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HR+ Metastatic Breast Cancer: Upfront CDK4/6 Inhibition

Panelists: Joyce O Shaughnessy, MD, Baylor-Sammons Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital; Adan M. Brufsky, MD, PhD, Comprehensive Breast Cancer Center; Heather L. McArthur, MD, MPH, Cedars-Sinai Medical Center; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Friday, Jan 25, 2019



Transcript:

Joyce O’Shaughnessy, MD:
Before we go on to what we do after CDK4/6 [cyclin-dependent kinases 4 and 6] inhibition, which is a really interesting question, let me ask Heather something. Do you think there’s any reason to use fulvestrant up front with a CDK4/6 inhibitor or is there no particular advantage over an aromatase inhibitor with CDK4/6?

Heather L. McArthur, MD, MPH: Well, I think it depends on the specific scenario, and as we just touched on the prior exposure to aromatase inhibitor, there’s the duration of the exposure to the prior aromatase inhibitor. I think it really is dependent on their specific history. I think tangentially—not to answer that question—one of the interesting things that actually came out of the PALOMA data was the time to chemotherapy.

Because there was this discussion in the background about whether CDK inhibition exposure was actually creating a more aggressive phenotype of disease. And that was concerning to a lot of us, and it was influencing our decision about applying CDK inhibitors to the first-line versus waiting until a later date, especially in the absence of any clear survival benefit with all the preceding reports. So it was very reassuring to me that the time to chemotherapy was the same, indicating that there wasn’t this biologic change, at least for the population overall.

Joyce O’Shaughnessy, MD: Yes. But now with the MONALEESA-3 data, we have FDA approval for one of the CDK4/6 inhibitors with fulvestrant in the first-line setting. Probably biologically you could use any of them, but from an FDA approval standpoint we have ribociclib and fulvestrant. So, like you said, it just depends on what the previous exposure was.

Heather L. McArthur, MD, MPH: The duration of exposure.

Joyce O’Shaughnessy, MD: Yes, duration of exposure.

Tiffany A. Traina, MD: Which is driving your ESR1 [estrogen receptor 1].

Heather L. McArthur, MD, MPH: And the menopausal status as well because we have data, of course, in combination with tamoxifen.

Joyce O’Shaughnessy, MD: That’s right.

Adam M. Brufsky, MD, PhD: Yes, but you can’t use it.

Joyce O’Shaughnessy, MD: Not with ribociclib.

Adam M. Brufsky, MD, PhD: Not with ribociclib.

Joyce O’Shaughnessy, MD: Yes, but it is good to know. It is good to know that if you think that you’d rather have fulvestrant, at least now we have that option first-line for patients. Any time that you would choose abemaciclib first-line with MONALEESA-3, is that with fulvestrant? The ribociclib is a differentiator there, if you will. It also has the premenopausal FDA approval, and that’s first-line, in MONALEESA-7: ribociclib and letrozole with an LHRH [luteinizing hormone-releasing hormone] agonist. Second-line, we have data in the premenopausal setting with both palbociclib and abemaciclib. So we have premenopausal data with all 3 agents. But, in terms of FDA approval, we have the first-line approval with ribociclib. But, in terms of our 3 choices up front, is there any time people prefer one over another, any subsets of patients, let’s say? Anybody?

Adam M. Brufsky, MD, PhD: It’s tough. I think the biggest thing for me would be the risk of neutropenia. I think if someone comes in and has really been beat up from her adjuvant chemotherapy or maybe has had adjuvant chemotherapy before we used hormones, maybe that’s someone I would consider that for because clearly there’s less neutropenia with abemaciclib.

Joyce O’Shaughnessy, MD: Yes.

Adam M. Brufsky, MD, PhD: But, if you look at the curves, they’re all superimposable.

Heather L. McArthur, MD, MPH: And the hazard ratios.

Adam M. Brufsky, MD, PhD: And the hazard ratios are the same. It’s going to be hard. You’re really making a decision based on adverse effects, right, more than anything.

Heather L. McArthur, MD, MPH: I have to say I’ve been using abemaciclib mostly as monotherapy in the chemotherapy refractory populations, particularly when there’s a history of brain metastasis because of this potential CNS [central nervous system] penetration. So that’s been my primary application, as monotherapy.

Ruth O'Regan, MD: I think the problem is that we were all very used to using palbociclib. So that’s one of the issues. I think if I had a premenopausal patient, just following the data, I might consider RIBO in that patient because it really seems very similar adverse-effect-wise to palbociclib.

Joyce O’Shaughnessy, MD: This is interesting. I guess we don’t know because the other 2 agents have not been looked at in precisely the same way as the New England Journal of Medicine paper that carved out that 20% that was primary refractory, where there wasn’t a benefit from palbociclib. So the question is—but we don’t know the answer—whether ribociclib or abemaciclib would be different. I heard with interest here from The University of Texas MD Anderson Cancer Center, in a poster discussion, preclinical work differentiating abemaciclib and saying that it inhibited across a bunch of cell lines and it inhibited not only CDK4/6 but also CDK1 and 2. And so that’s the cyclin E. But it also shut down cells in G1 but also G2, so some differentiating characteristics. I tend to utilize it in those patients where I think the degree of endocrine therapy resistance is going to be higher. I’m worried that I’m really in an endocrine therapy resistant setting, It’s similar to where I used to use chemotherapy because I’m using  much less chemotherapy.

Adam M. Brufsky, MD, PhD: There are some translation data showing that if you have cyclin E overexpression, you don’t respond as well.

Joyce O’Shaughnessy, MD: That’s right. That’s with palbociclib. That’s PALOMA-3.

Adam M. Brufsky, MD, PhD: That’s with palbociclib? I didn’t know which one it was.

Joyce O’Shaughnessy, MD: Yes.

Ruth O'Regan, MD: And I think also there are some preclinical data saying that ABEMA is the only one that really causes apoptosis. The other 2 do not as much. Some of the discussion asks if the response rate is higher with abemaciclib. But, actually, if you look across the trials at the patient populations, it’s very similar.

Adam M. Brufsky, MD, PhD: Even though they have all these great preclinical data, clinically we just haven’t seen any difference. That’s the issue.

Joyce O’Shaughnessy, MD: Right. We’re taking our boards, we check, they’re all the same, basically, of course. But there are some interesting questions that arise.

Transcript edited for clarity.

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Transcript:

Joyce O’Shaughnessy, MD:
Before we go on to what we do after CDK4/6 [cyclin-dependent kinases 4 and 6] inhibition, which is a really interesting question, let me ask Heather something. Do you think there’s any reason to use fulvestrant up front with a CDK4/6 inhibitor or is there no particular advantage over an aromatase inhibitor with CDK4/6?

Heather L. McArthur, MD, MPH: Well, I think it depends on the specific scenario, and as we just touched on the prior exposure to aromatase inhibitor, there’s the duration of the exposure to the prior aromatase inhibitor. I think it really is dependent on their specific history. I think tangentially—not to answer that question—one of the interesting things that actually came out of the PALOMA data was the time to chemotherapy.

Because there was this discussion in the background about whether CDK inhibition exposure was actually creating a more aggressive phenotype of disease. And that was concerning to a lot of us, and it was influencing our decision about applying CDK inhibitors to the first-line versus waiting until a later date, especially in the absence of any clear survival benefit with all the preceding reports. So it was very reassuring to me that the time to chemotherapy was the same, indicating that there wasn’t this biologic change, at least for the population overall.

Joyce O’Shaughnessy, MD: Yes. But now with the MONALEESA-3 data, we have FDA approval for one of the CDK4/6 inhibitors with fulvestrant in the first-line setting. Probably biologically you could use any of them, but from an FDA approval standpoint we have ribociclib and fulvestrant. So, like you said, it just depends on what the previous exposure was.

Heather L. McArthur, MD, MPH: The duration of exposure.

Joyce O’Shaughnessy, MD: Yes, duration of exposure.

Tiffany A. Traina, MD: Which is driving your ESR1 [estrogen receptor 1].

Heather L. McArthur, MD, MPH: And the menopausal status as well because we have data, of course, in combination with tamoxifen.

Joyce O’Shaughnessy, MD: That’s right.

Adam M. Brufsky, MD, PhD: Yes, but you can’t use it.

Joyce O’Shaughnessy, MD: Not with ribociclib.

Adam M. Brufsky, MD, PhD: Not with ribociclib.

Joyce O’Shaughnessy, MD: Yes, but it is good to know. It is good to know that if you think that you’d rather have fulvestrant, at least now we have that option first-line for patients. Any time that you would choose abemaciclib first-line with MONALEESA-3, is that with fulvestrant? The ribociclib is a differentiator there, if you will. It also has the premenopausal FDA approval, and that’s first-line, in MONALEESA-7: ribociclib and letrozole with an LHRH [luteinizing hormone-releasing hormone] agonist. Second-line, we have data in the premenopausal setting with both palbociclib and abemaciclib. So we have premenopausal data with all 3 agents. But, in terms of FDA approval, we have the first-line approval with ribociclib. But, in terms of our 3 choices up front, is there any time people prefer one over another, any subsets of patients, let’s say? Anybody?

Adam M. Brufsky, MD, PhD: It’s tough. I think the biggest thing for me would be the risk of neutropenia. I think if someone comes in and has really been beat up from her adjuvant chemotherapy or maybe has had adjuvant chemotherapy before we used hormones, maybe that’s someone I would consider that for because clearly there’s less neutropenia with abemaciclib.

Joyce O’Shaughnessy, MD: Yes.

Adam M. Brufsky, MD, PhD: But, if you look at the curves, they’re all superimposable.

Heather L. McArthur, MD, MPH: And the hazard ratios.

Adam M. Brufsky, MD, PhD: And the hazard ratios are the same. It’s going to be hard. You’re really making a decision based on adverse effects, right, more than anything.

Heather L. McArthur, MD, MPH: I have to say I’ve been using abemaciclib mostly as monotherapy in the chemotherapy refractory populations, particularly when there’s a history of brain metastasis because of this potential CNS [central nervous system] penetration. So that’s been my primary application, as monotherapy.

Ruth O'Regan, MD: I think the problem is that we were all very used to using palbociclib. So that’s one of the issues. I think if I had a premenopausal patient, just following the data, I might consider RIBO in that patient because it really seems very similar adverse-effect-wise to palbociclib.

Joyce O’Shaughnessy, MD: This is interesting. I guess we don’t know because the other 2 agents have not been looked at in precisely the same way as the New England Journal of Medicine paper that carved out that 20% that was primary refractory, where there wasn’t a benefit from palbociclib. So the question is—but we don’t know the answer—whether ribociclib or abemaciclib would be different. I heard with interest here from The University of Texas MD Anderson Cancer Center, in a poster discussion, preclinical work differentiating abemaciclib and saying that it inhibited across a bunch of cell lines and it inhibited not only CDK4/6 but also CDK1 and 2. And so that’s the cyclin E. But it also shut down cells in G1 but also G2, so some differentiating characteristics. I tend to utilize it in those patients where I think the degree of endocrine therapy resistance is going to be higher. I’m worried that I’m really in an endocrine therapy resistant setting, It’s similar to where I used to use chemotherapy because I’m using  much less chemotherapy.

Adam M. Brufsky, MD, PhD: There are some translation data showing that if you have cyclin E overexpression, you don’t respond as well.

Joyce O’Shaughnessy, MD: That’s right. That’s with palbociclib. That’s PALOMA-3.

Adam M. Brufsky, MD, PhD: That’s with palbociclib? I didn’t know which one it was.

Joyce O’Shaughnessy, MD: Yes.

Ruth O'Regan, MD: And I think also there are some preclinical data saying that ABEMA is the only one that really causes apoptosis. The other 2 do not as much. Some of the discussion asks if the response rate is higher with abemaciclib. But, actually, if you look across the trials at the patient populations, it’s very similar.

Adam M. Brufsky, MD, PhD: Even though they have all these great preclinical data, clinically we just haven’t seen any difference. That’s the issue.

Joyce O’Shaughnessy, MD: Right. We’re taking our boards, we check, they’re all the same, basically, of course. But there are some interesting questions that arise.

Transcript edited for clarity.
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