Progress Continues in HR+/HER2- Breast Cancer Paradigm

Kristin J. Richardson, MD

CDK4/6 inhibitors have been a practice-changing addition to the treatment armamentarium for patients with hormone receptor (HR)—positive metastatic breast cancer, said Kristin J. Richardson, MD. Now, investigators hope to move these agents into an earlier treatment setting.

There are currently 3 FDA-approved CDK4/6 inhibitors available for the treatment of patients with HR-positive, HER2-negative breast cancer: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). All 3 agents have shown consistent progression-free survival advantage across patient subgroups.

“I was starting my fellowship right when all of this was creating a big excitement in the field,” said Richardson, a hematology/oncology fellow at Rush University Medical Center. “I don’t know what things were like 20 years ago, but the more we can do to make it easier for the patient and improve their quality of life is wonderful to me.”

Beyond these inhibitors, the field is shifting toward a precision medicine approach as a way to treat patients who harbor specific mutations, such as PIK3CA. “About 40% of women with breast cancer have a PIK3CA mutation,” said Richardson. “This mutation [appears to be] a very good target for drugs—especially for patients who might be a little more hormone resistant.”

The alpha-specific PI3K inhibitor alpelisib (BYL719) has been shown to provide benefit in this patient population, but it is not without toxicities. Therefore, knowing how to manage associated adverse events is imperative when using this class of agents. In the SOLAR-1 trial, hyperglycemia was experienced by about 65% of patients treated with alpelisib plus fulvestrant (Faslodex).

OncLive^®: What impact have CDK4/6 inhibitors had in this space?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Richardson highlighted advances made with CDK4/6 inhibitors in the treatment of patients with HR-positive metastatic breast cancer and forecasted where treatment is headed in this space.Richardson: These inhibitors have made a huge impact on the overall management of women with HR-positive metastatic breast cancer. There have been 3 FDA approvals in the past few years, and these agents have really become the standard of care both in the first- and second-line settings.

Are there any concerns with the higher rate of diarrhea seen with abemaciclib?

What should be the next focus of research with CDK4/6 inhibitors?

Given their approvals in the first- and second-line settings, are there any sequencing challenges?

What advances have been made with PI3K inhibitors?

What would be your biggest take-home message for community oncologists to apply to clinical practice?

We have good combinations available; decisions depend on the comfort and experience of the provider. In our institution, we have much more experience with palbociclib, because that was the first agent to receive approval. We are a little more comfortable managing the AEs associated with the treatment. In terms of combination therapy, whether it's with an aromatase inhibitor or fulvestrant (Faslodex), you are able to apply a personalized approach based on your patient and what kind of prior therapies they have received.It's very manageable. At least in terms of the studies, investigators say if diarrhea is going to happen, it's going to happen early. You can anticipate this by giving patients antidiarrheal medications, such as loperamide (Imodium), which tends to be very effective. If you catch diarrhea early with this type of approach, most patients are able to tolerate [abemaciclib] fairly well.There are many ongoing trials evaluating the use of CDK4/6 inhibitors in an earlier setting to see if we can really prevent metastatic disease from happening. We could get durable remissions and prevent 50% of patients from developing metastatic disease. Therefore, if the CDK4/6 inhibitors might have a role in that, that would be great. I would love to be part of that research.It is all about a personalized approach. Thus far, there hasn't been anything to suggest that if you use a [CDK4/6 inhibitor] in the frontline setting, you can use a different 1 in the second-line setting. There are no data to lead us in that direction, so if you and your patient decide to start one CDK4/6 inhibitor upfront, you would have to use a different treatment strategy in the second-line setting.Thus far, there have been attempts at utilizing [a treatment] strategy with PI3K inhibitors, and while they did not seem to be that effective as single agents, combining them with endocrine therapy seems to be an effective strategy. However, there is a lot of toxicity associated with these agents. We are hoping to develop agents that are a little more tolerable, so patients can stay on the treatment longer and have an overall benefit.It's always good to review the data of how the CDK4/6 inhibitors became approved by the FDA and what the nuances are in terms of choosing among them. Knowing how to manage the AEs is a big factor.