Novel CDK4&6 Inhibitors Offer Further Potential in Breast Cancer

Evolving Paradigms, CDK4&6 Inhibition,

A number of highly effective cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors are currently in development as treatments for patients with metastatic breast cancer.

Abemaciclib is another agent that is rapidly advancing through clinical trials. This potent agent has received a breakthrough therapy designation from the FDA for its potential as a monotherapy for patients with refractory HR-positive advanced breast cancer. In addition to single-agent activity, this agent is also being explored in other subtypes of breast cancer, including the HER2- positive group.

To gain further insight into how these agents will be incorporated into the standard of care for patients with breast cancer,Targeted Oncologyspoke with Debu Tripathy, MD, Hope S. Rugo, MD, and Sara A. Hurvitz, MD.


Chair, Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

TARGETED ONCOLOGY:Can you discuss the various CDK4&6 inhibitors that are in development?

TRIPATHY: In many other fields of medicine, we have drugs that are similar and “me-too” drugs but, in cancer, we are finding there is enough difference between one person to another and the biology of their tumor that we have to look at each drug on its own. That is why it’s so important for us to look at the whole landscape of CDK4&6 inhibitors—not only palbociclib, but ribociclib, too. Abemaciclib is another drug that’s in clinical trials; these are all unique drugs that we need to explore.

From a community oncologist’s perspective, how can CDK4&6 inhibitors be integrated into the management of breast cancer?

The importance of CDK inhibition in the management of hormone receptor-positive cancers is critical. Palbociclib is a drug that more than doubles progression-free survival (PFS). We are still waiting on survival data, and it is a drug that is reasonably well tolerated.

The important take-home message is that it is an important option to delay progression. One issue that comes up a lot is, in the absence of a survival advantage, should we be using the drug—and when should we be using it? Most of us, and our patients, feel that something could clearly extend PFS, but when patients progress they might need to move to chemotherapy sooner and their quality of life might decease. This is important and we need to await those data.

However, the fact that it is a well-tolerated drug is important. It does require more monitoring; you have to check more blood counts and you have to adjust doses if needed. There are a small number of patients who have to come off of therapy because of this. Fortunately, the rate of increase and febrile neutropenia is very low, but it is important that clinicians be aware of how to use the drug, what the patient selection would be, and, particularly, how to monitor some of the toxicities and adjust the drugs.

Very recently, palbociclib was also approved in the second-line setting. The first trial—the first approval—was in combination with letrozole for patients who were candidates for treatment with aromatase inhibitors. Specifically, the trial enrolled patients who either have never seen hormonal therapy in the adjuvant setting or were more than 1 year out from an aromatase inhibitor or hormonal therapy.

The more recent study was in second-line patients who had previously been exposed to hormonal therapy, were in the metastatic setting, or who recurred within 1 year. This compared fulvestrant (Faslodex) to fulvestrant with palbociclib. It also showed a significant PFS improvement.

How has the incorporation of these agents changed secondor third-line treatments?

It has created a lot of dilemmas. This is because, now, a lot of people are getting this as their frontline therapy, and we have very little information on the natural history of these patients. How should we treat them when they progress? What are the different options available for them? These are things that need to be sorted out with future trials.


Clinical Professor, Department of Medicine (Hematology/Oncology)

Director, Breast Oncology Clinical Trials Program

University of California, San Francisco

How do you foresee the CDK4&6 inhibitors being used for the treatment of women with breast cancer?

RUGO: So you know, the whole world of hormone receptor-positive disease now, in the metastatic setting, is about targeted therapy and how we can improve response. We talk about reverse resistance, but really what we’re trying to do is improve response to endocrine therapy and improve the duration of response. I think those are our two biggest goals.

The CDK data is really fascinating because it came from UCLA. Dennis Slamon was, as usual, looking ahead to the next step and where things can come from. They have a series of cell lines at UCLA and they were able to expand this research further and show that where CDK inhibitors were most likely to have a benefit was in estrogen receptor (ER)‒positive—like disease, and HER2-positive disease, which is another area. I remember somebody telling me from one of the companies that has a CDK inhibitor, “Well it’s only luminal B’s,” but we don’t know that. There are absolutely no data that show it. But there will be data coming out of these trials, I think, that tells us more about it.

Can you discuss the clinical trials for the CDK4&6 inhibitors?

There were very intriguing data that led to the phase I and then the phase II trial, PALOMA-1, which of course, I think, somewhat surprisingly for many of us, led to accelerated approval in the first-line setting with letrozole.

We’re going to see results from two other very interesting studies. So there’s the MONALEESA Trial with ribociclib, Novartis’ CDK4&6 inhibitor. And then there’s a third CDK4&6 inhibitor, which is a little bit different from the others, abemaciclib, from Lilly, and that drug had single-agent activity, which the other two don’t seem to have much of. And it was really fairly impressive single-agent activity in phase I.

So they did a single-agent phase II trial, the MONARCH Trial, that’s single-agent drug in refractory hormone receptorpositive breast cancer. And then, of course, they also have their fulvestrant study. Everybody who takes abemaciclib gets diarrhea, but it’s not bad diarrhea, and so you don’t have to take upfront prophylaxis but you have to be taking Imodium. So my patients who are on abemaciclib for a long time traveled with the Imodium.


Director of the Hematology/Oncology Breast Cancer Program,

Associate professor, Department of Medicine

University of California, Los Angeles

Are CDK4&6 inhibitors also being studied in HER2-positive patients?

HURVITZ: There is a study that is about to get started, or has just started, that is looking at HR-positive/ HER2-positive metastatic breast cancer. Our own cell line data on CDK4&6 inhibitors in breast cancer shows that not only luminal ER-positive/ HR-positive breast cancer cell lines are sensitive to CDK4&6 inhibition but, indeed, a number of HER2-positive lines are sensitive, as well.

Abemaciclib, which is being explored in this setting, has a different safety profile than other CDK4&6 inhibitors, so it is also going to be interesting to see how that plays out in a larger patient population in these larger, ongoing studies that are going to be presented in the next 6 to 12 months.

What work would you like to see done in this field?

We’re really beginning to appreciate the fact that HR-positive/ HER2-positive breast cancer behaves quite differently. It has different surgical and long-term outcomes compared with HR-negative/ HER2-positive breast cancer. We are also beginning to see a difference in outcomes with PI3K pathway activation status, so that may help inform decision-making and make treatment options available in the future.