FDA–AACR Strategies for Optimizing Dosages for Oncology Drug Products: Early-Phase Trials Using Innovative Trial Designs and Biomarkers

Dosage selection for oncology drugs has traditionally relied on initial dose-finding trials to determine an MTD, which is then further evaluated in approval-supporting registrational trials. Although this approach may have established optimized dosages for cytotoxic chemotherapeutics, many modern oncology drugs developed through this approach have been poorly optimized, requiring additional dosage optimization efforts in the postmarket setting. Recent initiatives of the FDA outline the unsustainability of this approach, instead recommending the identification of a potentially optimized dosage at earlier stages through a direct comparison of multiple dosages before marketing application submission. The selection of dosages for further investigation outside of the MTD requires fit-for-purpose techniques that address the specific promises and concerns of the drug under investigation. Although such strategies have been developed, they are currently rarely applied in favor of the MTD paradigm. Innovative trial elements, including various integral, integrated, and exploratory biomarkers as well as backfill and randomized dose-expansion cohorts, represent potential avenues to create and leverage additional data and thereby make more informed dosing decisions. Additionally, modeling approaches such as clinical utility index can integrate these disparate datatypes into a single metric, facilitating more quantitative selection. This article, the second in a series of three articles addressing different stages of dose optimization, outlines best practices and areas for further development with regard to innovative techniques for the selection of dosages for further evaluation prior to final dosage selection for registrational trials in oncology.