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The ASCO Post – How to Get the Dose Right

The ASCO Post – How to Get the Dose Right

OCE Insights is an occasional column developed for The ASCO Post by members of the Oncology Center of Excellence (OCE) at the U.S. Food and Drug Administration (FDA). In this installment, Mirat Shah, MD, of the Office of Oncologic Diseases, Center for Drug Evaluation and Research, FDA; Atiqur Rahman, PhD, Director, Division of Cancer Pharmacology II, Center for Drug Evaluation and Research, FDA; Marc R. Theoret, MD, Deputy Director, OCE; and Richard Pazdur, MD, Director, OCE, discuss the issue of dose selection in oncology therapies and Project Optimus, an FDA initiative seeking to change the dosing paradigm for oncology drugs.

October 2021, we published a perspective titled “The Drug Dosing Conundrum in Oncology: When Less Is More,” emphasizing the need for better dose selection for oncology drugs.We highlighted that dose selection for oncology drugs is often based on a “more is better” paradigm, which can lead to doses that are inadequately characterized prior to a registration trial. Doses for approved drugs that have not been optimized may cause toxicity that could be preventable and high rates of dose interruptions, reductions, and discontinuations.

Selecting the highest dose tolerated in early drug development, rather than properly characterizing the dose, is a prevailing approach in cancer drug development due to the disease’s life-threatening nature and the need to get new treatments to patients quickly. It is perpetuated by decades of experience with cytotoxic chemotherapies that are characterized by steep dose-response relationships for efficacy and safety and a narrow therapeutic index. Based on these properties—the highest dose a patient could “tolerate” assessed over a short period—would be chosen for a registration trial and eventual approval. This dose-selection paradigm, which perhaps should also have been questioned during the development of some chemotherapies, particularly needs to change now, so patients can receive maximal benefit from new oncology therapies.

Need for Dose Optimization

Rather than indiscriminately attacking rapidly dividing cells, current oncology therapies are more selective for specific targets, offering the promise of substantial clinical benefit with less toxicity. Compared with cytotoxic chemotherapies, these targeted therapies, such as kinase inhibitors and monoclonal antibodies, may have a wider therapeutic index, meaning that patients could experience similar clinical benefits at a broad range of doses, and a dose that causes “dose-limiting” toxicity may never be reached.Due to this property, it does not make sense to primarily base dose selection on identification of the maximum tolerated dose or highest dose tested.

Although these targeted therapies are less likely to cause traditional dose-limiting toxicities, they are still associated with a range of symptomatic toxicities (eg, diarrhea) and more serious toxicities (eg, pneumonitis), which are important to consider in dose selection. Unfortunately, high rates of dose modifications at approved doses for targeted therapies are common, and sometimes the recommended doses of approved drugs need to be revised post approval due to safety concerns.

Unlike cytotoxic chemotherapies that patients may receive for a few cycles, patients take certain targeted drugs (eg, oral kinase inhibitors) chronically. Attention to long-term tolerability is important, so patients do not unnecessarily opt out of an efficacious therapy due to avoidable symptomatic toxicities. Furthermore, not every targeted drug that enters a phase I clinical trial receives marketing approval, and poor dose optimization may be one reason for that failure. A focus on dose optimization as an essential component of oncology drug development is necessary to realize the promise of targeted therapies.

Establishment of Project Optimus

For at least the past decade, patients, advocacy groups, academic oncologists, representatives of drug companies, and regulators have been calling for change to the prevailing dosing paradigm rooted in cytotoxic chemotherapeutics.2 The FDA and others have also led efforts to educate key stakeholders regarding methods of dose optimization for targeted therapies. Despite broad awareness of the issue of poor dose selection for oncology drugs, there has not been widespread implementation of new approaches to dose optimization.

In 2021, the FDA’s Oncology Center of Excellence established Project Optimus to take a more proactive role in changing the dosing paradigm in oncology.3 This project brings together scientists with expertise in clinical pharmacology, medical oncology, biostatistics, pharmacology/toxicology, and other areas from across the FDA and outside the agency to address how best to select doses for oncology drugs. Its mission is to ensure that doses of oncology drugs are optimized to maximize efficacy as well as safety and tolerability.

We are working to learn, educate, innovate, and collaborate with patients and the oncology community to implement dose selection strategies that can meet this mission. Toward this goal, we are co-hosting a workshop entitled “Getting the Dose Right: Optimizing Dose Selection Strategies in Oncology” with ASCO, which will take place virtually on May 3 and May 5, 2022.4 The workshop will discuss challenges to better dose optimization and highlight strategies to achieve dose optimization for oncology drugs.

Key Principles for Dose Optimization

To identify an optimized dose, the goal in early dosing trials needs to shift from the identification and selection of only the maximum tolerated dose for evaluation in registration trials to the selection of several doses for further evaluation based on pharmacokinetic and pharmacodynamic data, as well as preliminary information regarding activity, safety, and tolerability. The doses can be evaluated more thoroughly, preferably early in development with randomized evaluations of multiple doses, to obtain a more comprehensive assessment of dose-response and exposure-response relationships for efficacy, safety, and tolerability. These evaluations will, in turn, inform the dose or doses for a registration trial and eventual drug approval.

Rather than evaluation of life-threatening toxicities alone, safety and tolerability assessments could incorporate dose modifications and frequencies of low-grade symptomatic toxicities. Randomization is important to determine whether observed differences in antitumor activity or adverse reactions are due to dissimilarities in the underlying patient populations. It is important to note that although these strategies are uncommon in oncology drug development, they are not new and have successfully supported the development of drugs for other diseases.

We strongly believe that the best setting for dose optimization is prior to drug approval. Focusing on dose optimization starting early in clinical development rather than in the postmarketing setting will allow more efficient identification of an optimal dose. This will prevent exposure of a large number of patients to a dose that may cause excessive toxicity or may be less efficacious. Additionally, early dose optimization of one drug may allow more streamlined development of combination therapies that may ultimately have better antitumor activity.

We encourage drug companies to plan for dose optimization early and to design and conduct trials intended for dose optimization. Despite significant advances in cancer therapeutics, there remains a great unmet medical need for better therapies for patients, and speed is still vital. With proactive planning and open communication, the rapid availability of promising new therapies can be achieved congruently with better dose selection.

Our role as regulators includes communicating expectations and providing guidance to drug makers. We urge drug companies to share their plans with the FDA and provide updated data throughout clinical development. We are open to providing advice tailored to the specific drug development program at all stages, including before a first-in-human trial is initiated. The best approaches for dose optimization may vary based on the type of drug and disease setting, and we encourage innovation in strategies to meet our expectations for dose optimization.

Scientific progress has led to the development of entire new classes of targeted drugs with different properties from cytotoxic chemotherapies. Due to these new therapies, many patients, including those with advanced cancer, are living longer. Patients also want to live well, and they expect more tolerable drugs. Dosing strategies need to evolve, based on the science of current therapies and designed to meet patients’ expectations for tolerability. We recognize that characterizing several doses rather than choosing the highest dose tolerated or tested represents a paradigm shift in oncology. By working collaboratively, oncology can bring about this long overdue change to realize the full potential of targeted drugs to maximize benefit for patients.

DISCLOSURE: The authors reported no conflicts of interest.


1. Shah M, Rahman A, Theoret MR, et al: The drug-dosing conundrum in oncology: When less is more. N Engl J Med 385:1445-1447, 2021.

2. Friends of Cancer Research: Optimizing dosing in oncology drug development. Friends of Cancer Research Annual Meeting 2021. Available at Accessed April 11, 2022.

3. FDA Oncology Center of Excellence: Project Optimus. Available at Accessed April 11, 2022.

4. U.S. Food and Drug Administration: Getting the dose right: Optimizing dose selection strategies in oncology: An FDA-ASCO virtual workshop. Available at Accessed April 11, 2022.