CDK4/6 Inhibitors Continue to Offer Hope in Breast Cancer

Jacqueline Vuky, MD

CDK4/6 inhibitors have excited the field of advanced breast cancer with 3 FDA approvals in the last 3 years. The introduction of this class of agents has allowed for additional therapeutic options, including more combination therapy, said Jacqueline Vuky, MD.

Palbociclib (Ibrance) received an accelerated approval from the FDA in 2015 for use in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. This approval was converted to a full approval by the FDA in March 2017. This CDK4/6 inhibitor is now indicated for use in combination with other aromatase inhibitors (AIs) in this setting.

The second CDK4/6 inhibitor to be approved in breast cancer was ribociclib (Kisqali), which is indicated for use in combination with an AI for the frontline treatment of postmenopausal women with hormone receptor (HR)—positive, HER2-negative advanced breast cancer. In January 2018, this agent was also granted a breakthrough designation for use in combination with tamoxifen or an AI in patients with pre- or perimenopausal HR-positive, HER2-negative breast cancer.

In February 2018, abemaciclib (Verzenio) was approved in combination with an AI for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. In September 2017, the agent was approved for use in combination with fulvestrant following progression on endocrine therapy. It was also approved as a single agent for patients who had received endocrine therapy and chemotherapy.

OncLive: Can you give an overview of your presentation on CDK4/6 inhibitors?

How does multiple approvals of CDK4/6 inhibitors impact treatment for these patients?

If a patient progresses on a CDK4/6 inhibitor, is there rationale to move them to another?

Vuky, associate professor of medicine, School of Medicine, Oregon Health and Science University, discussed the management of metastatic disease and CDK4/6 inhibitors in breast cancer during an interview at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer.Vuky: CDK4/6 inhibitors are very exciting. We haven't had a breakthrough with endocrine therapy for metastatic disease, or even early-stage disease, for a while. What is exciting about these is that the trials are designed very rationally. For a long time now, we have been trying combinations with endocrine therapy and therapeutic targets. The fact that this is the first combination that has changed median progression-free survival (PFS) is very exciting for our patients. Giving them more options is why we do clinical research and take care of patients. Much like with other therapies, such as VEGF inhibitors or mTOR inhibitors, it is exciting that we do have choices, but it does seem that each one is a little different. Although the data show good efficacy as well as median PFS, the fact that they have different side effects and schedules, and even different abilities to bind to CDK4/6, is pretty exciting. We like choices. Although, we do have to be concerned about the price of all of these drugs. Still, from a patient care standpoint, it is very exciting to have all of these choices.As you know, there are no data yet. Once these new drugs come out, we can basically use them the way that we want to. However, we would like to have more data. Right now, we do not really know. In my practice, I have given sort of a second-line CDK4/6 inhibitor, and that is abemaciclib because it has single-agent activity. I would not say that there is a mass experience out there, I am not aware of a trial that addresses that at this point.

What are your thoughts on combinations with CDK4/6 inhibitors?

What about the potential with abemaciclib plus pembrolizumab (Keytruda)?

Although, there is a very interesting trial that is looking at giving a CDK4/6 inhibitor to patients on an AI who are starting to progress. These are very well-selected patients who have responded for a long time. I find that fascinating and, even though it is early, these questions need to be answered. We participated in a combination of ribociclib, everolimus (Afinitor), and exemestane. When you look at the pathways for activation of the CDK4/6 inhibitors, one of the pathways is activated through estrogen and ER, but one of the other pathways is HER2/neu through the PI3K and mTOR pathways. It actually makes some sense to decrease the dose of the mTOR inhibitor—at least in our patients, it was really well tolerated. There are other triplet combinations that may overcome endocrine resistance and it is pretty fascinating. Lilly Oncology has some information on that preclinical data, as well as the neoMONARCH trial, which is the neoadjuvant abemaciclib trial where they looked at abemaciclib as a way to prime tumor cells for immune recognition. There is a phase I trial with pembrolizumab and abemaciclib that I believe is actively accruing.

Do you have any advice for physicians deciding between agents?

In the HER2/neu space, there is abemaciclib plus trastuzumab (Herceptin), as well.First, I would ask the question of whether the patient needs combination therapy versus AI therapy. We know that there is a subgroup of patients with a good prognosis who might do well with an aromatase inhibitor alone. Patients who have poor prognostic features, such as liver metastases or a short time from adjuvant endocrine therapy to relapse, might do better with combination therapy. That is the first question they have to ask: “Is it combination or single-agent therapy?”

The second thing to do is look at the toxicities; if a patient is on an antiarrhythmic I would not give ribociclib. I do think there are some clinical judgements to make.