Questions and Controversies in Treating Breast Cancer - Episode 4

Emerging CDK4/6-Targeted Therapy for Breast Cancer


Adam M. Brufsky, MD, PhD: Debu brought up the MONARCH 2 trial, which is being presented at this year’s ASCO. Carlos, are you familiar with the MONARCH 2 design?

Carlos L. Arteaga, MD: I am. MONARCH 2 is a study that uses abemaciclib, the third CDK4 inhibitor that may have subtle differences that may or may not matter clinically in that it has a better inhibition of CDK4 over CDK6, compared to ribociclib and palbociclib. It’s also the drug that has shown single-agent activity in the MONARCH 1 trial. So, these are subtleties where we anticipate that this would be a pretty good CDK4 inhibitor.

MONARCH 2 is a large randomized study in the second-line setting, where randomization was between fulvestrant and abemaciclib versus fulvestrant and placebo. The other difference with this trial is that the CDK4 inhibitor was given continuously. The toxicity profile is a little different: It has less myelosuppression and more diarrhea, probably consistent with the fact that CDK6 is inhibited less and CDK4 is inhibited better. We will learn more about the tolerability and management of this diarrhea, but it can be a bit of an issue as of now.

The hazard ratio in this study was way in favor of the combination, 0.55, with a difference in progression-free survival of 9 months versus 16 months. So, that is remarkable. The other thing worth pointing out about this study is that these were patients who were totally chemotherapy naive in the metastatic setting. This suggests that, maybe fortuitously or intentionally, this study identified a truly ER-dependent population. At any point before the trial enrollment, no clinician had an inkling of giving a patient chemotherapy, which sometimes is driven by a perception that this tumor is not that hormone dependent. So, that is different about this trial and may explain the impressive progression-free survival in the control arm in second-line.

Adam M. Brufsky, MD, PhD: Right. It’s usually 4 months for fulvestrant alone, from effect; and then—from the palbociclib trial, at least—it was about 10 months or 12 months; and now you have 9.7 months and 16 months. I’m struggling in trying to understand that difference, and it could be the fact that patients didn’t get chemotherapy.

Carlos L. Arteaga, MD: It could also be that abemaciclib may be a little better. I don’t know. We’ll find out.

Adam M. Brufsky, MD, PhD: It’s a great question. Has anybody had personal experience with abemaciclib?

José Baselga, MD, PhD: Yes. I am the principal investigator of the MONARCH 1 study. It was just published last week. I think it’s a different drug. I think Carlos is right on it. It probably hits CDK4 more. Now, we don’t know how this will play out. It has the activity of a single agent, but it also has diarrhea. Now, diarrhea could be something of concern when you are talking about combining this with fulvestrant, another AI. So, at the end of the day—I think that Kim was making this point—we need to have data on all of these scenarios, and we will decide based on the data that we’ll gather. This could be impossible. But I would agree that, of the 3, this is the 1 that is most different.

Adam M. Brufsky, MD, PhD: It is. It’s much more potent. The IC50 is a lot lower than the other drugs, and things like that. It’s going to be very interesting to see what happens with this drug, especially for MONARCH 1, where, if it gets approved, people will use it in that setting based on MONARCH 1. In MONARCH 1, it was heavily pretreated patients getting the single agent.

José Baselga, MD, PhD: Yes. We had very interesting activity, and we’re talking about partial responses in patients with pretreated disease. They were not small. But I do think that these agents will need to be given in combination with hormone therapy. I don’t see it as…

Adam M. Brufsky, MD, PhD: As a single agent.

José Baselga, MD, PhD: I don’t.

Denise A. Yardley, MD: I think the other interesting thing, too, is the trials that are ongoing in patients with CNS activity, because it has penetration into that. So, it will be interesting to see.

Adam M. Brufsky, MD, PhD: Do you think it’s going to be a class effect, though? Do you think it will be a class effect on everybody? Do you think this is going to be a class effect on all brain metastases, or not? In other words, will it matter what CDK4 inhibitor you give to get CNS penetration, or will it be specific to the drug?

Debu Tripathy, MD: I think some of the preclinical models suggest that there is actually better CNS penetration with abemaciclib—that it is agent-specific.

Adam M. Brufsky, MD, PhD: Really, seriously, it’s going to be agent-specific?

Debu Tripathy, MD: Well, the human studies haven’t been done, but these are from preclinical models about CNS penetration.

Carlos L. Arteaga, MD: And there are a number of studies now that will be using abemaciclib post-progression on palbociclib or ribociclib, and so those will tell us whether or not there will be some incomplete cross-reactivity.

Debu Tripathy, MD: And there’s an ongoing study specifically for CNS metastasis with abemaciclib.

Transcript Edited for Clarity