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FDA Approval for Abemaciclib

Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Published Online: Sunday, Nov 12, 2017



Transcript: 

Adam M. Brufsky, MD, PhD: Abemaciclib was approved by the FDA for 2 very interesting indications, 1 of which overlaps with ribociclib and palbociclib and 1 of which does not. I think that’s probably going to be the most important indication. Abemaciclib was approved by the FDA for the treatment of hormone receptor-positive metastatic breast cancer that has progressed on an aromatase inhibitor, in use with fulvestrant. That was based on the MONARCH-2 trial, which was fulvestrant with or without abemaciclib in women who had progressed on an aromatase inhibitor. They were on an aromatase inhibitor in the adjuvant setting, or they had progressed in the metastatic setting.

The important part of that particular trial was that the women did not have chemotherapy at all. And it really, in many cases, was a first-line metastatic therapy, but in people who had progressed on adjuvant aromatase inhibitors. The interesting thing about that trial is that the progression-free survival is about 16-and-a-half to 17 months, 16.7 months, which is a lot higher than the 8 or 9 months seen in the MONALEESA studies as well as in the PALOMA-3 study, which were similar patient populations. Except they were allowed to have chemotherapy. So, those were a little bit of a later line than with abemaciclib.

And so, therefore, it’s got the same indication with fulvestrant as a second-line therapy for the treatment of ER-positive metastatic breast cancer progressed on an aromatase inhibitor. But the unique indication for abemaciclib is as a single-agent in heavily-pretreated metastatic breast cancer for patients who already had endocrine therapy and chemotherapy. I think that is the way the label is written. That’s based on the MONARCH-1 trial, where these patients had a response rate of about 20% and had, in the most recent data, an overall survival of about 22 months, which is quite high for that patient population. So, I think that really is a novel indication, one that a lot of us are going to use first in our practice.

I think that these drugs clearly have changed the natural history of metastatic breast cancers that are ER-positive. It will be a few years before we see the real-world survival data, but there’s no doubt, even if in the clinical trials we don’t see it. But I think when the real-world registry data and other kinds of data, EMR data, come out, we are going to see that these drugs clearly—all 3 of them—have moved the needle for the treatment of metastatic ER-positive breast cancer. The issue is which drug to use when. I think that is really the bigger issue.

The first approval was expected. Were these approvals expected by the FDA? I think the first one was. I think that the MONARCH-2 data were very clear, very similar to the MONALEESA data and to the PALOMA-3 data, and I think that everybody is very excited about that. What was interesting was really the even more significant label, which is for the heavily pretreated patients. That trial, MONARCH-1, was a 128-patient phase II trial that didn’t meet its primary endpoint. The primary endpoint was a response rate, I think, of 25%. It didn’t meet that. And so, everybody was shocked. But I think it’s great. I think it’s fabulous. I think it’s very forward thinking of the FDA to do this. I think that this is where this drug may make the biggest impact, at least initially, in the treatment of metastatic breast cancer.

Where will I use abemaciclib at this point? I think that abemaciclib, clearly based on the MONARCH-3 trial, is very similar in its efficacy to ribociclib as well as palbociclib. The biggest issue in this first-line setting is going to be diarrhea. There’s going to be less neutropenia, but there clearly is more diarrhea that has to be managed. I think that it’s going to be a real challenge to decide which drug to use. I think that palbociclib, really, is easy to give. The biggest side effect is neutropenia. Ribociclib is pretty much the same, although with ribociclib there are some issues with QT prolongation and drug interaction, specifically with antidepressants and antinausea agents, that can be problematic.

With palbociclib, there’s not a lot of dosage flexibility. You have to order a completely new set of pills for somebody if they need a dose reduction from 125 mg to 100 mg. So, all 3 of them have issues of various kinds, and I think it’s going to depend on the physician’s choice —their comfort with that particular agent. But I think they all work really well in that first-line setting, although abemaciclib is not approved there, actually. It’s only approved in the second-line setting.

In terms of the second-line setting with fulvestrant, I think all of the drugs seem to be about the same in their efficacy. I think the big difference in progression-free survival that we see in the MONARCH-2 trial is because these patients were less heavily pretreated. I think the rule of thumb is going to be to treat whatever disease state you have with hormone therapy and double the PFS with a CDK4/6 inhibitor. That seems to be what it is. And so, in that second-line setting, the same issues apply. I think it’s going to depend on individual physician comfort with the various side effects. Do we want to worry about dosage flexibility with palbociclib? Do we want to worry about QT prolongation and drug interaction with ribociclib? Or do we want to worry about diarrhea with abemaciclib? And I think that it’s going to be up to individual physicians. I think they’re all going to work really well. They’re all really good drugs. They all really have moved the needle dramatically, and it’s going to depend on the physician’s comfort with each individual potential side effect profile.

I think the biggest area where abemaciclib is different from the other 2 is its single-agent activity. The other drugs may have single-agent activity, but I think there are no big trials that have shown that. We are presenting at San Antonio, our group, some data in far-advanced metastatic disease. It’s very similar to the MONARCH-1 population. We did an expanded access trial before palbociclib was approved, and we’re actually presenting clinical data, response data, from those patients at San Antonio this year. So, we’ll have some data with other drugs. But on the other hand, I think abemaciclib has the most data, and it has the approval from the FDA. The other 2 do not. I think this is a really interesting idea.

People who have been heavily pretreated have had a lot of different therapies. Maybe they haven’t had a CDK4/6 inhibitor yet, and I think this is an area where there are not a lot of things that are efficacious. People will tolerate having the diarrhea a lot more, put up with it, because they now have a therapy where they didn’t have anything before. I think that, to me, is where this agent may actually start. It will probably be used everywhere, but I think a lot of us will want to use it in that setting first.

The big thing in managing the diarrhea for abemaciclib is to be proactive, to really start antidiarrheals fairly early. Let the patient know that diarrhea is going to be an issue and that it can be controlled. Generally, most people tachyphylax to it in either 1 or 2 cycles. So, I think that, especially in that heavily-pretreated setting, it’s going to be really interesting to see the activity in the real world of abemaciclib.

Transcript Edited for Clarity 
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Transcript: 

Adam M. Brufsky, MD, PhD: Abemaciclib was approved by the FDA for 2 very interesting indications, 1 of which overlaps with ribociclib and palbociclib and 1 of which does not. I think that’s probably going to be the most important indication. Abemaciclib was approved by the FDA for the treatment of hormone receptor-positive metastatic breast cancer that has progressed on an aromatase inhibitor, in use with fulvestrant. That was based on the MONARCH-2 trial, which was fulvestrant with or without abemaciclib in women who had progressed on an aromatase inhibitor. They were on an aromatase inhibitor in the adjuvant setting, or they had progressed in the metastatic setting.

The important part of that particular trial was that the women did not have chemotherapy at all. And it really, in many cases, was a first-line metastatic therapy, but in people who had progressed on adjuvant aromatase inhibitors. The interesting thing about that trial is that the progression-free survival is about 16-and-a-half to 17 months, 16.7 months, which is a lot higher than the 8 or 9 months seen in the MONALEESA studies as well as in the PALOMA-3 study, which were similar patient populations. Except they were allowed to have chemotherapy. So, those were a little bit of a later line than with abemaciclib.

And so, therefore, it’s got the same indication with fulvestrant as a second-line therapy for the treatment of ER-positive metastatic breast cancer progressed on an aromatase inhibitor. But the unique indication for abemaciclib is as a single-agent in heavily-pretreated metastatic breast cancer for patients who already had endocrine therapy and chemotherapy. I think that is the way the label is written. That’s based on the MONARCH-1 trial, where these patients had a response rate of about 20% and had, in the most recent data, an overall survival of about 22 months, which is quite high for that patient population. So, I think that really is a novel indication, one that a lot of us are going to use first in our practice.

I think that these drugs clearly have changed the natural history of metastatic breast cancers that are ER-positive. It will be a few years before we see the real-world survival data, but there’s no doubt, even if in the clinical trials we don’t see it. But I think when the real-world registry data and other kinds of data, EMR data, come out, we are going to see that these drugs clearly—all 3 of them—have moved the needle for the treatment of metastatic ER-positive breast cancer. The issue is which drug to use when. I think that is really the bigger issue.

The first approval was expected. Were these approvals expected by the FDA? I think the first one was. I think that the MONARCH-2 data were very clear, very similar to the MONALEESA data and to the PALOMA-3 data, and I think that everybody is very excited about that. What was interesting was really the even more significant label, which is for the heavily pretreated patients. That trial, MONARCH-1, was a 128-patient phase II trial that didn’t meet its primary endpoint. The primary endpoint was a response rate, I think, of 25%. It didn’t meet that. And so, everybody was shocked. But I think it’s great. I think it’s fabulous. I think it’s very forward thinking of the FDA to do this. I think that this is where this drug may make the biggest impact, at least initially, in the treatment of metastatic breast cancer.

Where will I use abemaciclib at this point? I think that abemaciclib, clearly based on the MONARCH-3 trial, is very similar in its efficacy to ribociclib as well as palbociclib. The biggest issue in this first-line setting is going to be diarrhea. There’s going to be less neutropenia, but there clearly is more diarrhea that has to be managed. I think that it’s going to be a real challenge to decide which drug to use. I think that palbociclib, really, is easy to give. The biggest side effect is neutropenia. Ribociclib is pretty much the same, although with ribociclib there are some issues with QT prolongation and drug interaction, specifically with antidepressants and antinausea agents, that can be problematic.

With palbociclib, there’s not a lot of dosage flexibility. You have to order a completely new set of pills for somebody if they need a dose reduction from 125 mg to 100 mg. So, all 3 of them have issues of various kinds, and I think it’s going to depend on the physician’s choice —their comfort with that particular agent. But I think they all work really well in that first-line setting, although abemaciclib is not approved there, actually. It’s only approved in the second-line setting.

In terms of the second-line setting with fulvestrant, I think all of the drugs seem to be about the same in their efficacy. I think the big difference in progression-free survival that we see in the MONARCH-2 trial is because these patients were less heavily pretreated. I think the rule of thumb is going to be to treat whatever disease state you have with hormone therapy and double the PFS with a CDK4/6 inhibitor. That seems to be what it is. And so, in that second-line setting, the same issues apply. I think it’s going to depend on individual physician comfort with the various side effects. Do we want to worry about dosage flexibility with palbociclib? Do we want to worry about QT prolongation and drug interaction with ribociclib? Or do we want to worry about diarrhea with abemaciclib? And I think that it’s going to be up to individual physicians. I think they’re all going to work really well. They’re all really good drugs. They all really have moved the needle dramatically, and it’s going to depend on the physician’s comfort with each individual potential side effect profile.

I think the biggest area where abemaciclib is different from the other 2 is its single-agent activity. The other drugs may have single-agent activity, but I think there are no big trials that have shown that. We are presenting at San Antonio, our group, some data in far-advanced metastatic disease. It’s very similar to the MONARCH-1 population. We did an expanded access trial before palbociclib was approved, and we’re actually presenting clinical data, response data, from those patients at San Antonio this year. So, we’ll have some data with other drugs. But on the other hand, I think abemaciclib has the most data, and it has the approval from the FDA. The other 2 do not. I think this is a really interesting idea.

People who have been heavily pretreated have had a lot of different therapies. Maybe they haven’t had a CDK4/6 inhibitor yet, and I think this is an area where there are not a lot of things that are efficacious. People will tolerate having the diarrhea a lot more, put up with it, because they now have a therapy where they didn’t have anything before. I think that, to me, is where this agent may actually start. It will probably be used everywhere, but I think a lot of us will want to use it in that setting first.

The big thing in managing the diarrhea for abemaciclib is to be proactive, to really start antidiarrheals fairly early. Let the patient know that diarrhea is going to be an issue and that it can be controlled. Generally, most people tachyphylax to it in either 1 or 2 cycles. So, I think that, especially in that heavily-pretreated setting, it’s going to be really interesting to see the activity in the real world of abemaciclib.

Transcript Edited for Clarity 
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