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Differences Among CDK4/6 Inhibitors in HR+ mBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute; Michael Gnant, MD, Medical University of Vienna; Joyce A. OShaughnessy, MD, Baylor University Medical Center; Hope S. Rugo, MD, University of California San Francisco Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published Online: Wednesday, Oct 11, 2017



Transcript: 

Michael Gnant, MD: I think that in almost every respect, palbociclib and ribociclib—and you can look at the molecular structure, which is very similar—are probably doing the same. There’s one difference, which I believe is unfortunate that in the MONALEESA trial the issue of QTc prolongation popped up, which has led to a little bit differential regulatory rules about ECG and to be done at the start of the treatment in many environments. But I think in terms of efficacy and also in terms of the side effect profile, they’re very much the same. So, the difference has come down to the number of tablets to take per day, scheduling, and I’m pretty sure that the marketing departments in either company will dwell on this.

Adam M. Brufsky, MD, PhD: Is there any reason theoretically, a metabolite or anything like that, to believe that? Because I agree. Joyce had said this before, the curves look pretty close, the drugs look very, very similar. Is there any theoretical or other reason to believe that a patient who’s not responding to, say, palbociclib and an AI would not respond to ribociclib and an AI?

Hope S. Rugo, MD: No.

Michael Gnant, MD: Honestly, I don’t think so. I think most of us would believe that abemaciclib is different.

Adam M. Brufsky, MD, PhD: We’ll get to that one in a second.

Michael Gnant, MD: Yes, but the 2 others pretty much similar also in the clinical application.

Adam M. Brufsky, MD, PhD: It’s just really is more in the formulation and the side effect profile, etc.

Hope S. Rugo, MD: Right, that’s it, and the pills and how easy it is to dose reduce and things like that.

Michael Untch, MD: We are going to face the same, not problem, but the same process of this discussion in Germany now, and many other places in Europe, having ribociclib approved since last week in Europe. We are going to have the same discussion.

Now, I would like to see, and I hope that we are going to see—and with this data we might convince more the G-BA, this authority, which is going to make the payment procedure coming down to the patient—life quality. They want to see life quality data. Did the patients who were put on ribociclib compare to the standard arm? Did they have less pains, for example? If that is on the chart, if that is going to be proven, then this is more convincing. Having time to progression as an endpoint is fine. And maybe in some of the subgroups—these are also convincing data for the authority—we might be able to show a survival benefit. I don’t know, maybe bone-only disease.

And again, coming back to the life quality issue, the G-BA was stating—and this is not correct—that CDK4/6 inhibitors have a similar side effect spectrum like chemotherapy, like neutropenia. Now neutropenia is something you measure from the blood—asking the patient, “Did you know that you have neutropenia?” and they say, “I don’t know, I didn’t know that I have neutropenia.” If the patient has neutropenic fever, then it’s different. So, this is the point of convincing, where we have to convince this authority that chemotherapy-induced side effects and CDK4/6 side effects are different.

Michael Gnant, MD: Because this is happening actually in several environments. Maybe it’s super provocative, but I would suggest that we should make a clear statement. Overall survival in luminal breast cancer is not a rational endpoint any longer. There is a simple reason for this, and this is the numerics—as we fortunately are able to treat our patients with multiple lines of endocrine-targeted interventions plus chemotherapy maybe, if needed. The median overall survival of metastatic luminal breast cancer is now exceeding 5 years for many, many patients. And even our most spectacular PFS differences are just a small proportion of this, one-fifth or something like this. It’s highly unlikely, even when we observe a hazard ratio—which we are carried away with—is 0.4, 0.3, that this can actually translate into significance, that this can be significant over survival benefits in everything.
 
So, while I accept that it was fair that authorities obviously have the job to define value and what is the cost of which benefit, I think we should try as clinician scientists to send this message to say, in this segment of the disease, overall survival is not the most rational endpoint any longer. This does not take away the obligation to talk about side effects, which I guess we will do in a minute, and clearly, patients don’t know. I can tell you when you start doing this—and you all know this—you receive frantic calls from husbands, from GPs putting G-CSF into these patients.

So, I think it’s a matter of education of our colleagues, of ourselves, and of patients and their families to say, “Well, yes, numerical neutropenia is the main side effect of this class of drugs.” However, it is mechanistically different from the neutropenia we see after chemotherapy, because essentially to these neutrophil precursor cells, the same happens—we hope and know that it happens to cancer cells. They are stopped but they are not damaged, and they’re available once you stop the drug to immediately produce neutropenic fever. As you have mentioned, it’s an extremely rare observation. I think it was less than 2% in all these trials, which I think is an important message to you. And I tell you, using these drugs in the early breast cancer setting in clinical trials, that there is a huge communication of effort necessary for the whole system, that this is a completely different ballpark from chemotherapy-induced neutropenia.

Transcript Edited for Clarity 

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Transcript: 

Michael Gnant, MD: I think that in almost every respect, palbociclib and ribociclib—and you can look at the molecular structure, which is very similar—are probably doing the same. There’s one difference, which I believe is unfortunate that in the MONALEESA trial the issue of QTc prolongation popped up, which has led to a little bit differential regulatory rules about ECG and to be done at the start of the treatment in many environments. But I think in terms of efficacy and also in terms of the side effect profile, they’re very much the same. So, the difference has come down to the number of tablets to take per day, scheduling, and I’m pretty sure that the marketing departments in either company will dwell on this.

Adam M. Brufsky, MD, PhD: Is there any reason theoretically, a metabolite or anything like that, to believe that? Because I agree. Joyce had said this before, the curves look pretty close, the drugs look very, very similar. Is there any theoretical or other reason to believe that a patient who’s not responding to, say, palbociclib and an AI would not respond to ribociclib and an AI?

Hope S. Rugo, MD: No.

Michael Gnant, MD: Honestly, I don’t think so. I think most of us would believe that abemaciclib is different.

Adam M. Brufsky, MD, PhD: We’ll get to that one in a second.

Michael Gnant, MD: Yes, but the 2 others pretty much similar also in the clinical application.

Adam M. Brufsky, MD, PhD: It’s just really is more in the formulation and the side effect profile, etc.

Hope S. Rugo, MD: Right, that’s it, and the pills and how easy it is to dose reduce and things like that.

Michael Untch, MD: We are going to face the same, not problem, but the same process of this discussion in Germany now, and many other places in Europe, having ribociclib approved since last week in Europe. We are going to have the same discussion.

Now, I would like to see, and I hope that we are going to see—and with this data we might convince more the G-BA, this authority, which is going to make the payment procedure coming down to the patient—life quality. They want to see life quality data. Did the patients who were put on ribociclib compare to the standard arm? Did they have less pains, for example? If that is on the chart, if that is going to be proven, then this is more convincing. Having time to progression as an endpoint is fine. And maybe in some of the subgroups—these are also convincing data for the authority—we might be able to show a survival benefit. I don’t know, maybe bone-only disease.

And again, coming back to the life quality issue, the G-BA was stating—and this is not correct—that CDK4/6 inhibitors have a similar side effect spectrum like chemotherapy, like neutropenia. Now neutropenia is something you measure from the blood—asking the patient, “Did you know that you have neutropenia?” and they say, “I don’t know, I didn’t know that I have neutropenia.” If the patient has neutropenic fever, then it’s different. So, this is the point of convincing, where we have to convince this authority that chemotherapy-induced side effects and CDK4/6 side effects are different.

Michael Gnant, MD: Because this is happening actually in several environments. Maybe it’s super provocative, but I would suggest that we should make a clear statement. Overall survival in luminal breast cancer is not a rational endpoint any longer. There is a simple reason for this, and this is the numerics—as we fortunately are able to treat our patients with multiple lines of endocrine-targeted interventions plus chemotherapy maybe, if needed. The median overall survival of metastatic luminal breast cancer is now exceeding 5 years for many, many patients. And even our most spectacular PFS differences are just a small proportion of this, one-fifth or something like this. It’s highly unlikely, even when we observe a hazard ratio—which we are carried away with—is 0.4, 0.3, that this can actually translate into significance, that this can be significant over survival benefits in everything.
 
So, while I accept that it was fair that authorities obviously have the job to define value and what is the cost of which benefit, I think we should try as clinician scientists to send this message to say, in this segment of the disease, overall survival is not the most rational endpoint any longer. This does not take away the obligation to talk about side effects, which I guess we will do in a minute, and clearly, patients don’t know. I can tell you when you start doing this—and you all know this—you receive frantic calls from husbands, from GPs putting G-CSF into these patients.

So, I think it’s a matter of education of our colleagues, of ourselves, and of patients and their families to say, “Well, yes, numerical neutropenia is the main side effect of this class of drugs.” However, it is mechanistically different from the neutropenia we see after chemotherapy, because essentially to these neutrophil precursor cells, the same happens—we hope and know that it happens to cancer cells. They are stopped but they are not damaged, and they’re available once you stop the drug to immediately produce neutropenic fever. As you have mentioned, it’s an extremely rare observation. I think it was less than 2% in all these trials, which I think is an important message to you. And I tell you, using these drugs in the early breast cancer setting in clinical trials, that there is a huge communication of effort necessary for the whole system, that this is a completely different ballpark from chemotherapy-induced neutropenia.

Transcript Edited for Clarity 
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