Advances in breast medical oncology are driving changes in drug dosing and regimen design. Traditional chemotherapy drug development and dosing relied heavily on finding the highest dose a patient could tolerate without severe side effects — the maximum tolerated dose (MTD). Current drug development centers on molecularly targeted agents, where MTD is increasingly being replaced by tailored dosage optimization strategies.

At the 2024 San Antonio Breast Cancer Symposium^®, experts will provide an in-depth look at these approaches during Clinical Workshop: Dose Optimization in Breast Medical Oncology, Tuesday, December 10, from 2 to 3:45 p.m. CT in Stars at Night Ballroom 1-2 at the Henry B. Gonzalez Convention Center.

The session will be moderated by Mirat Shah, MD, Clinical Lead for Project Optimus, an initiative to reform dose selection paradigms, at the U.S. Food and Drug Administration’s Oncology Center of Excellence, and Patricia LoRusso, DO, PhD (hc), Amy and Joseph Perella Professor of Medicine, Chief of Experimental Therapeutics, and Associate Cancer Center Director for Experimental Therapeutics at the Yale School of Medicine.

“Continued reliance on an MTD approach can lead to doses and schedules of molecularly targeted agents that are inadequately characterized before the initiation of registration trials,” Dr. Shah said.

“Patients may be receiving these novel therapeutics for longer periods of time to maximize the benefit, which ideally includes longer survival and improved quality of life,” she continued. “Poorly characterized dosing schedules can lead to selection of a dosage that provides more toxicity without additional efficacy, severe toxicities that require a high rate of dose reductions, intolerable toxicities that lead to premature discontinuation, a missed opportunity for continued benefit from the drug, and potentially persistent or irreversible toxicities that limit subsequent therapeutic options.”

While MTD approaches are based on severe or life-threatening toxicities, dosage optimization allows the selection of dosages to provide the best balance of treatment benefits and risks, Dr. Shah explained. This new paradigm evaluates more comprehensive information, including pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy, and it assesses dose- and exposure-response relationships.

Regimen optimization also aims to maximize the benefit-risk profile for patients, Dr. Shah continued. Treatment regimens containing multiple phases — for example, neoadjuvant and adjuvant treatment — are becoming more common. And it is not always clear that all elements of a particular regimen are necessary or appropriate in order to maximize the long-term outcome.

Patient preferences also play a growing role in dosing decisions. Drug-related toxicities that are less than life-threatening can still be intolerable. Patients may reject potentially effective drugs and regimens because of intolerable side effects.

“Patients have highlighted the importance of considering chronic, low-grade symptomatic toxicities such as diarrhea when making dosing decisions,” Dr. Shah said. “Grade 2 diarrhea constitutes an increase of four to six stools per day over baseline and can have an extremely negative impact on quality of life if it must be endured for months. Patients and advocates have also emphasized the value of patient-reported outcomes data when trying to understand drug tolerability.”

The workshop will also feature discussion on another important trial design issue: crossover.

Many patients prefer a trial design that allows those randomized to standard of care to access the investigational drug if their disease progresses, Dr. Shah explained. Researchers may have different preferences because that approach can complicate the assessment of longer-term endpoints like overall survival.

“As a result of our session, we hope patients and oncologists will advocate for dosage optimization earlier in drug development and clinical investigators will evaluate questions of dosage and regimen optimization in clinical trials supporting drug approvals,” Dr. Shah said.