Pharmacodynamic Biomarkers: Falling Short of the Mark?

Abstract

In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treatedtypically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail.

Biorepositories and Biomarker Development: Regulatory Challenges

“…The American Society of Clinical Oncology estimates that routinely testing people with colon cancer for mutations in the K-RAS oncogene would save at least US $600 million a year [6,7]. This may necessitate to consider-among others-predictive as well as pharmacodynamics biomarker for selection of patients or pharmacodynamic effects of a drug, respectively [8].…”

Non-small cell lung cancer biomarkers and targeted therapy - two faces of the same coin fostered by nanotechnology

“…Predictive biomarkers provide information on the efficiency likelihood of a certain treatment; whereas prognostic biomarkers provide information about patient's disease outcome independently of any cancer therapeutics. Some biomarkers can be simultaneously predictive and prognostic [28,30,31]. The information yielded by biomarkers is crucial for the selection of an adequate therapy, leading to personalized and targeted cancer therapy [32].…”

Using Pharmacogene Polymorphism Panels to Detect Germline Pharmacodynamic Markers in Oncology

“…For PK studies, drug exposure represents a relatively easily collected phenotype; however, in vivo PD phenotypes are less well established, as described in this CCR Focus section by Gainor and colleagues (13). The current NCI clinical trials measures of toxicity are ordinal in nature and do not allow for accurate quantitation of phenotype severity or complexity.…”