Ribociclib for HR+ Advanced Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: On top of FALCON coming out, we now have a CDK4/6 inhibitor. We have PALOMA showing that palbociclib has an improved progression-free survival, almost doubling it actually to—depending on who you talk to—24 months versus 10 or 12. But now the big news, I think, is what do we do? Ribociclib has now been developed. Ribociclib had its big announcement with the big clinical trial in the New England Journal of Medicine 3 or 4 months ago. So, Kim, you want to talk about MONALEESA when you participated in it?

Kimberly L. Blackwell, MD: The MONALEESA studies are looking at the Novartis CDK4/6 inhibitor, ribociclib. With the CDK inhibitors, there are very slight differences in how much they target CDK4 versus CDK6. To date, I haven’t really seen a huge differentiation between what that means in the clinic. If there’s more CDK6 inhibition, then there’s more diarrhea. I might have that backwards. For some people, possibly there’s some more neutropenia depending on the differential inhibition of the 4 versus 6. But we have 2 large studies, MONALEESA-2 and the PALOMA series of studies, that look at palbociclib and that have compared the CDK inhibitors layered on top of a type 2 aromatase inhibitor, in both studies, letrozole. And, in both studies, there has been a double digit improvement in PFS when the CDK inhibitor was added to the letrozole backbone. So, these are important studies. Ribociclib has not been approved here in the United States, but I think we all anticipate that it will be. You’ll like this, I think we should just have the companies at this year’s ASCO meeting just punch it out. You could be like the ringmaster, we’ll just decide. So, I think that’s actually going to be the harder decision. I hope that my patients will see that the competition or having both might drive the patient costs down a little bit. I hope that that’s going to be the case. MONALEESA-2 is an important study. It’s published in the New England Journal of Medicine, similar benefits to what we saw with the PALOMA study with the addition of palbociclib to a type 2 aromatase inhibitor.

Adam M. Brufsky, MD, PhD: A couple of questions related to that. Mark, do you think there’s any difference between the 2 drugs?

Mark E. Robson, MD: I don’t have any experience with ribociclib, but just at least reading stuff, it doesn’t look to me that there are a lot of differences.

Adam M. Brufsky, MD, PhD: What about the side effect profile? Kim, you participated in this. You’re going to be named author on the paper?

Kimberly L. Blackwell, MD: Yes, I was. At the end of the day, there is this very teeny, teeny signal of QTc prolongation that was seen in less than 10 patients with the addition of ribociclib in the phase II studies. And there were, I think, 4 deaths—some well described, others not well described—in the MONALEESA-2 trials. That has not been described with palbociclib. That doesn’t mean it doesn’t exist. Because, assuming that these are same-in-class agents, I would imagine that if you looked hard enough, you’re going to see the signal, if it really is there. It will be interesting to see what the actual label is for ribociclib.

Adam M. Brufsky, MD, PhD: I think that’s the big thing.

Kimberly L. Blackwell, MD: We all experienced this with the eribulin approval. I don’t know what it’s like in your practice, but they saw QTc prolongation in a phase II study in like 6 patients. And, in the label for eribulin, it says monitor potassium and magnesium.

Adam M. Brufsky, MD, PhD: Really? Do you?

Kimberly L. Blackwell, MD: No, but when it says to consider giving them an EKG, none of us do that when we’re starting eribulin in the metastatic setting. So, again, I think that this, to be quite honest, will be more like, what really are the differences? And, at least from where I sit, if you have to go down to there were 4 patients in a thousand-patient study, and there weren’t 0 in an 800-patient study, that tells me that from a toxicity standpoint, they’re probably very similar. But I think we’ll hear a lot about that because that’s the only toxicity difference we can see comparing PALOMA with MONALEESA-2. Again, I think I have a very different threshold of what I ask my patients to do, like with the eribulin example, if they’re facing metastatic breast cancer. I answer that the toxicity is exactly the same, but for those of you who are following this more of the CDK inhibitors, just be aware that there was this very small signal of QTc prolongation. And there’s going to be post approval surveillance both for palbociclib and for ribociclib, and a signal will emerge, I believe, if it’s there.

Adam M. Brufsky, MD, PhD: If it’s there. It’s interesting. You definitely have a little bit different pharmacology, as we said, looking at pharmacodynamics, maybe even different pharmacokinetics and metabolism. Will it be like the aromatase inhibitors? I always wonder. So, in other words, if you’re on palbociclib and you have really bad neutropenia—like there was evidence now from the Asian population, but they seem to have a little bit more neutropenia and you can’t really get in the 125 mg dose of palbociclib—will there be differences? And if they have trouble with palbociclib, we’ll switch to ribociclib and vice versa? Do you think that’s going to happen?

Aditya Bardia, MD, MPH: We don’t have data at this time, but one thing to note is that it is an important issue. So, with palbociclib, neutropenia is the most common side effect, same with ribociclib as well. But with palbociclib, the dose is 125 mg and the capsules come as 125 mg. So, if you have the dose reduced to 100 mg, patients have to get a different capsule. But, with ribociclib, it’s all 200 mg capsules.

Adam M. Brufsky, MD, PhD: Right, it comes in a blister pack.

Aditya Bardia, MD, MPH: So, the dose reduction becomes much easier, and I think over time, we’ll see how it goes.

Kimberly L. Blackwell, MD: And there are data for ribociclib with the Asian subpopulation from MONALEESA-2 that it was actually probably, again, an unfair cross-trial comparison. You just didn’t see the extent of the neutropenia.

Adam M. Brufsky, MD, PhD: Really?

Kimberly L. Blackwell, MD: Yes. I think that is going to get submitted to ASCO this year. Again, it’s—I am going to pull an Adam Brufsky —whatever costs the least for my patient when they go down to the pharmacy. And, to be quite honest, one of the things that has been a pretty sizable hassle with these drugs is you go into the patient’s room, you recommend it, and then it takes you 2 weeks. This is a patient who has either just progressed or just relapsed. They want to start a study. And so, the hassle factor is going to drive some of my prescribing patterns, unless there is something that emerges that really shows a clear difference between the 2 studies.

Mark E. Robson, MD: I suspect the payers will, too. I suspect that the label is going to be key, exactly what the parameters are at the label. And these will probably all be specialty pharmacy drugs and the individual payers will negotiate contracts. You may wind up with a preferred one for your payer.

Adam M. Brufsky, MD, PhD: One or the other, right.

Transcript Edited for Clarity