Biomarkers in early drug development


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Josep Tabernero1
1Val d'Hebron University Hospital, Barcelona, Spain

Abstract

Rational and efficient development of new molecular cancer therapeutics requires discovery, validation, and implementation of informative biomarkers. The potential for biomarker studies to affect the clinical development strategy may be greatest in appropriately designed early trials by identifying patients likely to benefit or at risk for toxicity - predictive marker - or assisting in optimal dose determination - pharmacodynamic marker. For proper biomarker development, investigators need strong preliminary data linking biomarker changes to agent effects, robust technologies and certified assays suitable for scientific and clinical interpretation, in addition to well-defined specimen collection, processing and storage methodologies and procedures. Decisions regarding whether to evaluate the biomarker prospectively or retrospectively, whether to collect tumour or a surrogate tissue (CTCs or cfDNA), whether to retrieve archival tumour samples or obtain recent fresh biopsies and also whether to incorporate functional imaging studies as biomarker measurements are important steps in the process of early drug trial design. In phase I trials, exploratory pharmacodynamic biomarkers can be studied at selected doses to confirm effects on target, decide whether to escalate or expand a dose level. Additionally, biomarkers can have an integral role within the clinical trial when used to determine eligibility or to stratify patients to different arms of the trial. The preselection process is a key challenge and pre-analytical and analytic issues need to be addressed before clinical studies are initiated to ensure valid scientific inference of trial results. These trials provide a proof-of-concept opportunity that can encourage further research with the drug or target. Prioritization based on solid science is required when investigators aim to terminate patient enrolment because of lack of activity in biomarker-defined population. Furthermore, improved operational efficiency, coordinated team work and financial resources for prescreening procedures need to be assured for the ultimate goal of personalized oncology drug development.