A new study calls for a paradigm shift in how cancer drug dosages are determined, concluding that the long-standing practice of using the “maximum tolerated dose” (MTD) may be outdated, harmful to patients, and ill-suited for modern cancer therapies.
“The Totality of the Evidence: Optimizing Dosage Selection Strategies in Oncology,” a report published July 24 in the Journal of Clinical Oncology, is the result of a joint collaboration between ASCO and the U.S. Food and Drug Administration (FDA). It identifies critical shortcomings in the current MTD-centric paradigm and outlines five guiding principles for optimizing cancer therapy dosage moving forward.
“We are seeing a clear and pressing need to modernize our approach,” said R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA, FASCO, Vice President, Clinical Research & Executive Director, Woodruff Industry Sponsored Clinical Trials, Woodruff Health Sciences Center; and Professor, Hematology and Medical Oncology and Pharmacology and Chemical Biology, Emory University School of Medicine, who co-chaired Getting the Dose Right: Optimizing Dose Selection Strategies in Oncology, a series of FDA-ASCO workshops held in 2022 and 2023. “For today’s more complex therapies, a higher dose often does not mean a better cancer outcome, but it almost always means more toxicity.”
R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA, FASCO
The report highlights the negative impact the MTD approach may have on patients, citing a survey where 86% of patients with metastatic breast cancer reported significant treatment-related side effects, often leading to dose reductions. It also points to the burden on oncologists, who often make decisions to lower prescribed doses to protect their patients from side effects without sufficient evidence to understand the trade-offs between safety and efficacy.
The report emphasizes that waiting to study dosages in the post-approval setting is an inadequate solution, as these studies often take years to complete, leaving many patients exposed to suboptimal dosages in the interim. Therefore, it advocates for “dose optimization”—finding the dose that best balances benefit and risk—to be completed before a drug receives initial approval.
The report outlines five ways drug developers, researchers, and regulators can optimize dosage: (1) Collect and use broader safety and patient-reported data beyond early severe toxicities; (2) tailor trial designs for drug type and patient population to better understand variability; (3) use modern, randomized trial designs that assess multiple dosages; (4) broaden eligibility criteria to reflect real-world populations; and (5) refine pharmacologic analyses to link dose, exposure, and outcomes.
© American Society of Clinical Oncology. ASCO in Action. July 24, 2025. All rights reserved.
