In a perspective article published in The New England Journal of Medicine entitled “The Drug-Dosing Conundrum in Oncology—When Less Is More,” four authors from the U.S. Food and Drug Administration (FDA) argue for the need to jettison the “more is better” paradigm in dose selection for oncology drugs that characterized the development of cytotoxic agents. They also discuss the need to adopt more detailed and robust procedures for identifying optimal doses of targeted and biologic agents to be tested in registration trials.
‘More Is Better’ Paradigm
As noted by the authors (Mirat Shah, MD; Atiqur Rahman, PhD; Marc R. Theoret, MD; and Richard Pazdur, MD), the practice of identifying the maximum tolerated dose of an oncology drug as the dose to be moved forward in clinical trials—the “more is better” paradigm characteristic of dose selection for cytotoxic agents—reflects both the desire to hasten the availability of drugs for patients with limited treatment options and the belief that higher doses will exert greater antitumor activity. The approach often involves testing of escalating doses in small groups of patients for a single treatment cycle.
Optimal Dose Selection for Targeted and Biologic Agents
In recognition of the different mechanisms of action and toxicities of targeted and biologic agents and the often-prolonged durations of therapy with these agents, the authors argued that identifying dose regimens to be assessed in registration trials should be a more intensive process that should include the following elements:
- Collection of pharmacokinetic and pharmacodynamic data early in clinical development
- Selection of two or more doses during initial dose-escalation testing on the basis of exposure, target saturation, and other pharmacodynamic markers to be compared in a subsequent randomized trial.
They noted that randomized trials can also be used to guide dose selection in cases in which sponsors intend to submit a drug for approval on the basis of a single-group trial. In this case, an early randomized trial assessing response rates for several doses can include a prespecified dose-response analysis to guide dose selection. The trial can then be continued as a single-group trial, including patients from the randomized trial who receive the selected dose and a group of newly enrolled patients to be treated at that dose.
Examples of Less and More Adequate Dose Selection
The authors provided examples of recent cases in which some form of the “more is better” approach resulted in approval of dose regimens of oncology drugs that had to be changed post approval to reduce drug exposure in order to reduce the risk of toxicities; these include the small-molecule agents ceritinib (to reduce gastrointestinal adverse effects), dasatinib (to reduce hematologic toxic effects and fluid retention), niraparib (to reduce thrombocytopenia in patients with lower platelet count or lower body weight), and ponatinib (to reduce vascular occlusive events).
They observed that a more thorough evaluation of optimal dosing was undertaken for several PD-1 inhibitors during early development, including early evaluation of multiple dose regimens in randomized and nonrandomized cohorts. The studies included extensive clinical pharmacologic analyses that permitted better understanding of factors such as receptor occupancy and the relationship between exposure and response in terms of both efficacy and safety. On the part of pembrolizumab and nivolumab, for example, such efforts led sponsors to select doses to be evaluated in registration trials that were lower than the highest tested and that nevertheless preserved efficacy.
The authors concluded, “The concept that higher drug doses would necessarily be associated with greater efficacy, which was pervasive in cytotoxic drug development for decades, brought its own challenges. Oncology has benefited from more than 70 years of cytotoxic drug development, but agents with new mechanisms of action and greater efficacy and different safety profiles than older drugs, as well as those that are expected to be used long-term, require a reexamination of past practices. Sponsors should carefully evaluate exposure-response, efficacy, and safety data from early trials to inform dose selection, rather than automatically selecting the maximum tolerated dose. The answer to the dose-selection conundrum may sometimes be that less is more.”
Disclosure: For full disclosures of the study authors, visit nejm.org.
