Pharmacogenomics Testing in Phase I Oncology Clinical Trials: Constructive Criticism Is Warranted.

Abstract

Simple SummaryPhase I clinical trials are a cornerstone of pharmaceutical development in oncology. Many studies have now attempted to incorporate pharmacogenomics into phase I studies; however, many of these studies have fundamental flaws that that preclude interpretation and application of their findings. Study populations are often small and heterogeneous with multiple disease states, multiple dose levels, and prior therapies. Genetic testing typically includes few variants in candidate genes that do no encapsulate the full range of phenotypic variability in protein function. Moreover, a plurality of these studies do not present scientifically robust clinical or preclinical justification for undertaking pharmacogenomics studies. A significant amount of progress in understanding pharmacogenomic variability has occurred since pharmacogenomics approaches first began appearing in the literature. This progress can be immediately leveraged for the vast majority of Phase I studies. The purpose of this review is to summarize the current literature pertaining to Phase I incorporation of pharmacogenomics studies, analyze potential flaws in study design, and suggest approaches that can improve design of future scientific efforts.While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24–31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.