The EORTC Molecular Screening programme SPECTA

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1 The EORTC Molecular Screening programme SPECTA February 2016 Denis Lacombe, MD, MSc EORTC, Director General Brussels, Belgium

2 The changing shape of clinical research Phase I RESOURCES Phase III

3 The changing clinical research pathway From trials designed to learn to real life situation Early clinical trials (R&D) Biology / imaging driven Integrated TR Screening platforms Collection of high quality data from various sources Pivotal trials Highly targeted Large differences Population-based studies Real world data Quality of life Health economics HTA Pragmatic trials Burock et al. Eur.J.Cancer (2013),

4 The SPECTA collaborative platform Molecular Screening Platform Academic capture of biological sub groups coupled with technological expertise Standard treatment (no open trial) 1 st line trial Standard treatment First line 2 nd line trial Third line First line Second line 3 rd line trial Industry cooperation for drug development Standard treatment (no open trial) 4

5 SPECTA Platforms Systematic SANGER panel NGS

6 Harmonization of the SPECTA program Common overseeing board for all platforms Harmonized individual platform governance SPECTA protocol template available Identical biobanking policy among platforms Single sequencing facility for all platforms Identical e-infrastructure among platforms Identical database among platforms: handling and linking of data follows harmonized procedure Cross-fertilization of research and diagnostics 6

7 SPECTA in the collaborative approach Genomic screening of a large number of patients, with appropriate QA/QC safeguards Increased patient access to clinical trials testing personalized approaches Follow up of all patients throughout the course of their disease irrespective of treatment or clinical trial participation Collection of overall survival data, even if not included in the endpoints of clinical trials Linking with reimbursement, hospital, and registry data would enable a thorough assessment of participating patients 7

8 NGS in SPECTA Immediate identification of molecular subtypes for clinical trial recruitment Future analyses for mutational signatures of response and resistance Develop guidelines and work practices to implement in several cancer types Courtesy of Ultan McDermott, The Cancer Genome Project, WTSI 8

9 Courtesy of Dr Philip Beer, Director of Medical Genomics, 14M Genomics 10

10 14 MG NGS panel V1 Some examples: EGFR, KRAS, ALK, ROS 1, RET KIT, PIK3CA, BRAF, Trk, FGFR gene fusions 328 Genes (all exons) Copy number variants Regulatory regions Breakpoints Signalling Transcription Factor Transcriptional control Apoptosis DNA damage response Cell cycle control Miscellaneous/Unknown Immune-related Structural components The breakdown by function is for unique features (n=411), i.e. a gene tiled for copy number and for mutations is only counted once.

11 Challenges To develop the adequate QA/QC environment for multigene/ngs panel -use in clinical decision making in the EU. To address technical and (pre/post) analytical issues for assay development. To develop guidelines for appropriate levels of Quality Assurance for biomarker assays and reporting To ensure uniform interpretability of genes and clinical correlations across platforms by performing permanent NGS ring studies. To establish the infrastructure and logistics for inter-european and transcontinental interlaboratory comparison studies for new emerging technologies such as NGS. 13

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13 Quality assurance for NGS International Cross Laboratory and Cross Platform NGS Comparison Project (EORTC, NCI, WTSI) Molecular Advisory Board Defines genes/mutations of interest to be included in the NGS panel for each cancer type Defines genes/mutations of interest to be reported to local clinicians (actionable mutations, potentially germline fidnings, etc.) Advisory role towards local clinicians for the clinical interpretation of NGS findings Biorepository Working Group Responsible for harmonization of pre-analytical procedures (tumor content determination, DNA extraction) across SPECTA program Participation of central biobanks to proficiency testings for pre-analytical procedures 15

14 Some figures > 600 DNA samples sent for NGS analysis 476 NGS Patient Test Reports released to local clinicians through RAPHAEL web portal 16

15 Future developments for SPECTA RNA-seq for further extension of the gene panel (e.g. for detection of gene fusions that cannot be technically captured with currently-used panel) and for possible transcriptomic analysis Blood-based NGS (ctdna / liquid biopsies) Whole-Exome (or Genome) Sequencing Unique pan European multi tumor highly curated sequencing data: collected in a longitudinal manner with phenotype information as well treatments details and outcome along side high quality Molecular Advisory Board validated reports 17

16 Downstream collaborations 1 Pharma-sponsored biomarker-driven clinical trial will use SPECTAcolor and SPECTAlung (SPECTAmel?) for biomarker screening for study entry 1 Pharma-sponsored clinical trial will use SPECTAbrain as TR platform (biomarker discovery) 1 Pharma company for a molecular epidemiology study (SPECTArare) 1 Diagnostics company for validation of a blood-based NGS assay and its future implementation of systematic blood-based screening of SPECTAlung patients 1 Diagnostics company for validation of a blood-based diagnostic assay (EML4-ALK fusions in lung cancer patients) 1 Diagnostics company for validation of a gene expression platform 18

17 Challenges and Future directions Chaotic development of technologies Centralisation vs decentralisation vs QA Big data sets and bio informatics Algorythm and MABs, impact on treatment guidelines Tumor heterogeneity and escape mechanisms Shared HBM collections, data sharing Fragmentation of diseases Robustness of CT results, histology agnostic/basket studies Patient access To trials, to treatments, off label Costs and impact on health care systems Real life monitoring 19

18 Towards new healthcare systems Access to effective care: Outcome research Cost effectiveness Health Technology Assessment Real life situation Biomarker analytical and clinical validation Innovative trial designs Regulatory pathway / Staggered licensing Treatment guideline development QA/QC Clinical, biological, imaging data

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