Abstract 2514: Refining oncology dose selection: A framework for tailored dose optimization in the era of targeted and immunotherapies

Abstract Historically, oncology dose selection was driven by the identification of the maximum tolerated dose, often resulting in significant toxicity. The advent of molecular targeted therapies and immunotherapies has created opportunities to achieve similar efficacy at a lower, more tolerable dose. Recent FDA draft guidance highlights the importance of dose optimization in drug development. Building on this, we present a novel framework categorizing drugs into four molecular classes based on their mechanisms of action: (1) small molecule targeted therapies and antibody-drug conjugates, (2) large molecule antagonists, (3) cancer immunotherapy agonists, and (4) molecules with limited or no single-agent activity. Unique considerations and strategies for dose optimization are detailed for each class, supported by case examples. We propose integrating proof of activity as a gating criterion for dose expansion to inform robust dose decisions and maximize the use of patient resources. This perspective underscores the integration of preclinical and clinical data—including pharmacokinetics, pharmacodynamics, and patient-reported outcomes—combined with quantitative pharmacology and statistical modeling, to optimize doses effectively while balancing efficacy and safety. While no one-size-fits-all approach exists, this tailored guidance for specific mechanistic classes provides balanced approaches to dose optimization that ultimately enhance the probability of success in drug development. Citation Format: Neekesh Dharia, Jiawen Zhu, Amy Schroeder, Sabine Frank, Christophe Boetsch, Candice Jamois, Nastya Kassir, Koorosh Korfi, Elizabeth Punnoose, Anjali Vaze, Peter Trask, Pritti Gosai, Jane Fridlyand, Chunze Li. Refining oncology dose selection: A framework for tailored dose optimization in the era of targeted and immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2514.