IMI CANCER-ID: Validation of novel blood-based biomarker technologies in clinical settings Thomas Schlange 1 , Thomas Krahn 1 , Sabrina Pleier 1 , Klaus Pantel 2 , Leon Terstappen 3 , Barbara Baggiani 4 1 Global Biomarker Research, Bayer Pharma AG, Wuppertal, Germany; 2 Department of Tumor Biology, University Cancer Center Hamburg/Eppendorf, Hamburg, Germany; 3 Faculty of Science and Technology, Medical Cell BioPhysics, Enschede, The Netherlands; 4 Menarini/Silicon Biosystems, Bologna, Italy INTRODUCTION • The Innovative Medicines Initiative (IMI) was launched in 2008 as a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) • IMI aims to facilitate the collaboration of healthcare stakeholders, such as academic and clinical researchers, pharmaceutical industry and small- and medium-sized enterprises (SMEs) in Europe, in order to address key issues in drug development and patient access to innovative medicines • Major obstacles for cancer diagnosis and treatment are tumor heterogeneity and the dynamic changes at the molecular level during disease progression; this makes longitudinal monitoring of malignant disease highly desirable, in order to choose the best treatment options and to monitor treatment efficacy • As access to tumor tissue is often the limiting factor and historic samples are not predictive for the current state of the disease, new blood-based biomarkers are explored as liquid biopsies to support personalized treatment of cancer patients 1604 May Jun Jul Aug Sep Oct Nov Dec Jan Feb 2014 2015 09 Sep: Submission of FPP 13 May: Expression of Interest evaluation hearing at IMI Joint Undertaking in Brussels 13 Jun: Notification of the academic CANCER-ID consortium 18 Jun: Kick-off between EFPIA and academic partners for FPP 01 Jan: Project start 18 Dec: Final version of the Project Agreement 05/06 Feb: Kick-off meeting in Amsterdam Figure 4. Current status of the project EFPIA, European Federation of Pharmaceutical Industries and Associations; FPP, Full Project Proposal Preparation; IMI, Innovative Medicines Initiative EFPIA Clinical sites Academic institutions Non-profit organizations Non-EFPIA/non-SME SME Klaus Pantel Universitätsklinikum Hamburg-Eppendorf Leon Terstappen Universiteit Twente Figure 2. CANCER-ID partners Figure 1. Potential of CTCs in personalized medicine Pre-evaluation phase (Year 1) Technical evaluation phase (Year 1–4) Clinical validation phase (Year 3–5) WP0: Technology assessment Working group I: CTC enumeration Working group II: CTC isolation and NA extraction Working group III: ctDNA analyses Working group IV: miRNA analyses WP1: Lung cancer (large indication) Cross-comparison of technologies Clinical study testing of selected assays WP2: Her2-therapy resistant breast cancer (small indication) Cross-comparison of technologies Clinical study testing of selected assays WP3: Data management and bioinformatics WP4: Project management and dissemination of results Figure 3. Experimental strategy and key objectives CTC, circulating tumor cell; ctDNA, circulating tumor DNA; Her2, human epidermal growth factor receptor 2; miRNA, microRNA; NA, nucleic acid; WP, work package The academic leaders of CANCER-ID, Professor Klaus Pantel (Universitätsklinikums Hamburg-Eppendorf, Hamburg, Germany), who published >300 reports and high impact review articles on disseminating tumor cells, and Professor Leon Terstappen (Universiteit Twente, The Netherlands), developer of the FDA-approved benchmark CellSearch ® CTC detection system, are the pioneers in the field of blood-based cancer biomarkers CTC, circulating tumor cell; EFPIA, European Federation of Pharmaceutical Industries and Associations; FDA, Food and Drug Administration; SME, small- and medium-size enterprise Acknowledgments Under the authors’ conceptual direction, editorial assistance was provided by the Prime Medical Group (Knutsford, UK), and was supported by Bayer Poster presented at the American Association for Cancer Research Annual Meeting, 18–22 April 2015, Philadelphia, PA OBJECTIVES I – The science • CANCER-ID (www.CANCER-ID.eu) was established in 2014 • The consortium aims to validate technologies for blood-based biomarkers such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and microRNAs (miRNAs) for patient stratification, prediction of treatment response and early detection of developing resistance (Figure 1) • The focus is on technologies that have the potential to go beyond the current standards (e.g. CellSearch ® ) and that have the maturity to enter the market within the next 5–7 years • To prove multicenter applicability and the clinical utility of the consortium’s technologies and protocols, the validated assays will be deployed in controlled clinical studies (TRACERx, NCT01888601; NVALT17, NTR4410; SPECTAlung, NCT02214134; and patients receiving standard of care [SoC] treatment) in non-small cell lung cancer (NSCLC) and Her2-resistant metastatic breast cancer (Her2RMBC) – These indications were chosen based on the limited access to tumor biopsies, low number of CTCs and the relatively well characterized molecular subtypes in NSCLC – For comparison, Her2RMBC is ideally suited, as higher numbers of CTC can be expected, and resistance is a frequently observed phenomenon (developing under therapy or in treatment naïve-patients) • A key issue to be addressed in CANCER-ID is the definition of CTCs that includes tumor cells that do not express epithelial cell adhesion molecule (EpCAM), resulting in more precise methods for CTC enumeration and isolation II – The consortium • CANCER-ID is a unique network of experts in the fields of tumor biology, biomarker development, clinical sciences and bioinformatics with a total budget of €14.5 million • The consortium joins the forces of 17 academic groups (with 12 clinical sites), 6 EFPIA companies, 2 diagnostics companies, 6 SMEs with advanced technologies for CTC isolation or for complex data analysis and big data handling, and 2 non-profit organizations (Figure 2) • In order to fully exploit the synergies created by CANCER-ID, the consortium invites regulatory agencies and patient advocacy groups to take an active role in the project Breast n=177 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 35 40 45 50 10.9 months 21.9 months Log-rank p<0.0001 <5 CTCs n=89 (50%) ≥5 CTCs n=88 (50%) Probability of survival (%) Colorectal n=451 0 4 8 12 16 20 24 28 8.5 months ≥3 CTCs n=117 (26%) 19.1 months <3 CTCs n=334 (74%) Log-rank p<0.0001 Time from baseline (months) Prostate n=219 Log-rank p<0.0001 0 4 8 12 16 20 24 28 11.5 months ≥5 CTCs n=125 (57%) 21.7 months <5 CTCs n=94 (43%) Prognostic biomarker Predictive biomarker Responders Non-responders III – The project frame • The program is divided into 3 phases: pre-evaluation, technical assay validation and clinical validation (Figure 3) – During the pre-evaluation phase (year 1), 4 working groups will evaluate biomarker technologies, establish protocols and set the criteria to be met for any technology before moving to the next phase 33 partners: • 6 EFPIA companies (lead Bayer, co-lead Menarini) • 17 academic/clinical sites • 6 SMEs • 2 non-profit organizations • 2 non-SME/non-EFPIA Today* • Counting of CTCs indicates only patient survival • CTCs are currently merely a prognostic indicator Future • Into a source of predictive biomarkers • CTCs can be used to characterize genomic content • Specific markers guide effective personalized treatment 48% of recently approved oncology therapies have associated predictive biomarkers – In the 2nd stage (technical evaluation phase, year 1–4), the technologies identified as promising will be implemented at the sites of the consortium members where the optimized assays can be tested on patient samples – In the 3rd stage (clinical validation phase, year 3–5), validated assays will be implemented in prospective clinical studies enrolling patients with NSCLC and breast cancer, and in patients from these respective indications receiving SoC therapies KEY DELIVERABLES OF THE FULL PROJECT • Establish criteria for evaluation of different CTC isolation technologies • Sample collection and development of storage protocols for selected CTC isolation technologies, allowing shipment and biobanking for collection and analysis at different research sites • Comparison of methods for the molecular analysis of CTCs with respect to correlation with primary tumor material, clinical outcome, treatment response and ctDNA status of patients • Evaluation of different ctDNA/miRNA analysis methodologies, in terms of compatibility with sample collection and storage procedures as well as reproducibility in clinical samples • Development of database and data analysis infrastructure for correlative studies of CTCs, ctDNAs and miRNAs in clinical samples CTC, circulating tumor cell *Figure adapted from: McCormack R. Contemporary Issues in Circulating Tumor Cell Testing; ADAPT, 13–16 September 2010, Arlington, VA, USA Modified from: Circulating Tumor Cells [CTCs] and Cancer Stem Cells [CSCs] Market Report 2013; Research Trends and Clinical Utility Available at: http://www.SelectBiosciences.com/marketreports/