During its virtual Annual Meeting 2021 held on November 9 and 10, Friends of Cancer Research (Friends) urged all stakeholders in the cancer community to work together to optimize dosing in oncology drug development to maximize benefit for patients and reduce treatment toxicity, and to abandon the “more is better” notion that a higher dose leads to higher efficacy.
During the meeting, Friends released a white paper, “Optimizing Dosing in Oncology Drug Development,” which provides strategies to overcome challenges associated with the launch of appropriate oncology dose-finding studies to understand the therapeutic window of a drug and to ensure that all patients with cancer receive optimal care.
“Over the past decades, life-changing therapy, such as targeted therapy, immunotherapy, and chimeric antigen receptor T-cell therapy, have revolutionized cancer treatment.…However, the prevailing mindset in drug development that ‘more is better’ is loud and clear from our patients: the drugs are too toxic and the physicians are tied to the dosing schedule in the package insert that provides a reality check for all of us,” said Nam Atiqur Rahman, PhD, a coauthor of the white paper and Director, Division of Cancer Pharmacology II, Office of Clinical Pharmacology at the U.S. Food and Drug Administration (FDA), during the meeting. “Dose optimization remains the pitfall in the development of cancer therapy.”
Currently, cancer drugs are tested and approved by the FDA for use at the maximum tolerated dose, which is unlike how most drugs outside of oncology are evaluated in randomized dose-ranging trials that support a broader understanding of the impact of different doses on efficacy and toxicity. Since maximum tolerated dose was initially developed for systemic chemotherapies, in this era of new molecular targeted agents and immunotherapies, according to the white paper, oncology drug dose-finding approaches should be revised. Additionally, new dose-optimization guidance for oncology drugs may be coming soon from the FDA.
Recently, the FDA announced it is working on a new guidance called Project Optimus, which will provide drug manufacturers with general advice and recommendations on dose optimization for oncology drugs. During the Friends of Cancer Research Annual Meeting, Mark J. Ratain, MD, FASCO, a coauthor of the Friends white paper and Leon O. Jacobson Professor of Medicine; Director, Center for Personalized Therapeutics; Associate Director, Clinical Sciences at the Comprehensive Cancer Center; and Chief, Hospital Pharmacology at the University of Chicago Medicine, moderated a panel discussion called “Maximizing Benefit and Improving Tolerability for Patients Through Dose Optimization.” The panel members included Lokesh Jain, PhD, Senior Director, Quantitative Pharmacology & Pharmacometrics, Oncology Clinical Development at Merck; Anne Loeser, a metastatic breast cancer survivor and Founder of the Patient-Centered Dosing Initiative; Mirat Shah, MD, Clinical Reviewer, Breast and Gynecologic Malignancies Team at the FDA’s Office of Oncologic Diseases at the Center for Drug Evaluation and Research (CDER); and Laurie Strawn, PhD, Senior Director, Worldwide Safety and Regulatory at Pfizer.
The panel members discussed a range of topics on drug-dosing optimization, including the development of Project Optimus and how dose optimization can benefit patients.
“The focus of Project Optimus right now is to emphasize the importance of dose optimization early as a component of free-market drug development,” said Dr. Shah. “I spend a lot of time talking to patients in the clinic about all the toxicities they are experiencing from treatment… and it’s very impactful in terms of quality of life, but really is necessitating dosage or options and a lot of time away from therapy. So, I think this emphasis on dose optimization is long overdue.”
Ms. Loeser agreed that reducing drug toxicities will have a profound effect on patients’ quality of life and on their ability to maintain their treatment protocol, especially for those patients with incurable cancers that may need lifelong treatment.
“First, these patients may no longer need to skip a scheduled treatment or completely stop a working treatment as often as they do now,” said Ms. Loeser. “Second, the need for acute care, such as emergency room visits, may diminish. And, finally, these patients may not suffer as many or as severe cumulative side effects as they proceed from one treatment to the next. This in turn may allow them to take full advantage of a complete list of therapies that are available to them, instead of opting out of treatment prematurely because their bodies can no longer withstand the toxicity.”
The Friends white paper offered these suggestions to improve oncology care by decreasing toxicities while maintaining efficacy and allowing more patients to benefit from treatments for longer periods of time.
- Rather than using maximum tolerated dose as the default approach, ideally, the preregistrational dose-finding study would be randomized, compare at least two doses, and confirm the dose selected for the registrational trial, which is the dose that maximizes benefit/risk by measuring efficacy among a sizable number of patients.
- Continued education will support a realization of the value of these studies in the premarket setting. Patients and providers should understand that treatments with higher doses are not always better and may, in fact, lead to increased side effects without the added benefit of higher activity.
- Sponsors should conduct preclinical research that supports a basic understanding of pharmacology based on suggestions from CDER’s Manual of Policies and Procedures and guidance documents. After performing preclinical work and establishing necessary data, sponsors should engage with the FDA to refine and build the dose-finding trial.
- The overarching goal is that dose-finding studies will be part of standard oncology drug development in the premarket setting to allow delivery of efficacious and tolerable doses to patients at initial marketing approval of a new drug.
For more information on the white paper, visit friendsofcancerresearch.org.