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Patient Selection for Neratinib in Metastatic Breast Cancer

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: Monday, Aug 15, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
I think they are great data. I agree it’s spectacular, the absolute difference in invasive disease–free survival with that extra year. How do we explain the ER/HER2 interaction here, and that it only seems to have that benefit in the ER-positive/HER2-positive patients?

Joyce A. O’Shaughnessy, MD: I just want to say one thing before—because we’ll get the biology—but I think the ER-negative subset is interesting because the curves split at about a year into the study. You’ve got that delta of about 2.5%, then the curves come back together again. It raises the question, at least in my mind, for patients whose cancers have persisted in spite of chemotherapy and trastuzumab. So, they don’t have that cancer that can die really easily, whether it needs to be longer. Maybe it was chronic. Maybe if you kept it going a longer period of time because that’s really bad if these patients still have persistent disease. If you get preoperative therapy and they still have persistent ER-negative disease, that’s a very poor prognosis. Though the data are not impressive so far with the year of neratinib, no question that in the ER-negative, I think it raises the hypothesis for a longer period of treatment.

Kimberly L. Blackwell, MD: And I think endocrine therapy, again, just to continue to use that. One of the big things at this year’s meeting plenary abstract 1 is if you have a targeted therapy and patients, we just don’t know who has residual disease. One day we will. We’ll have a scanner we’ll put the patient through; you’re done, you don’t need any more. But today we don’t, so we treat 100 patients to offer benefit somewhere between 2 to 4.

Adam M. Brufsky, MD, PhD: That’s 2 out of 100.

Kimberly L. Blackwell, MD: Honestly, I think a year probably for HER2-addicted disease that’s residual, it’s not good enough. Those are the patients that if we knew they had residual disease, we’d continue them forever.

Joyce A. O’Shaughnessy, MD: Interestingly, the HERA trial was negative for the 2 years.

Sunil Verma, MD, MSEd, FRCPC: And there was no difference in ER-positive cancer. So, the one thing that I think we’ll have to put into context is, where does this fall if you’re using neoadjuvant pertuzumab? Is the benefit going to be the same in patients on neoadjuvant trastuzumab? Is it more for patients who have residual disease post-neoadjuvant therapy? Should that be sort of the consideration? What level of disease burden with ER-positive breast cancer should be considered? Because, on the other side, we’re looking at, first, some of our ER-positive, T1a, T1b, T1c, maybe some T2s, we’re giving paclitaxel/trastuzumab, four cycles, deescalating treatment. And then, on the other hand, we’re giving anthracycline, taxane, pertuzumab, trastuzumab, now neratinib. How do we sort of balance that scale and how do we sort of define those patients?

Adam M. Brufsky, MD, PhD: Again, I think if this drug does get FDA approved, it looks like it’s kind of on the way. I think we’ll know. That’s where I’m thinking. I’m thinking of the patient with a fairly high disease burden after neoadjuvant chemotherapy. Say someone who presents either that uncommon adjuvant patient now who has a lot of nodes that’s triple-positive, I think that’s where I would place this in my regimen eventually. Actually, it’s going to be those triple-positive patients who are going to be able to have residual disease, right? It’s not really going to be those ER-negative/HER2-positives.

Kimberly L. Blackwell, MD: See, I’m a little different. I’m going to wait for my scanner, my super scanner that I put the patients through. I’m going to feel obligated if it’s approved to discuss it with pretty much all patients because we just don’t know. I think we think we know, but I don’t think we really know.

Carlos L. Arteaga, MD: But I agree with what you said—or maybe you said Kim—that you see it in the ER-positive group because those are the ones who are at a possibility, have late recurrences. Therefore, you can see that window.

Adam M. Brufsky, MD, PhD: Right. So, you don’t think there’s something scientific behind that, there’s some sort of …

Carlos L. Arteaga, MD: I can speculate on all kinds of things as we are not encumbered by any data. But let’s say that the majority of the recurrences are in the brain, which it may well be. And I know the brain is a site that has high levels of neuregulin. We know that ligands are a mechanism of escape, and that’s one mechanism where addition of a small molecule that brought us heterodimerization would be particularly effective like neratinib. So, again, this is just pure speculation. But like Kim, I would have to discuss it with a patient, with high burden disease, triple-positives that did not achieve pathologic complete response after TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab), for example.

Kimberly L. Blackwell, MD: I think we have to wait for the results of the adjuvant pertuzumab study to really even start to have that discussion, how I’d position neratinib with the results of …

Sunil Verma, MD, MSEd, FRCPC: No, but they’ll use the pertuzumab already in the clinical setting, right?

Adam M. Brufsky, MD, PhD: Yes, in the neoadjuvant setting.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
I think they are great data. I agree it’s spectacular, the absolute difference in invasive disease–free survival with that extra year. How do we explain the ER/HER2 interaction here, and that it only seems to have that benefit in the ER-positive/HER2-positive patients?

Joyce A. O’Shaughnessy, MD: I just want to say one thing before—because we’ll get the biology—but I think the ER-negative subset is interesting because the curves split at about a year into the study. You’ve got that delta of about 2.5%, then the curves come back together again. It raises the question, at least in my mind, for patients whose cancers have persisted in spite of chemotherapy and trastuzumab. So, they don’t have that cancer that can die really easily, whether it needs to be longer. Maybe it was chronic. Maybe if you kept it going a longer period of time because that’s really bad if these patients still have persistent disease. If you get preoperative therapy and they still have persistent ER-negative disease, that’s a very poor prognosis. Though the data are not impressive so far with the year of neratinib, no question that in the ER-negative, I think it raises the hypothesis for a longer period of treatment.

Kimberly L. Blackwell, MD: And I think endocrine therapy, again, just to continue to use that. One of the big things at this year’s meeting plenary abstract 1 is if you have a targeted therapy and patients, we just don’t know who has residual disease. One day we will. We’ll have a scanner we’ll put the patient through; you’re done, you don’t need any more. But today we don’t, so we treat 100 patients to offer benefit somewhere between 2 to 4.

Adam M. Brufsky, MD, PhD: That’s 2 out of 100.

Kimberly L. Blackwell, MD: Honestly, I think a year probably for HER2-addicted disease that’s residual, it’s not good enough. Those are the patients that if we knew they had residual disease, we’d continue them forever.

Joyce A. O’Shaughnessy, MD: Interestingly, the HERA trial was negative for the 2 years.

Sunil Verma, MD, MSEd, FRCPC: And there was no difference in ER-positive cancer. So, the one thing that I think we’ll have to put into context is, where does this fall if you’re using neoadjuvant pertuzumab? Is the benefit going to be the same in patients on neoadjuvant trastuzumab? Is it more for patients who have residual disease post-neoadjuvant therapy? Should that be sort of the consideration? What level of disease burden with ER-positive breast cancer should be considered? Because, on the other side, we’re looking at, first, some of our ER-positive, T1a, T1b, T1c, maybe some T2s, we’re giving paclitaxel/trastuzumab, four cycles, deescalating treatment. And then, on the other hand, we’re giving anthracycline, taxane, pertuzumab, trastuzumab, now neratinib. How do we sort of balance that scale and how do we sort of define those patients?

Adam M. Brufsky, MD, PhD: Again, I think if this drug does get FDA approved, it looks like it’s kind of on the way. I think we’ll know. That’s where I’m thinking. I’m thinking of the patient with a fairly high disease burden after neoadjuvant chemotherapy. Say someone who presents either that uncommon adjuvant patient now who has a lot of nodes that’s triple-positive, I think that’s where I would place this in my regimen eventually. Actually, it’s going to be those triple-positive patients who are going to be able to have residual disease, right? It’s not really going to be those ER-negative/HER2-positives.

Kimberly L. Blackwell, MD: See, I’m a little different. I’m going to wait for my scanner, my super scanner that I put the patients through. I’m going to feel obligated if it’s approved to discuss it with pretty much all patients because we just don’t know. I think we think we know, but I don’t think we really know.

Carlos L. Arteaga, MD: But I agree with what you said—or maybe you said Kim—that you see it in the ER-positive group because those are the ones who are at a possibility, have late recurrences. Therefore, you can see that window.

Adam M. Brufsky, MD, PhD: Right. So, you don’t think there’s something scientific behind that, there’s some sort of …

Carlos L. Arteaga, MD: I can speculate on all kinds of things as we are not encumbered by any data. But let’s say that the majority of the recurrences are in the brain, which it may well be. And I know the brain is a site that has high levels of neuregulin. We know that ligands are a mechanism of escape, and that’s one mechanism where addition of a small molecule that brought us heterodimerization would be particularly effective like neratinib. So, again, this is just pure speculation. But like Kim, I would have to discuss it with a patient, with high burden disease, triple-positives that did not achieve pathologic complete response after TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab), for example.

Kimberly L. Blackwell, MD: I think we have to wait for the results of the adjuvant pertuzumab study to really even start to have that discussion, how I’d position neratinib with the results of …

Sunil Verma, MD, MSEd, FRCPC: No, but they’ll use the pertuzumab already in the clinical setting, right?

Adam M. Brufsky, MD, PhD: Yes, in the neoadjuvant setting.

Transcript Edited for Clarity
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