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