Brad Davidson, PhD

INNOVATION IN ONCOLOGY DRUG DEVELOPMENT has occurred at a breakneck pace in recent years, illustrated by 60 new Food and Drug Administration (FDA) oncology drug approvals in 2024, comprising new uses for established drugs as well as novel therapeutics. While these approvals highlight the excellent work of researchers, drug developers and regulators, patients have begun calling for changes to a crucial aspect of drug development: dosing.

In the past, when chemotherapies were the primary cancer drugs being developed, treating patients with as much of a drug as possible was thought to be best since it would likely lead to more antitumor activity. As a result, the dose evaluated in oncology clinical trials and subsequently approved was traditionally the maximum tolerated dose. In the current era of precision medicine, however, most oncology drugs under development are targeted therapies. While chemotherapies damage cancerous and healthy cells, targeted therapies leverage each tumor’s specific molecular characteristics to eliminate cancer cells while mostly sparing the rest of the body. At a certain dose, targeted therapies saturate their target molecule—meaning more drug will not lead to more antitumor activity. Past this point, further dose escalation only adds more toxicity for the patient.

Drug development programs have been slow to modify their procedures to account for this difference, meaning maximum tolerated dose is still frequently used for both investigational and approved targeted therapies. While these treatments have transformed cancer care for the better, this means some patients are experiencing unnecessary toxicities that could potentially be eased without sacrificing effectiveness by using lower doses. Multiple FDA initiatives to address this discrepancy are underway. For example, Project Optimus, led by the FDA’s Oncology Center of Excellence, seeks to increase education and innovation in oncology dose optimization through guidance documents, workshops and public meetings. Other FDA programs also focus on optimizing drug doses, such as the Fit-for-Purpose Initiative and the Model-Informed Drug Development Paired Meeting Program, both of which encourage the use of innovative dose optimization methods through direct advising on drug development methodology.

Among these efforts was a 2024 workshop co-led by the American Association for Cancer Research (AACR) and the FDA’s Office of Clinical Pharmacology that sought to identify, outline and clarify best practices for dose optimization in clinical drug development. A forthcoming series of three articles in the AACR journal Clinical Cancer Research will describe these approaches in detail. (The AACR also publishes Cancer Today.)

A key takeaway from the workshop and the Clinical Cancer Research articles is the need to implement case-by-case drug development instead of defaulting to the one-size-fits-all approach of maximum tolerated dose. The articles highlight strategies to generate and use as much available data as possible to determine optimized doses. Among these approaches are recently developed clinical trial designs that flexibly adjust dosing levels throughout the trial to ensure all patients receive the most informed dose possible. The trial designs also collect long-term patient outcomes even in studies that typically only evaluate short-term outcomes. The articles also highlight modeling and simulation techniques that synthesize data across phases of drug development to identify doses that may most benefit patients. More information can be found on the workshop website and in the journal articles, which will be published on the Clinical Cancer Research website at a later date.

While the workshop and the recommendations summarized in the forthcoming papers represent progress, work remains to be done. For example, the FDA has required additional dosing-related studies on more than 50% of recently approved oncology drugs, many of which will test whether a lower dose could provide similar efficacy with less toxicity. The AACR and the FDA will continue to spur improvements in drug development by collaborating with various partners to improve cancer therapies and thereby save and enhance patients’ lives.

BRAD DAVIDSON, PhD, is a regulatory science and policy analyst for the American Association for Cancer Research (AACR).