the eortc molecular screening programme specta...the eortc molecular screening programme specta...
TRANSCRIPT
The EORTC Molecular Screening programme
SPECTA
February 2016
Denis Lacombe, MD, MSc
EORTC, Director General
Brussels, Belgium
The changing shape of clinical research
Phase I Phase III RESOURCES
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
From trials “designed to learn” to real life situation
The changing clinical research pathway
Burock et al. Eur.J.Cancer (2013), http://dx.doi.org/10.1016/j.ejca,2013.05.016
The SPECTA collaborative platform
Molecular Screening Platform
First line Second line 3rd line trial
2nd line trial First line Third line
1st line trial Standard treatment
Standard treatment (no open trial)
Standard treatment (no open trial)
Academic capture of biological sub groups coupled with technological expertise
Industry cooperation for drug development
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SPECTA Platforms
Systematic SANGER panel NGS
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
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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
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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
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Courtesy of Dr Philip Beer, Director of Medical Genomics, 14M Genomics
gene fusions
Some examples: EGFR, KRAS, ALK, ROS 1, RET KIT, PIK3CA, BRAF, Trk, FGFR
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.
328
111
29 10
Genes (all exons)
Copy number variants
Regulatory regions
Breakpoints
127
59
99
9
24
25
40
3 25
Signalling
Transcription Factor
Transcriptional control
Apoptosis
DNA damage response
Cell cycle control
Miscellaneous/Unknown
Immune-related
Structural components
14 MG NGS panel – V1
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.
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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
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Some figures…
• > 600 DNA samples sent for NGS analysis
• 476 NGS Patient Test Reports released to local clinicians through RAPHAEL™ web portal
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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
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Downstream collaborations
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• 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
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
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QA/QC
Clinical, biological, imaging data
Towards new healthcare systems
Biomarker
analytical
and clinical
validation
Innovative
trial designs
Regulatory
pathway /
Staggered
licensing
Access to effective care:
•Outcome research
•Cost effectiveness
•Health Technology Assessment
•Real life situation
Treatment
guideline
development