There is much to be learned and progress to be made in all these efforts toward the optimization of tolerability, safety, and efficacy of oncologic therapies.
One of the many rewarding aspects of working in oncology involves rectifying problems that impede treatment tolerability or quality patient care and treatment outcomes. Many instances require drug dose and/or schedule alterations for which available guidance in the product label or published literature is insufficient to satisfactorily resolve treatment toxicities without potentially compromising therapeutic goals. Because numerous older anticancer agents have outdated drug labeling that is not consistent with current knowledge and practice, clinicians must rely on other resources to guide treatment decisions. This problem is widely acknowledged, and we have now seen the first labeling revision approved through the Project Renewal initiative, with the release in December 2022 of updated prescribing information for capecitabine (Xeloda; Genentech), which is among approximately 30 to 40 long-standing oncology agents slated for review as part of this initiative.
Project Renewal is one of several health initiatives created by the FDA Oncology Center of Excellence (OCE), which was established in 2017 to advance the development and regulation of oncology products. Project Renewal aims to address the problem of outdated labeling of older oncology drugs by establishing processes and procedures to inform regulatory decisions and update prescribing and patient information using publicly available scientific evidence. Because the pace and amount of evidence acquired after a drug is approved can be substantial, the resources and workload required to keep drug labels updated are enormous. However, the OCE is working to accomplish this. All stakeholders, including oncologists, pharmacists, nurses, patients, and drug manufacturers, can contribute to these efforts.
Project Optimus is another important OCE initiative to reform the dose optimization and dose selection paradigm in oncology. Most hematologyoncology pharmacists have worked with patients experiencing intolerable treatment toxicities, which are frequently consequences of the “real-world utilization” of drug regimens that were not optimally developed prior to their FDA approval. As such, patients may be unable to benefit from potentially life-prolonging therapies, particularly molecularly targeted therapies, for which the current paradigm for treatment doses and schedules has historically been based on cytotoxic therapeutics.
Analyses of oncologic new molecular entities (NMEs) or original biologic applications approved in the past 10 to 15 years reveal that dose ranging or optimization for most agents did not occur beyond phase 1 dose escalation. Furthermore, only about 15% of the NMEs reviewed were issued a post-marketing requirement (PMR) as a condition of approval to improve their benefit-to-risk ratio profile. Although many of these PMRs are ongoing, they have resulted in several drug dosage changes. For example, earlier this year, the FDA released a draft guidance for industry for identifying optimal doses of drugs and biological products to treat oncologic diseases prior to applying for approval. By integrating dose optimization earlier during and throughout drug development, drug dose determinations will be more likely to maximize safety and tolerability in addition to efficacy.
The high costs of these new therapies, however, continue to strain health care budgets and present challenges to patient access to therapies. Examples of these include immune checkpoint inhibitors, for which alternative dosing strategies have been proposed to reduce costs. Approved dosing regimens for drugs such as pembrolizumab (Keytruda; Merck & Co) and nivolumab (Opdivo; Bristol Myers Squibb), which were initially weight based, were subsequently approved as fixed, or “flat,” doses—this is now commonly employed in practice. Although there are many benefits to fixed dosing, drug exposure is typically greater in patients with lower body weight compared with lower exposure in patients with higher body weight. Thus, for a considerable proportion of patients, fixed dosing will be more expensive than weight-based dosing and drug exposures will be higher than required for maximum antitumor efficacy. Although dose-rounding and vial sharing, among other practices to reduce drug costs, have been adopted into oncology programs for years, additional strategies such as extending dosing intervals, personalized weight-based dosing, hybrid dosing (eg, administering a weight-based dose with a maximum fixed dose), and limiting duration of treatment have been proposed. Pharmacokinetic and pharmacodynamic modeling and simulations and cost-saving estimates support these dosing strategies; various ongoing studies are examining the impact of these cost-effective dosing strategies on patient treatment outcomes.
There is much to be learned and progress to be made in all these efforts toward the optimization of tolerability, safety, and efficacy of oncologic therapies. Further, assessment of the most cost-effective dosing strategies for these therapies remains top of mind. With OCE initiatives such as Project Renewal and ongoing studies investigating cost-effective dosing strategies advancing this work, we can do our part by staying abreast of updates and implementing new information as it becomes available.
About the Author
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP, is the editor-in-chief of Pharmacy Times Oncology Edition. Davis holds positions as a clinical pharmacist in early-phase clinical trial and breast cancer programs at the University of Arizona (Arizona) Cancer Center in Tucson and as a clinical professor of pharmacy practice and science at the Arizona R. Ken Coit College of Pharmacy. Davis also sits on the Hematology/Oncology Pharmacy Association Board of Directors and is a member of the Cancer Prevention and Control Program and scientific review committee at the Arizona Cancer Center.