A new era in dosing: Dose optimization | SABCS 2024

Dose optimization is a reform effort that challenges the traditional “more is better” approach to cancer drug dosing: the belief that more medicine is more effective. Maues co-founded the Patient-Centered Dosing Initiative (PCDI) in 2019 to “question the practice of treating metastatic breast cancer patients with the highest tolerable doses.”

PCDI efforts gained the attention of the medical community and the FDA. And in 2021, the FDA launched Project Optimus, a collaborative effort to rethink drug dosing and selection in oncology.

Why dose matters

The side effects of breast cancer treatment affect daily life and can cause physical and mental distress. Higher doses can mean more side effects or worse side effects.

People living with metastatic breast cancer often stay on medicines for as long as they work before moving to another. Too often, people stop taking a potentially beneficial drug due to difficult side effects. A lower dose can sometimes improve side effects while still controlling cancer.

A survey of people with metastatic breast cancer found that 86% experienced at least one bad treatment-related side effect. Of those who were able to move to a lower dose, 83% felt better.

The need for dose optimization

Newer medicines, such as targeted therapies and immunotherapies, are driving the reform efforts. These drugs are effective at different doses. People stay on them longer, without breaks.

The hormonal therapy fulvestrant is an example of a drug that was initially tested in cancer at too low a dose, based on its use in fibroids and endometriosis. People with cancer tolerated the drug well but did not benefit as expected. Further research supported doubling the dose.

In contrast, oral chemotherapy capecitabine was first prescribed at a too high a dose for many patients to tolerate. In 2022, the FDA reviewed and lowered the recommended dose.

Strategies to optimize dosing

Yale School of Medicine’s Patricia LoRusso, DO, leads Phase I trials. These trials study safety, side effects, and treatment timing. Dr. LoRusso encourages colleagues to think about dosing early on when designing studies.

This may mean being creative and rethinking classic clinical trial design. The FDA does not mandate specific trial designs. Trials that increase the dose of a drug are still needed to prove that drugs are safe. Still, the maximum tolerated dose may not be the recommended dose for a phase II trial, which continues to look at safety, including side effects.

Dr. LoRusso emphasized the importance of predictive biomarkers, and that collecting biomarker data up front will help ensure that people trying the drug are likely to benefit. “We need to make every patient count—and every drug count in every patient—in early-phase clinical trials,” she said. Dr. LoRusso added that she is excited about the direction of the field.

Stacy Shord, Doctor of Pharmacy at the FDA, would like to see clinical trials that compare different doses. She stressed the importance of identifying dose ranges earlier and getting the dose right before approval. This is because it can be very challenging to revisit doses post-approval. She recognizes challenges in breast cancer treatment dose optimization, such as:

• How to measure safety
• How to gather information on whether a drug can be tolerated
• How to know sooner if a drug is working
• How to optimize the length and order of a treatment as part of an overall treatment plan
• How to think about dose optimization in different stages of treatment

Through Project Optimus, the FDA has developed a set of principles to guide healthcare professionals with dose optimization. The approach should be holistic and look at all available information.

For people undergoing breast cancer treatment, the Patient-Centered Dosing Initiative encourages talking with doctors about dosing. patients to talk with physicians about dosing PCDI published a flyer to help with these conversations. If side effects are a challenge, suggestions include talking with one’s doctor about:

• Adjusting the dose
• Changing the treatment schedule
• Recommending a different treatment

Regimens can be optimized as well, according to Mirat Shah, MD, also of the FDA. The FDA sometimes approves regimens, or certain drugs given in a specific order. She cited a study of the immunotherapy pembrolizumab (Keytruda) for high-risk, early triple-negative breast cancer in which participants were given the drug as both a neoadjuvant (given before surgery) and adjuvant (given after surgery) therapy. Yet it’s not entirely clear if both neoadjuvant and adjuvant treatment are needed.

Drug optimization benefits all

Optimal dosing can help people with breast cancer stay on treatment longer, miss treatment less often, have less need for emergency healthcare, and have better quality of life. Maues points out that the potential benefits extend to other players in the healthcare system as well.

Oncologists want their patients to live longer more comfortably. Serious side effects can lead to more specialist visits and care, costing insurers money. Pharmaceutical companies are less likely to pause drug availability to revisit dosing; people will stay on their drugs longer with fewer interruptions.