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Progression of HR+ Metastatic Breast Cancer

Panelists: Adam M. Brufsky, MD, University of Pittsburgh Cancer Institute; Ahmad Awada, MD, PhD, Jules Bordet Institute; Wolfgang J. Janni, MD, PhD, University of Ulm; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published Online: Thursday, Dec 29, 2016



Transcript:

Adam M. Brufsky, MD, PhD:
Let me ask the question a different way to everybody because it’s the same question. So, we’ve talked about the de novo patients which are maybe 40%, maybe less, depending on what part of the world you’re in. But, a typical patient in the United States, for example—and maybe in Europe, as well—is a woman who has been on endocrine therapy for maybe 2 years, 3 years, or 4 years. She’s postmenopausal. She has likely been on an aromatase inhibitor in the adjuvant setting and now develops a pleural effusion or new bone metastasis. What’s the right treatment, is it fulvestrant? Is it fulvestrant and a CDK4 inhibitor? Is it an AI and a CDK4 inhibitor? These are the questions I think people want to know right now.

Ahmad Awada, MD, PhD: I think when we’re speaking about therapeutic algorithm, we should take into account two things. For any clinical trial, I think the magnitude of affect is important. The delta is important. The side effects affect the quality of life and, of course, the cost burden. That’s from one side. The other side is, ‘Okay, we’ll discuss here the first line, but we should always think about second and third line and what we have in this line of therapy.’ This is the package in my opinion. If we take FALCON trials, the data I saw so far, okay there are differences.

Adam M. Brufsky, MD, PhD: It was 3 months, 16 versus 14 or 16 versus 13.

Ahmad Awada, MD, PhD: Except in this group of patients with no metastatic disease.

Adam M. Brufsky, MD, PhD: Which is like 22 versus 15 or something.

Ahmad Awada, MD, PhD: Let’s say, the therapy algorithm is in here, but we probably should individualize. I agree with Hope. Possibly, we have all these drugs in our hand, we have fulvestrant. We just saw it in first-line setting, let’s say. We have the CDK4/6. The magnitude of effect is really important, is huge. The difference in PFS is 10 months for the one study and not yet known for the MONALEESA-2 study. So, I think individualization, whenever possible, could be the thing to do, taking into account the situation of the patient’s disease, patient characteristics, symptoms and so on.

Hope S. Rugo, MD: I think if you have a patient relapsing while taking an AI, I would go with fulvestrant and a CDK4/6 inhibitor.

Adam M. Brufsky, MD, PhD: But, not fulvestrant alone?

Hope S. Rugo, MD: No, I would use a CDK4/6. I think that it’s particularly important in that setting because we are really doubling the progression-free survival and it’s very well tolerated. For patients who have gotten an AI before, this is where I think we really have a big question because we don’t really know the right answer. They got an AI before and then they relapsed 3, 5, or 6 years later.

Adam M. Brufsky, MD, PhD: That’s a different question than relapsing on an AI.

Hope S. Rugo, MD: Those patients I’ve given, generally, an AI and a CDK4/6 inhibitor to, although you could use fulvestrant and a CDK4/6 inhibitor.

Michael Untch, MD: What about using, in this situation, everolimus with exemestane?

Adam M. Brufsky, MD, PhD: Right. But, let’s put this in perspective. We have the first-line therapy, at least no de novo disease, right? Say the de novo is first and it sounds like we’ve agreed on fulvestrant or palbociclib plus an AI in somebody who’s never been treated. That probably could extend to the woman who has maybe had her AI, but now has been off therapy for 3 or 4 years. So, it’s the same kind of patient, treat de novo and that kind of patient’s the same even though we’re not quite sure they really are the same. Before we go on to the second line, let me ask you a question. Does it matter which CDK4 you would use? Because we now have the ribociclib data that just came out. Does it matter? Will it matter?

Michael Untch, MD: Up until today, there was a difference because I thought CDK4/6 inhibitor equalized to palbociclib. Now, with the new data, ribociclib, seeing what the side effects are, it seems to me personally, they are more or less overlapping. So, they are very similar. Maybe we will go to abemaciclib, but we have ribociclib and palbociclib, so it seems that they are very effective drugs and have more or less the same percentage of side effects.

Adam M. Brufsky, MD, PhD: Do you agree? You guys agree?

Hope S. Rugo, MD: I think so, and I don’t know where it’s all going to fall out. We’re going to have a anastrozole/letrozole sort of situation is my guess, but with one drug that has data also with fulvestrant. We don’t have that yet with ribociclib. We’ll see. Palbociclib is already in the large adjuvant PALLAS trial. There are neoadjuvant trials going on.

Michael Untch, MD: Post-neoadjuvant?

Adam M. Brufsky, MD, PhD: Post-neoadjuvant, yes. That’s PALLET, I think. PALLET is in post-neoadjuvant?

Hope S. Rugo, MD: Yes, the Cooperative Group trial.

Michael Untch, MD: PENELOPEB.

Hope S. Rugo, MD: So, there are two. The PENELOPEB, which is being run by GBG and is an international collaboration, is another post-neoadjuvant trial that is 1 year versus 2 years for PALLAS. And then, we have abemaciclib, which crosses the blood-brain barrier where there’s a brain study. There’s also single-agent activity, although modest, it causes diarrhea. It’s more of a CDK4 rather than a CDK6 inhibitor. And so, we’ll see, because that data with abemaciclib are emerging. And then, there are combination data from the preclinical setting where if you combine a PI3 kinase or mTOR inhibitor with CDK4/6 or CDK4, you can significantly enhance activity. There’s actually a study with an IV PI3 kinase inhibitor, gedatolisib, that’s being given with palbociclib in people who have progressed on palbociclib and either letrozole or fulvestrant in phase Ib. But, quite intriguing, there is a randomized, phase II trial looking at ribociclib and everolimus with exemestane compared to just the exemestane/everolimus. I think it’s actually fascinating right now to see what we’re going to be doing with combinations, how we’re going to balance the toxicity.

Adam M. Brufsky, MD, PhD: Right. But, right now, clinically, it sounds like we don’t have a consensus yet on how to do them. It sounds like everybody should get fulvestrant at some point with or without a CDK4. Someone should give an AI with or without a CDK4, in some combination in the first and second line. We don’t quite know which way.

Hope S. Rugo, MD: And, we still have everolimus.

Adam M. Brufsky, MD, PhD: Now, back to your original question, where does that put exemestane? Where do we put exemestane with everolimus, after all of that? So, after fulvestrant, an AI and palbociclib in some combination?

Michael Untch, MD: I think so.

Adam M. Brufsky, MD, PhD: Then, exemestane with everolimus is like third line?

Ahmad Awada, MD, PhD: I think if CDK4/6 move to the first-line setting, in these patients, exemestane/everolimus would be next.

Adam M. Brufsky, MD, PhD: Let’s do the clinical scenario. So, a woman comes in 3 years after finishing all her endocrine therapy. You give her letrozole with palbociclib and it’s now 2 years later, and she progresses again. Your choices then are exemestane/everolimus or fulvestrant.

Michael Untch, MD: Fulvestrant.

Ahmad Awada, MD, PhD: Taking into account the side effects, I would go to, of course, fulvestrant, but I saw Hope’s study looking to reduce mucositis problem. It’s a very interesting study, honestly. It’s very easy; 0.5 mg dexamethasone in 5 mL, that’s correct?

Hope S. Rugo, MD: Yes.

Ahmad Awada, MD, PhD: I’ve had a lot of patients reduce significantly the mucositis. But, there are other side effects, to be honest.

Hope S. Rugo, MD: There are. We have pneumonitis and fatigue.

Adam M. Brufsky, MD, PhD: Pneumonitis is something to worry about.

Ahmad Awada, MD, PhD: Once again, possibly individualizing the strategy of the patient with the aim that they receive the maximum of benefit from the available therapy.

Hope S. Rugo, MD: I think a lot of people may go to fulvestrant next because they’ve used an AI, and then they go to the AI again with the idea of recovering sensitivity, etc. And with everolimus, I think most patients are worried about starting at a lower dose going up, having an earlier dose reduction, etc. Toxicity does seem to correlate with exposure to drug, and so that’s probably a way to manage it.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
Let me ask the question a different way to everybody because it’s the same question. So, we’ve talked about the de novo patients which are maybe 40%, maybe less, depending on what part of the world you’re in. But, a typical patient in the United States, for example—and maybe in Europe, as well—is a woman who has been on endocrine therapy for maybe 2 years, 3 years, or 4 years. She’s postmenopausal. She has likely been on an aromatase inhibitor in the adjuvant setting and now develops a pleural effusion or new bone metastasis. What’s the right treatment, is it fulvestrant? Is it fulvestrant and a CDK4 inhibitor? Is it an AI and a CDK4 inhibitor? These are the questions I think people want to know right now.

Ahmad Awada, MD, PhD: I think when we’re speaking about therapeutic algorithm, we should take into account two things. For any clinical trial, I think the magnitude of affect is important. The delta is important. The side effects affect the quality of life and, of course, the cost burden. That’s from one side. The other side is, ‘Okay, we’ll discuss here the first line, but we should always think about second and third line and what we have in this line of therapy.’ This is the package in my opinion. If we take FALCON trials, the data I saw so far, okay there are differences.

Adam M. Brufsky, MD, PhD: It was 3 months, 16 versus 14 or 16 versus 13.

Ahmad Awada, MD, PhD: Except in this group of patients with no metastatic disease.

Adam M. Brufsky, MD, PhD: Which is like 22 versus 15 or something.

Ahmad Awada, MD, PhD: Let’s say, the therapy algorithm is in here, but we probably should individualize. I agree with Hope. Possibly, we have all these drugs in our hand, we have fulvestrant. We just saw it in first-line setting, let’s say. We have the CDK4/6. The magnitude of effect is really important, is huge. The difference in PFS is 10 months for the one study and not yet known for the MONALEESA-2 study. So, I think individualization, whenever possible, could be the thing to do, taking into account the situation of the patient’s disease, patient characteristics, symptoms and so on.

Hope S. Rugo, MD: I think if you have a patient relapsing while taking an AI, I would go with fulvestrant and a CDK4/6 inhibitor.

Adam M. Brufsky, MD, PhD: But, not fulvestrant alone?

Hope S. Rugo, MD: No, I would use a CDK4/6. I think that it’s particularly important in that setting because we are really doubling the progression-free survival and it’s very well tolerated. For patients who have gotten an AI before, this is where I think we really have a big question because we don’t really know the right answer. They got an AI before and then they relapsed 3, 5, or 6 years later.

Adam M. Brufsky, MD, PhD: That’s a different question than relapsing on an AI.

Hope S. Rugo, MD: Those patients I’ve given, generally, an AI and a CDK4/6 inhibitor to, although you could use fulvestrant and a CDK4/6 inhibitor.

Michael Untch, MD: What about using, in this situation, everolimus with exemestane?

Adam M. Brufsky, MD, PhD: Right. But, let’s put this in perspective. We have the first-line therapy, at least no de novo disease, right? Say the de novo is first and it sounds like we’ve agreed on fulvestrant or palbociclib plus an AI in somebody who’s never been treated. That probably could extend to the woman who has maybe had her AI, but now has been off therapy for 3 or 4 years. So, it’s the same kind of patient, treat de novo and that kind of patient’s the same even though we’re not quite sure they really are the same. Before we go on to the second line, let me ask you a question. Does it matter which CDK4 you would use? Because we now have the ribociclib data that just came out. Does it matter? Will it matter?

Michael Untch, MD: Up until today, there was a difference because I thought CDK4/6 inhibitor equalized to palbociclib. Now, with the new data, ribociclib, seeing what the side effects are, it seems to me personally, they are more or less overlapping. So, they are very similar. Maybe we will go to abemaciclib, but we have ribociclib and palbociclib, so it seems that they are very effective drugs and have more or less the same percentage of side effects.

Adam M. Brufsky, MD, PhD: Do you agree? You guys agree?

Hope S. Rugo, MD: I think so, and I don’t know where it’s all going to fall out. We’re going to have a anastrozole/letrozole sort of situation is my guess, but with one drug that has data also with fulvestrant. We don’t have that yet with ribociclib. We’ll see. Palbociclib is already in the large adjuvant PALLAS trial. There are neoadjuvant trials going on.

Michael Untch, MD: Post-neoadjuvant?

Adam M. Brufsky, MD, PhD: Post-neoadjuvant, yes. That’s PALLET, I think. PALLET is in post-neoadjuvant?

Hope S. Rugo, MD: Yes, the Cooperative Group trial.

Michael Untch, MD: PENELOPEB.

Hope S. Rugo, MD: So, there are two. The PENELOPEB, which is being run by GBG and is an international collaboration, is another post-neoadjuvant trial that is 1 year versus 2 years for PALLAS. And then, we have abemaciclib, which crosses the blood-brain barrier where there’s a brain study. There’s also single-agent activity, although modest, it causes diarrhea. It’s more of a CDK4 rather than a CDK6 inhibitor. And so, we’ll see, because that data with abemaciclib are emerging. And then, there are combination data from the preclinical setting where if you combine a PI3 kinase or mTOR inhibitor with CDK4/6 or CDK4, you can significantly enhance activity. There’s actually a study with an IV PI3 kinase inhibitor, gedatolisib, that’s being given with palbociclib in people who have progressed on palbociclib and either letrozole or fulvestrant in phase Ib. But, quite intriguing, there is a randomized, phase II trial looking at ribociclib and everolimus with exemestane compared to just the exemestane/everolimus. I think it’s actually fascinating right now to see what we’re going to be doing with combinations, how we’re going to balance the toxicity.

Adam M. Brufsky, MD, PhD: Right. But, right now, clinically, it sounds like we don’t have a consensus yet on how to do them. It sounds like everybody should get fulvestrant at some point with or without a CDK4. Someone should give an AI with or without a CDK4, in some combination in the first and second line. We don’t quite know which way.

Hope S. Rugo, MD: And, we still have everolimus.

Adam M. Brufsky, MD, PhD: Now, back to your original question, where does that put exemestane? Where do we put exemestane with everolimus, after all of that? So, after fulvestrant, an AI and palbociclib in some combination?

Michael Untch, MD: I think so.

Adam M. Brufsky, MD, PhD: Then, exemestane with everolimus is like third line?

Ahmad Awada, MD, PhD: I think if CDK4/6 move to the first-line setting, in these patients, exemestane/everolimus would be next.

Adam M. Brufsky, MD, PhD: Let’s do the clinical scenario. So, a woman comes in 3 years after finishing all her endocrine therapy. You give her letrozole with palbociclib and it’s now 2 years later, and she progresses again. Your choices then are exemestane/everolimus or fulvestrant.

Michael Untch, MD: Fulvestrant.

Ahmad Awada, MD, PhD: Taking into account the side effects, I would go to, of course, fulvestrant, but I saw Hope’s study looking to reduce mucositis problem. It’s a very interesting study, honestly. It’s very easy; 0.5 mg dexamethasone in 5 mL, that’s correct?

Hope S. Rugo, MD: Yes.

Ahmad Awada, MD, PhD: I’ve had a lot of patients reduce significantly the mucositis. But, there are other side effects, to be honest.

Hope S. Rugo, MD: There are. We have pneumonitis and fatigue.

Adam M. Brufsky, MD, PhD: Pneumonitis is something to worry about.

Ahmad Awada, MD, PhD: Once again, possibly individualizing the strategy of the patient with the aim that they receive the maximum of benefit from the available therapy.

Hope S. Rugo, MD: I think a lot of people may go to fulvestrant next because they’ve used an AI, and then they go to the AI again with the idea of recovering sensitivity, etc. And with everolimus, I think most patients are worried about starting at a lower dose going up, having an earlier dose reduction, etc. Toxicity does seem to correlate with exposure to drug, and so that’s probably a way to manage it.

Transcript Edited for Clarity
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