Depicting the evolving scenario of translational-guided drug development

Abstract

The development process of most important targeted agents currently used in oncologic clinical practice has unveiled the fact that using these types of drugs efficaciously is best supported by the availability of appropriate predictive biomarkers. Conversely, the magnitude of the effect obtained from administering such drugs to patients that respond to them on the basis of known biomarkers is likely to be diluted by concomitantly administering the drugs to an unselected patient population as well. This scenario could compromise the future of bona fide compounds due to the bias of non-selection when measuring drug benefit. Usually this agent-biomarker matching process and its approval based on positive indications of spent takes in identifying a rational biomarker, and then the back end process of validating the assay used to measure it. In this regard, Bando and collaborators compare, in this issue of the journal, the three methods for determining KRAS mutation in colorectal carcinoma with the goal of delineating the best test for this purpose. The history of the role of KRAS mutations in metastatic colorectal carcinoma well illustrates the diverse processes underlying predictive biomarker identification for antineoplastic targeted agents during the last 20 years, as reviewed in Table 1. Mutations in codons 12, 13, 61 and 126 of the KRAS protein were accepted as determinants of resistance to treatment with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) in colorectal carcinoma, years after cetuximab was first granted approval for its treatment by regulatory agencies [1, 2]. At that time, the development of anti-EGFR MoAbs was focused on EGFR amplification and overexpression as the primary characteristics for selecting patients for clinical trials [3, 4]. The discovery of the role of KRAS mutations redirected the development plans for these compounds, causing some ongoing clinical trials to be amended to exclude patients with KRAS activating mutations. When this new approach was instituted, clinical endpoints were successfully met, leading these drugs to broad approval in many clinical settings of colorectal carcinoma. This example and other successes resulting from the correct implementation of translational research data in clinical trials have shifted the panorama of drug development (Table 1). Accordingly, we have witnessed in the last decade clinical and translational research in oncology being brought closer together in a process intended to develop in parallel the best targeted agents and to align them with the best predictive biomarkers to guide their use starting with in early phases of the drug development process. This rapprochement bridging the gap between research and clinical application has modified both arenas. Such alignment is shown not only in the increasing number of research institutes linked to health care facilities but also by the changes that phase 1 clinical trial units have undergone [5]. In keeping with this trend, the search for biomarkers of drug effect (pharmacodynamic markers) and identification of potential target subpopulations of patients that, until recently, has occurred only in the last phases of drug G. Argiles (&) J. Rodon J. Tabernero Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain e-mail: gargiles@vhebron.net