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

Area of Science:

• Oncology
• Clinical Pharmacology
• Genetics

Background:

• Pharmacogenetics-based patient stratification can enhance clinical trial success by identifying responsive patients and minimizing toxicity.
• However, current phase I oncology study designs often limit the conclusions that can be drawn from pharmacogenetic data.

Purpose of the Study:

• To evaluate the extent and limitations of pharmacogenetics endpoints in published phase I oncology studies.
• To identify opportunities for improving future phase I study designs.

Main Methods:

• A comprehensive review of phase I oncology studies with pharmacogenetics endpoints was conducted.
• Studies were analyzed for their evaluation of toxicity, response, progression-free survival (PFS), and pharmacokinetics.
• The number of genotype-directed studies and the variants evaluated were assessed.

Main Results:

• Out of over 10,000 phase I oncology studies, fewer than 1% incorporate pharmacogenetics.
• Eighty-four studies with pharmacogenetics endpoints were identified, focusing mainly on topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents.
• Only eight studies were genotype-directed, and most analyzed small patient cohorts (median 28) with limited pharmacogenetic variants and hypothesis justification.

Conclusions:

• Phase I oncology studies have significant limitations for robust pharmacogenetics analysis due to small sample sizes, population heterogeneity, and limited variant evaluation.
• Future phase I study designs must incorporate these factors to optimize success and address key scientific questions in personalized oncology.