Adam M. Brufsky, MD, PhD: We want to talk about the last of the 3 actually. MONARCH3 is going to be presented here. Speaking about side effects, we’ve talked about how palbociclib and ribociclib are the same, or very similar, drugs. Is abemaciclib qualitatively or quantitatively different?

Hope S. Rugo, MD: Abemaciclib is a really interesting drug because these drugs clearly have efficacy in the same setting. But abemaciclib, because it inhibits CDKs in a slightly different way, a different ratio—and we think that that’s what’s responsible for this differential toxicity—it doesn’t cause as much bone marrow toxicity, like one-third of the number of patients have grade 3/4 neutropenia. But you can give it continuously. So, that’s one thing. Instead of taking 3 weeks on and then letting the bone marrow recover for a week, you actually take it all the time. The second big issue, which we think is probably related to this differential inhibition of CDK, is that patients have diarrhea. And depending on the dose and the combination, you can actually get what is a clinically significant percentage of patients with grade 3 diarrhea.

They found in MONARCH2 that if we’re giving the drug in combination with fulvestrant, a smaller dose was required. So, after the first less than 200 patients who were enrolled, they reduced the dose and markedly reduced the amount of serious diarrhea. But apparently it didn’t impact efficacy because the trial, which had a group of patients without prior exposure to chemotherapy, had a tremendous benefit and even the patients who got the hormone therapy alone did better than some of the other trials because they were earlier in the course of disease.

Diarrhea seems to be fairly easily managed with treatment, in patients who need it, using an antidiarrheal therapy. But it doesn’t go away. It’s not as if you get a whole lot of diarrhea in the first month and then—like some of the other agents we’ll talk about in the sessions—it goes away. But patients have diarrhea on and off during the course of treatment and a little bit more of this GI discomfort.

Adam M. Brufsky, MD, PhD: So, we have abemaciclib, which looks like a slightly different drug. We have MONARCH1 that has, I think, single-agent abemaciclib in heavily-pretreated patients. And, Hope, you presented data, I believe, at ASCO about the survival of those patients.

Hope S. Rugo, MD: At ACR this year, and actually those data are being updated, essentially represented, here at ESMO, as well as some additional information. And the survival is quite good, I think, in those patients. It’s not any different than you would have expected. It’s another option of treatment for these patients who had 20% single-agent response. Some of the patients had quite durable responses. In fact, it’s certainly as good, if not better, than capecitabine as a single agent in that setting. So, I think that’s actually quite intriguing, and it does bring up the question of, what we do in sequence. Once we have 3 CDK4/6 inhibitors, do we give some first in combination and then we give one, like abemaciclib, after? Of course, abemaciclib doesn’t want to be after. Or do you give that up front? When would you use it, as a single agent?

And then there have been some data on abemaciclib in brain metastases very, very early, and we know that the drug gets into the brain. So, that’s going to be interesting to see as well, and maybe that will help us understand how to use these drugs.

Adam M. Brufsky, MD, PhD: Some of your European colleagues, is there interest in abemaciclib in Europe as well?

Michael Untch, MD: We don’t have it available at the moment.

Hope S. Rugo, MD: No one does.

Adam M. Brufsky, MD, PhD: No one does.

Michael Untch, MD: And we eagerly wait for the data, which at least we know from a press release that the data are positive. So, we’re very curious, and as Hope has stated, it comes from the same class of drugs, but it seemed that it has a different point of action and side effects. So, yes, these 2 drugs will add a lot to the heterogeneity and the possibility of treating our patients with HER2-negative hormone receptor-positive metastatic disease.

Michael Gnant, MD: I believe that when we discuss sequencing these agents, clearly that’s, in clinical terms, the next step to explore. It’s probably fair to say that, at this point, if you sequence 2 of these, it would be abemaciclib and one of the others. It’s one way or the other.

Adam M. Brufsky, MD, PhD: So, you wouldn’t do palbociclib/ribociclib, you’d do palbociclib/ abemaciclib or ribociclib/abemaciclib?

Michael Gnant, MD: I’m sure there will be some data about this, but from today’s point-of-view, I don’t think that there’s too much rationale to sequence palbociclib with ribociclib.

Hope S. Rugo, MD: It’s just AI’s.

Adam M. Brufsky, MD, PhD: Yes.

Michael Gnant, MD: It’s a little bit. It reminds me a little bit of the situation with anastrozole, letrozole, and exemestane.

Adam M. Brufsky, MD, PhD: Very similar.

Michael Gnant, MD: And with respect to the abemaciclib, I believe, based on the differential binding affinity to cyclin 1 and cyclin 2—what Hope has already alluded to—there is anti-monotherapy activity. There is a rationale that it could act a little bit differentially. Clearly, this comes with diarrhea, which is usually manageable if you titrate your loperamide accordingly. And I’m just saying from the neoadjuvant studies we have been contributing to, and clearly in clinical practice, it’s going to be an advantage to have continuous dosing. Because don’t forget, many of our patients are elderly. They have comorbidities, so it may not be the only tablet they take. It may be 1 out of 10. And sorting out the dose reduction, is it week 3 or week 4, and with everything else, it may be a challenge for some of our patients.

Transcript Edited for Clarity