Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

Abstract

Project Optimus is a U.S. Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. While there is much promise in this initiative, there are several challenges that need to be addressed, including multi‐dimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long‐term tolerability beyond dose‐limiting toxicities, and the lack of reliable biomarkers for long‐term efficacy. Through the lens of Totality of Evidence (ToE) and with the mindset of model‐informed drug development (MIDD), we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.

Moving the Needle for Oncology Dose Optimization: A Call for Action

“…Project Optimus offers a pivotal opportunity to reform the oncology dosing paradigm using a robust quantitative clinical pharmacology framework. 2,3,14,[30][31][32][33] By integrating a model development lifecycle, Bayesian trial designs, and a learning-and-confirming mindset across the development spectrum, this framework may be used to prospectively guide dose optimization.…”

“…Project Optimus is a major FDA initiative aimed at ensuring dose optimization in oncology drug development, moving away from the maximum tolerated dose paradigm and prospectively characterizing dose response for efficacy and safety for patient-focused maximization of benefit vs. risk. [1][2][3] Mitigating toxicities and enhancing overall benefit vs. risk of oncology therapies necessitates dose optimization with a commitment to evaluation of innovative dosing paradigms including individualized approaches, where appropriate. This requires the quantitative integration of pharmacological mechanism of action, efficacy, and safety in the context of associated population variability.…”

Moving the needle for oncology dose optimization: A call for action

“…Project Optimus offers a pivotal opportunity to reform the oncology dosing paradigm using a robust quantitative clinical pharmacology framework. 2 , 3 , 14 , 30 , 31 , 32 , 33 By integrating a model development lifecycle, Bayesian trial designs, and a learning‐and‐confirming mindset across the development spectrum, this framework may be used to prospectively guide dose optimization.…”

“…Project Optimus is a major FDA initiative aimed at ensuring dose optimization in oncology drug development, moving away from the maximum tolerated dose paradigm and prospectively characterizing dose–response for efficacy and safety for patient‐focused maximization of benefit vs. risk. 1 , 2 , 3 Mitigating toxicities and enhancing the overall benefit vs. risk of oncology therapies necessitates dose optimization with a commitment to evaluation of innovative dosing paradigms including individualized approaches, where appropriate. This requires the quantitative integration of pharmacological mechanisms of action, efficacy, and safety in the context of associated population variability.…”

Moving the needle for oncology dose optimization: A call for action

“…Project Optimus is a major FDA initiative aimed at ensuring dose optimization in oncology drug development, moving away from the maximum tolerated dose paradigm and prospectively characterizing dose–response for efficacy and safety for patient‐focused maximization of benefit versus risk. 1 , 2 , 3 Mitigating toxicities and enhancing overall benefit versus risk of oncology therapies necessitates dose optimization with commitment to evaluation of innovative dosing paradigms including individualized approaches, where appropriate. This requires the quantitative integration of pharmacological mechanism of action, efficacy, and safety in the context of associated population variability.…”