CDK4/6 Inhibitors: Changing the Treatment Landscape
Insights From: Debu Tripathy, MD, University of Texas MD Anderson Cancer Center
Debu Tripathy, MD: Well, the CDK4/6 inhibitors have really made a big difference in the management of hormone receptor-positive breast cancer—which is 70% of all the breast cancers—not only in the first-line setting, but in second-line therapy. So, the results have consistently shown that we are doubling time to disease progression when we combine it with standard hormonal therapy. Now, the data so far show that these are very well-tolerated drugs in general. There was always some concern that when we introduce biologics, we may now have a whole new set of side effects to deal with. And there are some side effects, but for the most part, they’re minor and we’re now finding as we’re getting used to them in practice, that we are now putting most of our patients on these agents.
The big question is, is there a group of patients who you shouldn’t put on it? Is there anybody who might not benefit from a doubling in disease-free survival? Our feeling is that even though an overall survival benefit has not yet been demonstrated, that’s in part because the trials weren’t designed to pick up a survival benefit. But the other thing we have to look at is, are we delaying the need for additional therapies, especially chemotherapy, which is associated with more side effects than any hormonal therapy? So, I would say that for the most part, at least in our practice, a vast majority of our patients are receiving CDK4/6 inhibitors in first-line, and if they haven't received it in first-line therapy, they’re receiving it in second-line therapy.
The CDK4/6 inhibitors have been tested for many years. The one that was first entered in clinical trials was palbociclib, and the first trial to be reported was in the first-line setting in combination with the aromatase inhibitor, letrozole. And both the pilot study and ultimately the larger phase II study then showed a clear benefit in disease-free survival. Subsequently, there was a second-line therapy with fulvestrant plus or minus palbociclib. So, palbociclib is indicated both in first-line therapy with an aromatase inhibitor or in second-line therapy with fulvestrant.
The next one to be approved and tested was ribociclib. That one was tested first in the first-line setting with letrozole plus or minus ribociclib, again showing comparable benefits and was subsequently approved for that.
Abemaciclib is a little bit different. It’s a CDK4/6 inhibitor like the others, but it has some activity against the other CDKs. It has a slightly different toxicity profile, and the first trial with abemaciclib was actually reported in refractory disease, patients who had received multiple therapies—again, hormone receptor-positive, HER2-negative. And it was tested as a single agent without hormonal therapy and it showed activity. And then shortly after that, the second-line trial was reported, the MONARCH-2, which was fulvestrant plus or minus abemaciclib. So, that indication just at the end of September was for refractory hormone receptor-positive, HER2-negative disease as a single agent but also in combination with fulvestrant in second-line therapy. The first-line therapy was just recently presented at ESMO, but the FDA label doesn’t cover that yet.