treatment PATHWAY TO Biomarkers PATHWAY TO Translational Science PATHWAY TO Precision Medicine 15

16 Drug Development Based on Specific Pathways/Biomarkers/CDx 16

17 The Case of EGFR in NSCLC EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Mutations in the EGFR oncogene are found in human cancers. The presence of these mutations correlates with response to certain tyrosine kinase inhibitor (TKI) (such as Gefitinib) cancer therapies.

18 Therapies Addressing the EGFR Pathway Tagrisso Afatinib BKM120 plx4032 QIAGEN partners: and many more... EGFR = Epidermal Growth Factor Receptor

19 The Up and Down - Iressa and EGFR Mutations

20 The IPASS Study Importance of EGFR Testing

21 Perfect Marriage of Rx + Dx Good science and data are essential don t make assumptions about clinical utility Precision medicine becomes a reality when the Rx and Dx industries align

22 Qiagen Assay in Mutation Coverage G719 S/A/C 2% Del % Del % Other 10% Total19 del. S768I 1% Exon 20 Total 3 Ins1% T790M 3% L858R Mutations 40% L861Q Mutations 1% EXON 18 EXON 19 EXON 20 EXON 21 EXON 22 EXON 23 EXON 24 Frequency of mutations in EGFR oncogene in lung cancer taken from the Catalogue of Somatic Mutations in Cancer (COSMIC) version 47

23 TKI Drug Development History Reversible inhibition Irreversible inhibition Irreversible inhibition First generation TKI Second generation TKI Third generation TKI Fourth generation TKI Gefinitib Afatinib Rociletinib Erlotinib T790M mutation (60%) Neratinib Specific for T790M mutation Osimertinib/ AZD9291/ Tagrisso C797S mutation? Icotinib The only third generation TKI FDA approved Dx: FFPE-EGFR PCR FFPE-EGFR (DRT) PCR ctdna-egfr (DRT) PCR EGFR NGS

24 Qiagen s Support to BI Studies BI Afatinib clinical trials with Qiagen FFPE-EGFR kit Study EGFR mutation Mutation percentage Response rate Median Progression-free Survival (PFS) 1 L858R, exon 19 deletion and other 35.6 (452/1,269) 56% (23% for Chemotherapy) 13.6 months (8.1 for Chemotherapy) 2 Del19, Leu858Arg and other 42.4% (923/2179) 66.9% (23% for Chemotherapy) 11 months (7 for Chemotherapy) 1. Sequist L, et al. Journal of Clinical Oncology, 2013, 31(27): James Chih-Hsin Y, et al. Lancet Oncology, 2015, 16(2):

25 Plasma ctdna for EGFR Mutation Detection ctdna has emerged as a specific blood-based detection for cancer mutations. EGFR mutations, including T790M mutation, detected in plasma ctdna are highly concordant with those detected in tumor tissue in patients ctdna-egfr testing is a feasible and minimally invasive alternative to tissue biopsy, especially for drug resistance testing. Bettegowda C, Sausen M, Leary R J, et al. Detection of circulating tumor DNA in early-and late-stage human malignancies. Science translational medicine, 2014, 6(224): 224ra24 Sample 2014 to Insight DIA, Inc. All rights reserved.

26 Qiagen s Support To Clovis Studies Clovis Rociletinib clinical trials with Qiagen Plasma EGFR kit EGFR mutation Mutation percentage Objective response Disease control T790M 57% (74/130) 59% (27/46) (T790M +) 29% ( 5/17) (T790M -) 93%(43/46) (T790M +) 59% ( 10/17) (T790M -) Objective response was defined as a complete response or a partial response. Disease control was defined as a complete response, a partial response, or stable disease for more than 6 weeks. Sequist L V. et al, New England Journal of Medicine, 2015, 372 (18):

27 The First-Ever Approved ctdna-egfr CDx Supported the NCT Iressa clinical trial, demonstrated high rates of co ncordance between matched tissue and plasma samples at 94.3%. QIAGEN s ctdna-egfr is now CE-IVD marked to assess EGFR mutation status in NSCLC patients based on plasma samples. QIAGEN pioneering the use of liquid biopsy-based companion diagnostics as a less-invasive option to complement surgical biopsies for genomic profiling of ca ncers. Sample 2014 to Insight DIA, Inc. All rights reserved.

28 Genetic Variation in Lung Cancer

29 Clinical trials with biomarkers for patient stratification test: ~11%

30 Whole Spectrum Biomarker Development Genomics Epigenomics Transcriptomics mirnomics Whole Genome/Exome Sequencing Targeted sequencing ARMS qpcr (therascreen RGQ PCR Assay) TaqMan qpcr (ipsogen Onco-Hematology PCR Assays) Droplet Digital PCR (ddpcr) Pyrosequencing (therascreen PyroMark Assay) FISH/CISH RNAseq miscript Primer Assays miscript mirna PCR Arrays RNA Interference Proteomics DNA Gene Expression RNA RNAseq RT 2 qpcr Primer Assays RT 2 Profiler PCR Arrays QuantiTect Primer Assays QuantiFast Probe Assays PROTEIN Immunoassay Western blotting Multi-Analyte ELISArray MSD Pathology Promoter Gene DNA Methylation by NGS DNA Methylation by Pyrosequencing (PyroMark CpG Assay) EpiTect Methyl II qpcr System Next-Generation Sequencing PCR-based Pyrosequencing-based Immunoassay Pathology Bioinformatics QIAGEN your Partner in Translational Medicine 30

31 Integrated Platform Solutions Biobanking & Sample prep NGS and Bioinformatics Genomics/Epigenomics Transcriptomics/miRNomics NextSeq Precision Medicine Biomarker Screening & Discovery Roto-Gene Q PyroMark Q24 GeneReader Companion Diagnostics Approval Suzhou Biomarker Validation ABI ViiA7 Droplet Digital PCR Pathology Patient Stratification Biomarker assay Development & Optimization Immunoassay MSD S 600 Nikon ECLIPSE Ni-U ThermoBrite Hybridization oven QIAGEN Your Partner in Translational Medicine SpectraMax i3 Bio-Rad V3 Western Workflow 31

32 Immunotherapy: Possible Cure for Cancer Immune checkpoint inhibitors, which unleash a patient s own T cells to kill tumors, are revolutionizing cancer treatment. Schumacher TN et al. Biomarkers in cancer immunotherapy. Cancer Cell. 2015;27(1):12-4. Chen et al, Immunity. 2013;39(1):

33 Growing Immuno-Oncology Testing Portfolio Genomics & Epigenomics Transcriptomics Proteomics Whole Genome/Exome Sequencing Targeted TMB by Sequencing NGS ARMS qpcr (therascreen RGQ PCR Assay) TaqMan MSI qpcr by (ipsogen PCR Onco-Hematology PCR Assays) Droplet Digital PCR (ddpcr) Pyrosequencing (therascreen PyroMark Assay) FISH/CISH >>> IRP panel by qpcr array or NGS RNA-seq miscript Primer Assays miscript mirna PCR Arrays >>> RNA Interference DNA Promoter Gene Expression Gene RNA RNA-seq RT 2 qpcr Primer Assays RT 2 Profiler PCR Arrays QuantiTect Primer Assays QuantiFast Probe Assays DNA Methylation by NGS DNA Methylation by Pyrosequencing (PyroMark CpG Assay) EpiTect Methyl II qpcr System PROTEIN Immunoassay Western PD-L1 by blotting IHC Multi-Analyte ELISArray dmmr by IHC MSD Pathology >>> Bioinformatics 33

34 PD-L1 Expression in Patient Samples Lung Squamous Cell Carcinoma Lung adenocarcinoma Tumor and/or infiltrating immune cells 0 ( 1%), 1 ( 1% but <5%), 2 ( 5 but <10%), 3 ( 10%)

35 PD-L1 Expression in Cancer Patients Mesothelioma Gastric Carcinoma Lung Carcinoma Esophageal Carcinoma 35

36 TMB as Biomarker

37 TMB as biomarker for response to immunotherapy TMB associated with clinical benefit of anti-pd-1 therapy in NSCLC D: discovery; V: validation; DCB: durable clinical benefit; NDB: no durable benefit; NR: no response; PFS: progression-free survival; PR: partial response; SD: stable disease; PD: progression of disease Rizvi et al., Science. 2015; 348(6230):

38 TMB as Biomarker for Response to 1 st -line Opdivo Retrospective study of CheckMate 026 shows TMB as a better biomarker in NSCLC patient stratification other than PD-L1 IHC Impact of Tumor Mutation Burden on the Efficacy of First-Line Nivolumab in Stage IV or Recurrent Non-Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 026. AACR Title, Location, Date 38

39 TMB test based on NGS 39

40 Microsatellite Instability and Mismatch Repair

41 MSI Analysis System Normal Sample MSI-H positive control sample Microsatellite instability assays using the MSI Analysis System. Matching normal sample (top panel) and MSIpositive test sample (bottom panel) were analyzed using the MSI Analysis System. Two nanograms of genomic DNA was amplified and analyzed using an ABI PRISM 3100 Genetic Analyzer with POP-4 polymer and a 36cm capillary, and the allelic patterns of the normal and test samples are shown. The presence of new alleles in the test sample (indicated by arrows) that were not present in the normal sample indicates MSI. PCR product sizes and respective fluorescent dyes for loci contained in the MSI Analysis System are provided in Table 1. Title, Location, Date 41

42 MSI analysis CRC patient MSI-H CRC patient (B210) showed a MSI-H genotype MSI-H Penta C B210C IHC: PD-L1 NR-21 BAT-26 BAT-25 NR-24 MONO-27 Penta D Penta C B210B NR-21 NR-24 BAT-26 BAT-25 MONO-27 Penta D 400x 200x Promega kit JOE labeled MSI loci (NR-21, BAT-25, MONO-27) FL labeled MSI loci (BAT-26, Penta D) TMR labeled MSI loci (NR-24, Penta C) 42

43 The Milestone Event for Biomarker and CDx Development FDA 加速批准首款不区分肿瘤来源的抗癌疗法 : 由默沙东 (MSD) 带来的 KEYTRUDA (pembrolizumab) 获批治疗带有微卫星不稳定性高 (microsatellite instability-high,msi-h) 或错配修复缺陷 (mismatch repair deficient,dmmr) 的实体瘤患者 43

44 Transform Biological Samples to Valuable Molecular Insights Complete Workflow Bioinformatics DNA Biomarker Analysis RNA Biomarker Interpretation Democratizing the creation and interpretation of biological data Protein Biomarker Reporting BIOLOGICAL SAMPLE Sample Technologies Assay Technologies VALUABLE MOLECULAR INSIGHTS Extract DNA, RNA and proteins in reliable process Make molecular info visible and available for interpretation QIAGEN Your Partner in Translational Medicine 44

45 QIAGEN (Suzhou) Translational Medicine Co., Ltd. Thank You Address, 9/F, B5 Building, 218 Xinghu St., Suzhou Industrial Park, China Zip code, Website, 45