Outcomes and therapy options have greatly improved over the years for patients with breast cancer (BC); however, many of these therapies are highly associated with adverse events (AEs) and toxicities. At the 2024 San Antonio Breast Cancer Symposium in San Antonio, Texas, experts discuss the crucial role of dose optimization and regimen optimization in addressing the unique needs of individual patients or specific patient populations. Through improving clinical trial approaches, addressing toxicities through dose optimization, and the inclusion of patient perspectives, investigators can develop more effective, personalized therapies for patients.1
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Cancer drug dosing has historically been determined through dose escalation studies based on the premise that higher toxicity yields greater efficacy. However, this approach is not applicable to newer treatments such as targeted therapies and immunotherapies and does not consider all the long-term AEs. With targeted drugs, increased doses may enhance antitumor activity. Additionally, dose-limiting toxic effects may not be observed, and serious toxic effects may only occur after multiple rounds of therapy. Therefore, addressing and optimizing treatment dosage and regimens can help health care professionals and trial investigators better gauge the best approach to treatment as use of these novel therapies increases.
Dose optimization is a critical priority to improve the safety, tolerability and long-term effectiveness of cancer treatments, and requires a patient-centered approach to balance efficacy and toxicity. Understanding dosage and duration of treatment is essential for effectively determining the risk-benefit of different doses, where overly high doses can lead to toxicity, but lower doses may not be as effective. Adjusting treatment doses is especially important for patients with metastatic BC (MBC) who will need to be able to tolerate treatments for longer periods of time. In these cases, lower doses may yield reduced toxicities and allow for more continuous well-tolerated treatment.
Patricia LoRusso, DO, PhD, FAACR, associate director of innovative medicine at Yale Medicine called specific attention to immune-mediated adverse reactions in the adjuvant setting, which can happen even after the initial treatment period. Clinical trial data and evidence around the prevalence and impact of immune-related adverse reactions are needed to develop a comprehensive strategy. Additionally, trials need to carefully evaluate the contributions of both neoadjuvant and adjuvant treatments to the overall development of immune-mediated toxicities.
Alternative approaches to clinical trial design and sequential trials can help to better evaluate the effectiveness of different treatment durations, providing more definitive guidance on the optimal length of cancer therapies for patients. LoRusso suggests a holistic approach that consists of 3 steps: identifying the dosage range, evaluating all clinical and nonclinical data including pharmacokinetics, pharmacodynamics, and biomarkers, and comparing it to the standard of care.
The new paradigm favors identifying the maximum biologically effective dose rather than the maximum tolerated dose to reduce AEs and improve tolerance to long-term treatment. In a 2016 study, investigators evaluated 90 FDA approved drugs to determine whether patients were receiving higher doses that were responsible for poorer tolerability and increased AE risk.
“And the conclusion from that study, and that's a retrospective review, was that 45% of patients on small molecules require dose modifications due to drug related toxicity in subsequent phase 3 trials,” explained LoRusso. “And as you can see, 48% were interruptions, 42% were dose reductions. And this is really important because as we're trying to develop combination strategies with most MTA, especially in the metastatic setting, combinations are very important, but are very, very challenging because of overlap and toxicity. So. it's important to look at ranges when trying to get the dose right and identifying whether or not that dose is right for all tumor types and in what studies.”
Optimizing dosing regimens beyond focusing on optimizing individual doses is another important consideration for patients with BC to prevent or mitigate toxicities and long-term AEs, as well as understand the drivers of efficacy and toxicity. When optimizing regimens, health care providers should consider initiation of sequential trials, trials with 3 or 4 treatment plans, or trials with re-randomization after surgery.
In the Keynote-522 trial (NCT03036488), data showed that adding pembrolizumab (Keytruda; Merck) to dosing regimens improved outcomes for patients.2
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"The trial design included a multi-phase regimen with neoadjuvant and adjuvant components, and the primary endpoint was [pCR] rate," said Mirat Shah, MD, of the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland. "The trial met its primary endpoint, showing a significant improvement in pCR rate and overall survival with the addition of pembrolizumab."
Shah noted that despite the favorable data, the overall trial results did not address questions about the optimal regimen and the need for both the neoadjuvant and adjuvant portions of treatment. She suggested that a sequential, adaptive trial design could be employed to fill that knowledge gap.
Patients experience a variety of benefits when there is deeper clinical understanding of appropriate dosing and treatment duration. The reduction of toxicities and treatment-related AEs (TRAE) leads to improved tolerance and quality of life, and incorporating patient perspectives and experiences can help guide dosage decisions. The Patient-Centered Dosing Initiative (PCDI) is a patient-led effort focused on ensuring that patients with MBC are treated with the highest tolerable dose, rather than the maximum tolerated dose. The initiative believes that using more tolerable doses can lead to fewer side effects, fewer missed treatments, and ultimately better quality of life and potentially longer survival for patients.
Based on the results of a survey including 1200 respondents, the PDCI found that 86% of the respondents experienced a least 1 bad TRAE during their cancer treatment. The survey findings illustrates the impact of these strategies and highlights the critical importance of tailoring cancer treatments to prioritize patient well-being and tolerance.
“Out of those, 20% had to visit the hospital because of a side effect to their cancer drug, and 43% missed the treatment because that drug was so toxic, so they couldn't get the drug because the drug is too toxic,” explained Julia Maues, MBC survivor, patient advocate at Guiding Researchers & Advocates to Scientific Partnerships, and co-founder of the PCDI. “And then we also asked about those reductions, and we found that 83% of the patients that did have a reduction in their dose experience felt better after that.”
The growing focus on dose optimization in BC treatment reflects a critical shift toward more patient-centered approaches that balance efficacy with tolerability. As emerging therapies like targeted treatments and immunotherapies reshape the treatment landscape, the traditional reliance on maximum tolerated doses is being replaced by strategies that emphasize the maximum biologically effective dose.
Additionally, sequential and adaptive trial designs offer the potential to refine treatment regimens by addressing gaps in understanding of optimal dosing and therapy duration. Incorporating biomarkers, pharmacokinetics, and real-world patient data is essential to developing personalized approaches that mitigate toxicities while maintaining efficacy.
As the field continues to evolve, collaboration between researchers, health care providers, and patients will be essential to reimagining the framework for cancer care to prioritizes treatment efficacy, as well as also long-term sustainability and improved quality of life for those who need it most.
REFERENCES
1. Shah M, LoRusso P, Maues J, et al. Clinical workshop: dose pptimization in breast medical oncology. Presented at: 2024 San Antonio Breast Cancer Symposium. December 10, 2024. San Antonio, TX.
2. Study of pembrolizumab (MK-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants with triple negative breast cancer (TNBC) (MK-3475-522/KEYNOTE-522). ClinicalTrials.gov Identifier: NCT03036488. Updated November 12, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT03036488