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CDK4/6 Inhibitors in Hormone Receptor-Driven MBC

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Wednesday, Jun 29, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
So, speaking about really cool science—now that we’ve touched on—the CDK4/6 inhibitors. I’m curious about the more scientifically oriented members of this panel—did you a priori think they were going to work in luminal A disease? Where did that come from?

Carlos L. Arteaga, MD: That came from a very important screen done by colleagues at UCLA.

Adam M. Brufsky, MD, PhD: Right.

Carlos L. Arteaga, MD: Actually I’m not surprised. I would argue that, for example, in triple-negative disease, many of us thought that it would be unlikely that it would work just because of the high prevalence of loss of RB (retinoblastoma). In HER2-positive disease, I personally did not anticipate it, but I’m not surprised that they are good in luminal.

Adam M. Brufsky, MD, PhD: Good point. The RB loss in triple-negative disease I think is where it came. It’s a very good point.

Carlos L. Arteaga, MD: A major target of the estrogen receptor is cyclin D1—some MEK and cyclin D1—so it’s intuitive that it would work in that setting.

Adam M. Brufsky, MD, PhD: Given that, Kim, let’s talk about things that were presented at ASCO this year. I think the big news really is PALOMA-3, among others. We’ll talk about a bunch of other CDK4/6 inhibitors, but the first one really was palbociclib in PALOMA-3. Can you kind of summarize that for us?

Kimberly L. Blackwell, MD: Yes. We now have three trials that basically look at the addition of palbociclib to anti-estrogen therapy—endocrine therapy—both fulvestrant and letrozole. And what we see across the board is almost a near doubling—give or take a month or two, in progression-free survival (PFS) with the addition of palbociclib to the endocrine therapy backbone. So, very exciting! To date, we’ve not seen a survival benefit, in part because this is a population of patients that’s very hard to see a survival benefit in. And, so, I think we’re quickly approaching a time where this becomes a standard of care for everyone receiving endocrine therapy in the metastatic setting.

Adam M. Brufsky, MD, PhD: So, preliminary abstracts from this trial show that it’s a 24-month progression-free survival. That’s 2 years for first-line therapy for metastatic disease. We’ve all been in this business a long time and to see that is fairly substantial. And I guess the question is, if it does become the standard of care, what are the role of some of these other things? I think that first of all, before we talk about that, let’s talk about other CDK4/6 inhibitors. We have data now from the MONARCH series of trials, the first presentation of abemaciclib. Joyce, do you want to talk about abemaciclib?

Joyce A. O’Shaughnessy, MD: Yes. Abemaciclib is a more CDK4 than CDK6 inhibitor, so it has less myelosuppression because it doesn’t get as much CDK6. But it has more GI toxicity; anorexia, diarrhea, some nausea, and tachyphylaxis over time. But, because it’s not myelosuppressive, it can be given daily so you don’t have to have the 3 weeks on, 1 week off schedule—which may end up being a therapeutic advantage at the end of the day. We will have to wait for randomized trials, but it’s a very interesting agent because it’s showing, in terms of the data we have so far, the most activity later-line. We’re waiting for early-line trials. The MONARCH series is coming earlier with letrozole and fulvestrant, but presented here are data from a large phase II trial—about 130 patients, later-line, fairly heavily pretreated patients, single-agent abemaciclib, again without an ER antagonist—showing a response rate of 17% at 8 months of follow-up and 19.7% at 12 month of follow-up but a clinical benefit rate of 42%, which is quite impressive for this single agent. So, a very powerful CDK4/6 inhibitor. We wait for earlier-line studies. The other thing about it is that it penetrates the CNS. I have a patient who’s been on it over 3 years now with multiple brain metastases. I have another patient who went to the University of Colorado to participate in their ongoing CNS-directed therapy trial. Right now, she’s responding. So, it’s a really exciting agent as well for brain metastases.

Sunil Verma, MD, MSEd, FRCPC: I think what was really appealing to me when we looked at the data is, whether the duration of response is sustained? Because the response rate is very important in this setting, but are these people going to be able to maintain on this treatment for a long period of time? And the duration of the response for those patients responding was close to 9 or 10 months. And this was a heavily pretreated patient population, all of them had taxane, half of them had capecitabine.

Joyce A. O’Shaughnessy, MD: That’s impressive!

Sunil Verma, MD, MSEd, FRCPC: That’s a good result. And I must say kudos to the FDA because they gave breakthrough designation to abemaciclib, they gave breakthrough designation to palbociclib, and they bet on it. And now that we have seen positive trials in PALOMA-2 and now in MONARCH-1. The process is working.

Kimberly L. Blackwell, MD: The PFS was 6 months, you think about all the other trials, even with first-line endocrine therapy—3.8 months that we’ve seen with exemestane and fulvestrant. So, this is a near doubling of PFS for patients who really had run out of endocrine-based options and had received chemotherapy. So, although the response rate of 19% at 12 months was a little underwhelming, I think the PFS, the duration of response, are the really exciting things to come out of that study.

Adam M. Brufsky, MD, PhD: And the thing that really excited me—I think Sunil was on to your point—the overall survival of that patient group was 17.7 months. That to me, in that group, that’s heavily pretreated like that... And we know from the EMBRACE trials of eribulin, even though it’s not quite the same correlation, the overall survival is about 13 or so months with eribulin. It’s kind of interesting.

Carlos L. Arteaga, MD: Yes, the suggestion that a targeted therapy would be better to chemotherapy in this setting a few years ago would have been almost heretical.

Adam M. Brufsky, MD, PhD: I know. This is really a sea change the way things are going.

Sunil Verma, MD, MSEd, FRCPC: And what you’re doing is you’re basically adding in another agent in the continuum of metastatic breast cancer therapies that is giving you the 6 months PFS, that is giving you this response rate. So, I think that allows us to have an option now in patients, and hopefully is going to improve survival.

Kimberly L. Blackwell, MD: It’s the first targeted therapy—if we exclude endocrine therapy, which we have had for a long time—that’s used as a single agent to demonstrate activity. We can’t say that about any of the approved HER2 targeted agents. I think it’s pretty exciting to have a single targeted therapy that’s been demonstrated to achieve this.

Carlos L. Arteaga, MD: The other thing is that a lot of these patients have ER-positive disease, and this is a drug, just because it may work in the same axis, that may dispense the need of the simultaneous anti-estrogen therapy. That may be beneficial for the quality of life of someone.

Adam M. Brufsky, MD, PhD: Yes, absolutely.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
So, speaking about really cool science—now that we’ve touched on—the CDK4/6 inhibitors. I’m curious about the more scientifically oriented members of this panel—did you a priori think they were going to work in luminal A disease? Where did that come from?

Carlos L. Arteaga, MD: That came from a very important screen done by colleagues at UCLA.

Adam M. Brufsky, MD, PhD: Right.

Carlos L. Arteaga, MD: Actually I’m not surprised. I would argue that, for example, in triple-negative disease, many of us thought that it would be unlikely that it would work just because of the high prevalence of loss of RB (retinoblastoma). In HER2-positive disease, I personally did not anticipate it, but I’m not surprised that they are good in luminal.

Adam M. Brufsky, MD, PhD: Good point. The RB loss in triple-negative disease I think is where it came. It’s a very good point.

Carlos L. Arteaga, MD: A major target of the estrogen receptor is cyclin D1—some MEK and cyclin D1—so it’s intuitive that it would work in that setting.

Adam M. Brufsky, MD, PhD: Given that, Kim, let’s talk about things that were presented at ASCO this year. I think the big news really is PALOMA-3, among others. We’ll talk about a bunch of other CDK4/6 inhibitors, but the first one really was palbociclib in PALOMA-3. Can you kind of summarize that for us?

Kimberly L. Blackwell, MD: Yes. We now have three trials that basically look at the addition of palbociclib to anti-estrogen therapy—endocrine therapy—both fulvestrant and letrozole. And what we see across the board is almost a near doubling—give or take a month or two, in progression-free survival (PFS) with the addition of palbociclib to the endocrine therapy backbone. So, very exciting! To date, we’ve not seen a survival benefit, in part because this is a population of patients that’s very hard to see a survival benefit in. And, so, I think we’re quickly approaching a time where this becomes a standard of care for everyone receiving endocrine therapy in the metastatic setting.

Adam M. Brufsky, MD, PhD: So, preliminary abstracts from this trial show that it’s a 24-month progression-free survival. That’s 2 years for first-line therapy for metastatic disease. We’ve all been in this business a long time and to see that is fairly substantial. And I guess the question is, if it does become the standard of care, what are the role of some of these other things? I think that first of all, before we talk about that, let’s talk about other CDK4/6 inhibitors. We have data now from the MONARCH series of trials, the first presentation of abemaciclib. Joyce, do you want to talk about abemaciclib?

Joyce A. O’Shaughnessy, MD: Yes. Abemaciclib is a more CDK4 than CDK6 inhibitor, so it has less myelosuppression because it doesn’t get as much CDK6. But it has more GI toxicity; anorexia, diarrhea, some nausea, and tachyphylaxis over time. But, because it’s not myelosuppressive, it can be given daily so you don’t have to have the 3 weeks on, 1 week off schedule—which may end up being a therapeutic advantage at the end of the day. We will have to wait for randomized trials, but it’s a very interesting agent because it’s showing, in terms of the data we have so far, the most activity later-line. We’re waiting for early-line trials. The MONARCH series is coming earlier with letrozole and fulvestrant, but presented here are data from a large phase II trial—about 130 patients, later-line, fairly heavily pretreated patients, single-agent abemaciclib, again without an ER antagonist—showing a response rate of 17% at 8 months of follow-up and 19.7% at 12 month of follow-up but a clinical benefit rate of 42%, which is quite impressive for this single agent. So, a very powerful CDK4/6 inhibitor. We wait for earlier-line studies. The other thing about it is that it penetrates the CNS. I have a patient who’s been on it over 3 years now with multiple brain metastases. I have another patient who went to the University of Colorado to participate in their ongoing CNS-directed therapy trial. Right now, she’s responding. So, it’s a really exciting agent as well for brain metastases.

Sunil Verma, MD, MSEd, FRCPC: I think what was really appealing to me when we looked at the data is, whether the duration of response is sustained? Because the response rate is very important in this setting, but are these people going to be able to maintain on this treatment for a long period of time? And the duration of the response for those patients responding was close to 9 or 10 months. And this was a heavily pretreated patient population, all of them had taxane, half of them had capecitabine.

Joyce A. O’Shaughnessy, MD: That’s impressive!

Sunil Verma, MD, MSEd, FRCPC: That’s a good result. And I must say kudos to the FDA because they gave breakthrough designation to abemaciclib, they gave breakthrough designation to palbociclib, and they bet on it. And now that we have seen positive trials in PALOMA-2 and now in MONARCH-1. The process is working.

Kimberly L. Blackwell, MD: The PFS was 6 months, you think about all the other trials, even with first-line endocrine therapy—3.8 months that we’ve seen with exemestane and fulvestrant. So, this is a near doubling of PFS for patients who really had run out of endocrine-based options and had received chemotherapy. So, although the response rate of 19% at 12 months was a little underwhelming, I think the PFS, the duration of response, are the really exciting things to come out of that study.

Adam M. Brufsky, MD, PhD: And the thing that really excited me—I think Sunil was on to your point—the overall survival of that patient group was 17.7 months. That to me, in that group, that’s heavily pretreated like that... And we know from the EMBRACE trials of eribulin, even though it’s not quite the same correlation, the overall survival is about 13 or so months with eribulin. It’s kind of interesting.

Carlos L. Arteaga, MD: Yes, the suggestion that a targeted therapy would be better to chemotherapy in this setting a few years ago would have been almost heretical.

Adam M. Brufsky, MD, PhD: I know. This is really a sea change the way things are going.

Sunil Verma, MD, MSEd, FRCPC: And what you’re doing is you’re basically adding in another agent in the continuum of metastatic breast cancer therapies that is giving you the 6 months PFS, that is giving you this response rate. So, I think that allows us to have an option now in patients, and hopefully is going to improve survival.

Kimberly L. Blackwell, MD: It’s the first targeted therapy—if we exclude endocrine therapy, which we have had for a long time—that’s used as a single agent to demonstrate activity. We can’t say that about any of the approved HER2 targeted agents. I think it’s pretty exciting to have a single targeted therapy that’s been demonstrated to achieve this.

Carlos L. Arteaga, MD: The other thing is that a lot of these patients have ER-positive disease, and this is a drug, just because it may work in the same axis, that may dispense the need of the simultaneous anti-estrogen therapy. That may be beneficial for the quality of life of someone.

Adam M. Brufsky, MD, PhD: Yes, absolutely.

Transcript Edited for Clarity
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