Dose Optimization in Oncology Drug Development: Risk Factors for Postmarketing Requirements and Commitments.

Optimal dosing of oncological drugs is historically determined based on the "higher is better" paradigm. However, a paradigm shift in optimal dose selection has occurred in the development of new modalities, including molecularly targeted drugs, antibody drugs, and immunotherapies. In 2021, Project Optimus was launched by the Food and Drug Administration Oncology Center of Excellence to reform the dose optimization and dose selection paradigm in oncology drug development. In August 2024, "Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases" was published, encouraging randomized evaluation of the benefit/risk profile of a range of doses before initiating a registration trial. Although Project Optimus offers general guidance on dose optimization, it does not specify which early clinical data requires a more cautious approach to dose optimization. This is the first comprehensive study to investigate newly approved oncology drugs by the FDA over a long period and to identify the risk factors for postmarketing requirement or commitment to dose optimization, using logistic regression analysis. Our findings show that when the labeled dose is the maximum tolerated dose, the percentage of adverse reactions leading to treatment discontinuation is increased, and an exposure-safety relationship is established, the risk for postmarketing requirement or commitment to dose optimization is increased. Our study will provide actionable, data-driven insights into dose optimization strategies by objectively and quantitatively evaluating risk factors. These findings will serve as valuable guidance for designing more effective early-phase trials, complementing the FDA Project Optimus guidance.