Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Hope S. Rugo, MD: The important question for clinicians now that has come up is, what do you do next? So, if you’ve given ribociclib or palbociclib in combination with an aromatase inhibitor as first-line therapy, what do you do with a patient on progression? Right now, probably our first step would be to give fulvestrant alone after progression. There are studies looking at continuing the CDK4/6 inhibitors after progression, but we don’t know the results of that, so right now, I wouldn’t continue them through progression. I would give fulvestrant because it’s in a different class of agents. We have recent data from a Cooperative Group randomized phase II trial that suggests that you can add everolimus to fulvestrant. So, one option that you have is to give fulvestrant and everolimus. You could give fulvestrant alone and give exemestane and everolimus as third-line therapy. Both options exist.
There are currently trials looking at the alpha-specific PI3 kinase inhibitors as well as combinations of interesting targeted agents. I think we’re going to see data from the PI3 kinase inhibitors at the end of the year and next year, so we’ll know better about what our next steps should be. Should we give these PI3 kinase inhibitors in combination with fulvestrant next? But today, our option is really as I described: fulvestrant with an mTOR inhibitor, everolimus, or give fulvestrant alone and use exemestane and everolimus as a third step. We have no evidence that there’s cross resistance, so I would definitely encourage clinicians to consider the use of everolimus as a second- or third-line combination with hormone therapy.
Sara Hurvitz, MD: At this time, we don’t have enough data to support the use of CDK4/6 inhibitors as a monotherapy. Although data for abemaciclib from a phase II single arm study supports the single-agent activity of abemaciclib in metastatic, heavily pretreated disease, it is not yet FDA approved for that indication.
Moreover, there are no data to support the use of continued CDK4/6 inhibitors beyond progression on a CDK4/6 inhibitor. There are clinical trials that are ongoing. One of them is called TRINITI-1 looking at whether or not patients will benefit from continued use of the CDK4/6 inhibitor after having their disease progress on a CDK4/6 inhibitor. These clinical trials are going to be very important in shaping the way that we treat our patients long-term. But until then, I would not recommend using these drugs in the absence of that data.
So, of the 3 CDK4/6 inhibitors, abemaciclib is slightly different from the other 2. Abemaciclib has more potent activity against CDK4 and cyclin-D than CDK6, and this may be part of the reason why we’re seeing less neutropenia with abemaciclib and more GI toxicity. Palbociclib and ribociclib, in contrast to abemaciclib, have more grade 3/4 neutropenia but less GI toxicity.
In addition, abemaciclib is given on a continuous b.i.d. dosing schedule, so there’s no need to hold the drug after 21 days in contrast to the other 2 CDK 4/6 inhibitors because abemaciclib does not cause as much neutropenia. In contrast, palbociclib and ribociclib are given days 1 to 21 followed by 7 days offer before initiating the next cycle.
Hope S. Rugo, MD: Now we are faced with 3 different CDK4/6 inhibitors that will be approved and on the market in the near future. We currently have 2, but we’ll have the third one, abemaciclib, on the market in the near future. The question is whether or not the differences in mechanism of action or the clinical activity have any meaningful differences in the clinic. How do we take this information into the clinic? We don’t know. There haven’t been head-to-head comparisons, and I will guess that probably there will be in the future, but those trials haven’t been designed yet and will be interesting to understand. So, really, the question facing us is, looking at the data that we have at hand, how do those impact our clinical decision making now? I think that what we understand now in terms of approval, we have palbociclib approved as first-line therapy, combination with AI, as second-line or greater line therapy with fulvestrant. And the abemaciclib approval will be in patients who didn’t ever have any chemotherapy, which is a little different from the PALOMA-3 population. So, there’s a little bit of apples and oranges in there, but my guess is because all of the trials are out there waiting to be finished and reported, that we’ll see approval across the board for all 3 agents.
So, what do we understand in the clinic? The toxicity is the biggest, I think, clinically meaningfully important difference—abemaciclib causing more diarrhea and palbociclib and ribociclib more neutropenia. And thinking about how we’re using this for a patient is important. Obviously, a patient who has a lot of GI issues already or problems with diarrhea, involvement of their gut, for example—as we see with lobular cancer—that would be a patient where you might not want to start with abemaciclib because the GI toxicity might be too great.
A patient who has low blood counts in the later-line metastatic setting, I think you would prefer to give abemaciclib rather than ribociclib or palbociclib as a drug. A patient who has a lot of problems with understanding 3 weeks on, 1 week off, maybe giving a drug by continuous dosing would be easier for the patient than giving a drug where you have to stop for a week and come in and check your blood counts. You still have to check blood counts for abemaciclib, so that is not going to be the key difference, but compliance and ability to understand and take the drug the way you give it, where you take a break, if that’s a problem for a patient, and giving continuous dosing might be better.
There is a lot of interest with the ability of these drugs to cross the blood-brain barrier. There are some very early data with low level responses but responses with abemaciclib as a single agent in brain metastases. So, that might also encourage you. For example, a patient who had previous brain metastases, you might want to use abemaciclib instead of the other 2 agents until there are more data with the other 2 agents in the clinic, which we don’t have yet. And then, of course, there will be other considerations over time, which studies have done data looking at HER2-positive disease, which is an emerging area, whether there’s any immune effects or immune combinations, etc. These are all questions for the future, but for today, I think those are really the issues that we will take to the clinic.