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Analyzing the Use of Eribulin in Metastatic Breast Cancer

Panelists:Adam M. Brufsky, MD, University of Pittsburgh; Sara A. Hurvitz, MD, David Geffen School of Medicine; Joyce A. O'Shaugnessy, MD, Baylor Charles A. Sammons Cancer Center; Hope S. Rugo, MD, University of California; Christy A. Russell, MD, University of Southern California
Published: Monday, Apr 25, 2016


Transcript:

Adam M. Brufsky, MD:
So let’s turn a little bit to the metastatic setting and talk a little bit about drugs that have been used for metastatic disease. And one of them that we talk about is eribulin. Are you guys specifically using eribulin for triple-negatives or you’re just using it for everybody, or for nobody?

Joyce A. O’Shaughnessy, MD: For everybody. I’m using it for everybody. It’s a very highly non-cross–resistant drug. I think we all appreciate that now. It really truly is that new drug we needed after the anthracycline, taxane, capecitabine, and now we have a really non-cross–resistant drug both in the ER-positive and the triple-negative space. And, of course, the study 301, the huge 1100-patient randomized trial looking at therapy after anthracycline and taxane pretreatment—capecitabine versus eribulin—was kind of on the money. The same level of efficacy was seen for the two agents. And then, intriguingly, in the subset analysis of the triple-negative group, about a five month improvement in overall survival was seen in favor of the eribulin. To your point, Christy, capecitabine had only about a nine-, 10-month overall survival in the metastatic setting. But who knows? Maybe we’re really selecting for a very, very heavily pretreated mesenchymal biology in the metastatic setting. But, yeah, eribulin is very non-cross–resistant.

And then at San Antonio, there was the quality of life assessment. Of course, it was very carefully done because that’s important in a lot of parts of the world in terms of getting reimbursement for the drug. And the eribulin had superior global quality of life and cognitive quality of life compared to capecitabine. But capecitabine had greater emotional quality of life because of the lack of hair loss. Everybody’s level of tumor burden symptoms improved on both arms of the trial. So it definitely is very important. I use it for both ER-positive and triple-negative patients.

Hope S. Rugo, MD: I’ve used it as a rescue drug in situations, particularly when it got approved and even now when nothing else is working very well. I also use gemcitabine/platinum combinations in that setting. But eribulin is an interesting drug, and I have to say there’s always a learning curve. So now I’ve learned how to give it in those rescue situations, which is not at full dose or even a half dose sometimes, because I’ve caused grade 3 mucositis which I hadn’t seen in a long, long time prior to giving eribulin. It’s such a little milligram/m2, but it makes a big difference at 1.4, right?

Adam M. Brufsky, MD: But it’s very potent, yes.

Hope S. Rugo, MD: I’ve given people .4 and .6, and gone up by .1 mg in each cycle to try and get it in and had it be a treatment which works when people’s livers are failing; it gives them another eight months of life.

Adam M. Brufsky, MD: How do you dose it in liver failure, by the way?

Hope S. Rugo, MD: Very low dose.

Joyce A. O’Shaughnessy, MD: They’ve looked at this, and it’s in the package insert which is very, very helpful.

Adam M. Brufsky, MD: I’ve looked. I mean, I’ve seen the package insert. I’m just trying to figure it out though.

Joyce A. O’Shaughnessy, MD: Yeah, because it looked at the Child-Pugh score.

Adam M. Brufsky, MD: Yes, so it’s really the Child-Pugh score. Yes, that’s how they do it.

Joyce A. O’Shaughnessy, MD: But the bottom line is that I go by the bilirubin level.

Hope S. Rugo, MD: It’s all bilirubin

Joyce A. O’Shaughnessy, MD: And basically you can give it, but I think it’s too aggressive in the package insert.

Hope S. Rugo, MD: I agree.

Joyce A. O’Shaughnessy, MD: The bottom line is cut the dose right in half, at the most, if the bilirubin is elevated—at the most.

Hope S. Rugo, MD: I’ve given it to people with bilirubins of 6 and 7, but then you should really be giving .4.

Joyce A. O’Shaughnessy, MD: Way down, way down.

Hope S. Rugo, MD: And you still are going to get mucositis, and it’s really pretty impressive, but it works.

Joyce A. O’Shaughnessy, MD: 25%.

Adam M. Brufsky, MD: I agree. I guess the question is, what’s the mechanism of why it works? You talk about mesenchymal disease. Do you think it’s preferential against mesenchymal disease?

Joyce A. O’Shaughnessy, MD: There are preclinical data to support that actually because it gets not only the mitotic spindle, it gets the leading invasive edges. It’s the leading edge of the microtubules that have to really form to invade and metastasize.

Adam M. Brufsky, MD: Good point.

Joyce A. O’Shaughnessy, MD: It’s also got antiangiogenic effects, as well. So there’s a lot of preclinical data. They actually looked at PIK3CA mutations in cell lines, etc. So there are a fair amount of data that will inhibit epithelial cadherin–negative cell lines, etc. So it’s interesting.

Adam M. Brufsky, MD: Before we get to immunotherapy, which is the hot topic—and we have one of the PIs of the immunotherapy studies here next to me—and we’ll talk about it in a minute. But more importantly, are you guys thinking about using the molecular characterization of triple-negative disease, the stuff that was done by Jennifer Pietenpol years ago?

Hope S. Rugo, MD: Well, let me just make one [comment], which is that Tiffany Traina at Memorial Sloan Kettering ran a study, which we participated in our translational breast cancer research consortium, of giving bicalutamide to patients who had androgen receptor (AR)-positive disease. It’s very hard to find those patients because the antibody they were using made it really hard, and we didn’t know then how to pick the people who might be more AR-positive. Now we know, right? Most of the people we test are going to be positive because we pick out the indolent people. So we treated those patients. We didn’t have anybody respond. We know the data, and there was a low level but reasonable response. She went back and did that characterization. Not a single one of them was luminal androgen receptor (LAR). They were all basal-like.

Adam M. Brufsky, MD: Really?

Hope S. Rugo, MD: So I was like, ‘Oh wow, good.’ What we thought we understood, we do not understand.

Adam M. Brufsky, MD: Maybe that’s why they didn’t respond. Maybe they have to be LAR?

Hope S. Rugo, MD: No, the people who responded were not LAR.

Adam M. Brufsky, MD: Were there any LARs that they found?

Hope S. Rugo, MD: I think there were a few, but most of them were basal.

Adam M. Brufsky, MD: But it was a small trial. It was only 30 patients, 34 patients.

Hope S. Rugo, MD: No, but we screened a ton of people.

Adam M. Brufsky, MD: I know.

Hope S. Rugo, MD: Anyway, it was fascinating. They’re going to look at it with a Medivation study, too. But I think it’s really fascinating.

Adam M. Brufsky, MD: Yeah, whether we use it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD:
So let’s turn a little bit to the metastatic setting and talk a little bit about drugs that have been used for metastatic disease. And one of them that we talk about is eribulin. Are you guys specifically using eribulin for triple-negatives or you’re just using it for everybody, or for nobody?

Joyce A. O’Shaughnessy, MD: For everybody. I’m using it for everybody. It’s a very highly non-cross–resistant drug. I think we all appreciate that now. It really truly is that new drug we needed after the anthracycline, taxane, capecitabine, and now we have a really non-cross–resistant drug both in the ER-positive and the triple-negative space. And, of course, the study 301, the huge 1100-patient randomized trial looking at therapy after anthracycline and taxane pretreatment—capecitabine versus eribulin—was kind of on the money. The same level of efficacy was seen for the two agents. And then, intriguingly, in the subset analysis of the triple-negative group, about a five month improvement in overall survival was seen in favor of the eribulin. To your point, Christy, capecitabine had only about a nine-, 10-month overall survival in the metastatic setting. But who knows? Maybe we’re really selecting for a very, very heavily pretreated mesenchymal biology in the metastatic setting. But, yeah, eribulin is very non-cross–resistant.

And then at San Antonio, there was the quality of life assessment. Of course, it was very carefully done because that’s important in a lot of parts of the world in terms of getting reimbursement for the drug. And the eribulin had superior global quality of life and cognitive quality of life compared to capecitabine. But capecitabine had greater emotional quality of life because of the lack of hair loss. Everybody’s level of tumor burden symptoms improved on both arms of the trial. So it definitely is very important. I use it for both ER-positive and triple-negative patients.

Hope S. Rugo, MD: I’ve used it as a rescue drug in situations, particularly when it got approved and even now when nothing else is working very well. I also use gemcitabine/platinum combinations in that setting. But eribulin is an interesting drug, and I have to say there’s always a learning curve. So now I’ve learned how to give it in those rescue situations, which is not at full dose or even a half dose sometimes, because I’ve caused grade 3 mucositis which I hadn’t seen in a long, long time prior to giving eribulin. It’s such a little milligram/m2, but it makes a big difference at 1.4, right?

Adam M. Brufsky, MD: But it’s very potent, yes.

Hope S. Rugo, MD: I’ve given people .4 and .6, and gone up by .1 mg in each cycle to try and get it in and had it be a treatment which works when people’s livers are failing; it gives them another eight months of life.

Adam M. Brufsky, MD: How do you dose it in liver failure, by the way?

Hope S. Rugo, MD: Very low dose.

Joyce A. O’Shaughnessy, MD: They’ve looked at this, and it’s in the package insert which is very, very helpful.

Adam M. Brufsky, MD: I’ve looked. I mean, I’ve seen the package insert. I’m just trying to figure it out though.

Joyce A. O’Shaughnessy, MD: Yeah, because it looked at the Child-Pugh score.

Adam M. Brufsky, MD: Yes, so it’s really the Child-Pugh score. Yes, that’s how they do it.

Joyce A. O’Shaughnessy, MD: But the bottom line is that I go by the bilirubin level.

Hope S. Rugo, MD: It’s all bilirubin

Joyce A. O’Shaughnessy, MD: And basically you can give it, but I think it’s too aggressive in the package insert.

Hope S. Rugo, MD: I agree.

Joyce A. O’Shaughnessy, MD: The bottom line is cut the dose right in half, at the most, if the bilirubin is elevated—at the most.

Hope S. Rugo, MD: I’ve given it to people with bilirubins of 6 and 7, but then you should really be giving .4.

Joyce A. O’Shaughnessy, MD: Way down, way down.

Hope S. Rugo, MD: And you still are going to get mucositis, and it’s really pretty impressive, but it works.

Joyce A. O’Shaughnessy, MD: 25%.

Adam M. Brufsky, MD: I agree. I guess the question is, what’s the mechanism of why it works? You talk about mesenchymal disease. Do you think it’s preferential against mesenchymal disease?

Joyce A. O’Shaughnessy, MD: There are preclinical data to support that actually because it gets not only the mitotic spindle, it gets the leading invasive edges. It’s the leading edge of the microtubules that have to really form to invade and metastasize.

Adam M. Brufsky, MD: Good point.

Joyce A. O’Shaughnessy, MD: It’s also got antiangiogenic effects, as well. So there’s a lot of preclinical data. They actually looked at PIK3CA mutations in cell lines, etc. So there are a fair amount of data that will inhibit epithelial cadherin–negative cell lines, etc. So it’s interesting.

Adam M. Brufsky, MD: Before we get to immunotherapy, which is the hot topic—and we have one of the PIs of the immunotherapy studies here next to me—and we’ll talk about it in a minute. But more importantly, are you guys thinking about using the molecular characterization of triple-negative disease, the stuff that was done by Jennifer Pietenpol years ago?

Hope S. Rugo, MD: Well, let me just make one [comment], which is that Tiffany Traina at Memorial Sloan Kettering ran a study, which we participated in our translational breast cancer research consortium, of giving bicalutamide to patients who had androgen receptor (AR)-positive disease. It’s very hard to find those patients because the antibody they were using made it really hard, and we didn’t know then how to pick the people who might be more AR-positive. Now we know, right? Most of the people we test are going to be positive because we pick out the indolent people. So we treated those patients. We didn’t have anybody respond. We know the data, and there was a low level but reasonable response. She went back and did that characterization. Not a single one of them was luminal androgen receptor (LAR). They were all basal-like.

Adam M. Brufsky, MD: Really?

Hope S. Rugo, MD: So I was like, ‘Oh wow, good.’ What we thought we understood, we do not understand.

Adam M. Brufsky, MD: Maybe that’s why they didn’t respond. Maybe they have to be LAR?

Hope S. Rugo, MD: No, the people who responded were not LAR.

Adam M. Brufsky, MD: Were there any LARs that they found?

Hope S. Rugo, MD: I think there were a few, but most of them were basal.

Adam M. Brufsky, MD: But it was a small trial. It was only 30 patients, 34 patients.

Hope S. Rugo, MD: No, but we screened a ton of people.

Adam M. Brufsky, MD: I know.

Hope S. Rugo, MD: Anyway, it was fascinating. They’re going to look at it with a Medivation study, too. But I think it’s really fascinating.

Adam M. Brufsky, MD: Yeah, whether we use it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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