Expert Shares How CDK4&6 Inhibitors Break the Mold on Breast Cancer Paradigm

Richard S. Finn, MD

A trio of cyclin-dependent kinase (CDK) 4&6 inhibitors have continued to revolutionize the field of breast cancer, explains Richard S. Finn, MD, adding that at some point in a patient’s course of treatment, a CDK4&6 inhibitor—whether palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)—should be administered.

Palbociclib was approved by the FDA in February 2016 for use in combination with fulvestrant (Faslodex) in pretreated patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, based on results of the phase III PALOMA-3 trial. Palbociclib was initially granted approval by the FDA for use in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)−positive, HER2-negative metastatic breast cancer.Second, the FDA approved ribociclib for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer. This decision was based on findings from the phase III MONALEESA-2 trial.

Finally, in September 2017, the FDA approved abemaciclib for use in combination with fulvestrant in women with HR-positive/HER2-negative advanced breast cancer with disease progression following endocrine therapy; the basis for the approval came from the MONARCH 2 trial. Abemaciclib was also approved as a single agent for patients with HR-positive/HER2-negative disease with metastatic disease who have previously received endocrine therapy and chemotherapy. The single-agent indication was considered based on the MONARCH 1 trial.

All 3 of the CDK4&6 inhibitors have demonstrated comparable levels of efficacy, but there are subtle mechanistic and toxicity differences, Finn added.

In an interview with Targeted Oncology, Finn, an associate professor of medicine at the Geffen School of Medicine at the University of California, Los Angeles, covers the evolution of CDK4&6 inhibition in the field of breast cancer and appropriately selecting patients for this type of therapy.

TARGETED ONCOLOGY:Can you share the history of CDK4&6 inhibitor development in breast cancer?

Finn:The field has changed very quickly in a short period of time after decades of, really, no real novel approaches in first-line estrogen receptor—positive breast cancer—let alone hormone-resistant breast cancer. We now have 3 CDK4&6 inhibitors approved. Several years ago, [we were] talking about CDK4&6 inhibitors at a time where we had only very early data with palbociclib, which came out of preclinical work done by Dennis Slamon and myself in collaboration with Pfizer. That led to the PALOMA-1 trial and, eventually, the accelerated approval of palbociclib and letrozole.

Now we have a phase III study with ribociclib and letrozole in a similar population and phase III data with palbociclib with letrozole. Recently, at the 2017 ESMO Congress, we saw the data with abemaciclib and nonsteroidal aromatase inhibitors. All these results, reassuringly, are very similar as far as efficacy. While there is some overlap with the toxicities, each molecule has a few unique aspects.

Now, with fulvestrant in patients who are felt to be resistant to nonsteroidal AIs, we have data with palbociclib and fulvestrant from PALOMA-3—as well as data with abemaciclib and fulvestrant from their phase III study, the MONARCH studies. There are now 6 randomized studies—many of them reading out only in the past year or year and a half—with CDK4&6 inhibitors and endocrine therapy. The landscape has changed very dramatically.

TARGETED ONCOLOGY:With these 3 CDK4&6 inhibitors available, how is a patient chosen to receive one regimen over the others?

Finn:As far as efficacy [goes], these combinations all seem very similar. The frontline regimens have similar efficacy, the second-line regimens have similar efficacy, and only recently, we now have abemaciclib approved as a single agent in patients who have never had a CDK4&6 inhibitor in heavily pretreated patients from the single-agent MONARCH 1 study.

Therefore, we have not been able to identify a biomarker or a patient population that does not benefit from the addition of a CDK4&6 inhibitor to endocrine therapy—whether that’s a nonsteroidal AI or fulvestrant. Somewhere, during the course of treatment, I would argue that a patient needs to get a CDK4&6 inhibitor. My bias is that perhaps this 10-month improvement we see in the frontline setting [with a CDK4&6 inhibitor] is the place to get the greatest benefit.

Then, as far as distinguishing them on toxicities, there are probably some unique places where you would go to one versus the other. Ribociclib requires some monitoring of QT interval of patients who are on drugs known to create QT, or have some arrhythmia that is related to prolonged QT. It might not be your first choice.

There is deep vein thrombosis [DVT]-association that came out with abemaciclib. There was an increased risk of DVT in their phase III study with a nonsteroidal AI. All [the CDK4&6 inhibitors] cause neutropenia to some degree—less so with abemaciclib—but abemaciclib has more gastrointestinal toxicities. Therefore, there are subtle things. As far as efficacy, they are all fairly similar, as far as we can tell. There are some subtle toxicity differences that a clinician may take into account. Access might be an issue for some people. We would all like to see that if we have 3 drugs competing in the same space, then the price should come down. But that is yet to be seen. 

TARGETED ONCOLOGY:Are there next-generation CDK4&6 inhibitors emerging in the pipeline?

Finn:We have seen, very rapidly, 3 molecules go into the same space. You can make the argument: Do you need 3 molecules that do similar things and give similar efficacy? But that is the case. The big question now is, “How will these work in early breast cancer?” The adjuvant studies with these molecules are ongoing, and maybe that will be a place where we will see an even bigger impact and cure.

There is a big interest in understanding acquired resistance to these drugs. What do you do after you progress on a CDK4&6 inhibitor? All the data we have with single-agent fulvestrant, exemestane, and exemestane with everolimus [Afinitor] were all generated in the pre-CDK4&6 era. Therefore, we need some sense of how these patients do, and that will probably come [more] from the phase III studies. We had some data from that on PALOMA-1—the phase II study. There is interest now in maybe targeting other CDK4&6 inhibitors to overcome resistance. It’s an area that has been looked at for a while. It has been limited a little bit by medicinal chemistry, but there is a lot still in play.

TARGETED ONCOLOGY:Could any of the CDK4&6 inhibitors have potential in combination with immunotherapy?

Finn: