Diagnostics in Oncology Mark Kockx MD, PhD

Transcription

1 HistoGeneX The Real World A Specialized of companion Biomarker & Integrated Pathology Laboratory Diagnostics in Oncology Mark Kockx MD, PhD 1

2 2 HistoGeneX located in Antwerp, Belgium and Chicago, Illinois US Histology Immunohistochemistry Imaging Molecular Services Tissue Biomarker development Clinical trial Testing GCP/ GCLP Focus on Predictive Biomarkers for Cancer therapy

3 HistoGeneX activities Assay Development Clinical Trial Patient Testing & Screening Translational Research Custom Reagent Phase I Phase II Phase III TMA Prep/ Analysis Tissue Expression Cell Model Studies IHC Transfer Real-Time PCR Imaging Validation FISH/CISH mrna ISH Nanostring Multiplex IHC Companion Dx CDx Class Assay Development Reproducibility & Precision Device Clinical Trials

4 Investigator & Test Site for PDL1 Companion Dx in NSCLC and Bladder cancer for Atezolizumab Screening, reproducibility & retrospective analysis for PDL1 ( Ventana / Roche) HistoGeneX FDA inspection 2016 Our Companion Diagnostics Experience Investigator & Test Site for EGFR mutations Companion Dxs Screening, reproducibility & retrospective analysis for EGFR real time PCR (Roche Molecular Systems) HistoGeneX FDA inspection 2015 Investigator & Test Site for Vemurafenib Companion Dx Screening, reproducibility & retrospective analysis for BRAF real time PCR (Roche Molecular Systems) Investigator & Test Site for K-ras testing Vectibix Screening, reproducibility & retrospective analysis for K-ras real time PCR (DxS/Qiagen) HistoGeneX FDA inspection 2011

5 Development of a predictive marker during clinical trials: Companion diagnostic Drug Development IND review Application review 5

6 What does FDA consider a Companion Diagnostic? When therapeutic decisions are made or optimized on the basis of a test result Or when the pivotal trial selected based on a test Examples include: o Specific drug target (e.g. target molecules) o Unique markers related to drug response or dosing o Distinct populations have adverse events 6

7 Why are Companion Diagnostics regulated? Drug usage depends on the biomarker/test results (if test doesn t work, the drug could be improperly administered) CoDx considered significant risk devices (Class III/PMA) o Used to make treatment decisions o Carry the same risk profile as the drug Co-development is a device and drug/biologic collaboration o Cross-labeling o Concurrent FDA approval 7

8 The K-RAS story: single gene/exon approach Mutational diversity in KRAS codon 12/13 hotspots in Exon 2 of K-ras 40 to 50% of phase IV metastatic colorectal cancer (mcrc) patients have KRAS positive tumors Greater than 98% of the activating KRAS mutations are found within 6 nucleotides in codons 12 and 13 In November 2008, NCCN guidelines were updated to recommend KRAS testing for all mcrc 8

9 The K-RAS story: HGX-Diagnostic-K-RAS Test (2007) DxS K-RAS Mutation Test Kit Seven most common somatic mutations of codons 12 and 13 (G12A, G12D, G12R, G12V, G12C, G12S, and G13D) allele-specific real-time PCR capable of detecting approximately 1% of mutated KRAS from background wild-type DNA. Amgen PCR KRAS exon 2/sequencing Gold standard / Accuracy of the method. 9

10 The K-RAS story: Increased PFS Observed in Patients with K-RAS Wild-type Tumors 10

11 The K-RAS story: FDA Approval / K-RAS CoDx Development based on a Prospective Retrospective Analysis Cetuximab in Combination with Folfiri / Therascreen On July 6, 2012, the U. S. Food and Drug Administration granted approval to cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly and Co) for use in combination with FOLFIRI (irinotecan, 5- fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mcrc) as determined by FDA-approved tests for this use. FDA also approved the Therascreen KRAS RGQ PCR Kit (QIAGEN Manchester, Ltd) concurrent with this cetuximab approval. 11

12 The K-RAS story: Beyond the exon 2 codon 12 and 13 mutation 12

13 Increasing numbers of biomarkers for each patient 13

14 Shift from Single Gene approach to Gene Panels 14

15 Antwerpen Diagnostic NGS Platform NGS Panels as companion diagnostic? NGS in Oncology Inca Report Report KCE Belgium NGS Guidelines / Cancer Center WIV Example Tumor Hotspot MASTR Plus Pan-cancer Diagnostics from Multiplicom 26 cancer related genes (INCa) Full coding regions covered for 10 drugable genes 15

16 FDA s regulatory oversight of In Vitro Diagnostics (IVDs) IVD meets safety and effectiveness requirements? Analytical validation o Correctly identifies target o Accuracy relative to reference standard o Sensitivity/specificity Clinical validation o Correctly identifies disease/condition Test is cleared and device can be legally marketed for clinical use 16

17 FDA Regulation of Laboratory-developed Tests (LDT) LDTs now regulated through the Clinical Laboratory Improvement Amendments (CLIA) FDA exercises enforcement discretion on LDTs. LDTs developed by a clinical laboratory for use at its own facilities can be sold without FDA premarket review FDA is concerned that CLIA regulations alone do not ensure required safety and effectiveness of diagnostic devices: o Aggressive direct to consumer marketing of genetic LDTs outside FDA pre-market review o Complex genetic LDTs not verifiable by an independent third party o Potential health risk of LDTs due to use of non-gmp Research Use Only reagents, software and instrumentation 17

18 CE-IVD CE mark implies the use of the product for medical diagnostic purposes Regulatory & QS requirements according to the IVD Directive 98/79/EC Registration of the manufacturer Registration of the product Vigilance procedure Manufacturer quality systems requirement, e.g. ISO13485

19 What is Behind the Label? Technical performance verification as the basis for labeling Assay Performance requirements Limit of Detection (LOD) LOD Verification of Genotypes Specificity Cross Reactivity Sensitivity using Clinical Specimens Exogenous Interference Endogenous Interference Linearity Genotype Linearity Precision Accuracy Whole System Failure RMC, QS and Sample Failure Rate Method Correlation Cross Contamination Reagent requirements Lot interchangeability Open Bottle Stability On Board Stability Shipping Stability Shelf life Specimen requirements Clinical Specimen Stability Primary Tube Equivalency Matrix (Specimen Type) Equivalency

20 What is Behind the Label? FDA clinical trials in addition to the CE labeling Assay Performance requirements Limit of Detection (LOD) LOD Verification of Genotypes Specificity Cross Reactivity Sensitivity using Clinical Specimens Exogenous Interference Endogenous Interference Linearity Genotype Linearity Precision Accuracy Whole System Failure Method Correlation Cross Contamination Results included FDA clinical trials Reproducibility & Lot to Lot Clinical Utility Results included 14040* 7066* * Numbers without controls

21 What is Behind the Label Stability results Reagent requirements Results included Study duration Lot interchangeability Open Bottle and on board Stability Shipping Stability week 1 month 1 month Shelf life (AET, FMCS, Stability) months EXP: xxx Stability and interchangeability based on 5,050 individual measurements Package insert is specific to CE-IVD IFU information

22 Example: FDA-cleared NGS instrument and tests for Cystic Fibrosis 22

23 View of the industry on NGS CDx in Oncology : Scalable NGS CDx Test Labeling Framework 23

24 NGS based Predictive Biomarkers Laboratory wants to use a NGS based test for a targeted therapy with NGS based method Each gene in the NGS Panel will need a predictive biomarker status for each tumor entity 24

25 How to survive in the real world (at least in Europe)? Controlled Flexibility Concept for Targeted NGS Panels NGS networks Molecular Advisory Boards User needs Connection between CTG-TGR Assay development Kit Manufacturer verification NGS provider verification RUO assay Kit Manufacturer Validation studies CE-IVD label CE-IVD assay 25

26 The End 26