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Extended Adjuvant Therapy for HER2+ Early Breast Cancer

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Mark E. Robson, MD, Memorial Sloan Kettering Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Kimberly L. Blackwell, MD, Duke Cancer Institute
Published: Friday, Mar 03, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
So, the next real question, though, getting to other things, we know that trastuzumab works really well, but now we have—it looks like it may get approval—a tyrosine kinase inhibitor. We have neratinib. And so, I’m curious about people’s thoughts about the ExteNET trial, where this is going, and the data that were presented at the San Antonio Breast Cancer Symposium about management of the diarrhea in the trial. What do people think? ExteNET was a trial where people had the standard therapy for their disease, and then within 1 year of finishing—so they could have had at least up to 2 years after getting their adjuvant chemotherapy—their adjuvant trastuzumab, they could be randomized to placebo or to neratinib. Everybody did really well, but there was a small yet significant benefit, as Kim was mentioning, in the ER-positive subgroup. There was probably like a 2% or 3% absolute benefit at 4 years in terms of disease-free survival. So, what do you think of ExteNET? Assuming it gets approved, would you use it and in what patients?

Aditya Bardia, MD, MPH: I think the data are a bit compelling for the ER-positive, HER2-positive group because that’s where you could really see the benefit. As Kim was mentioning earlier, there are, at least, a lot of preclinical data of this cross-talk between ER and HER2. So, you could make a case that potentially that’s why it’s working and we should be using it in this setting. The challenge is the potential toxicity, with the diarrhea being the most common side effect. And also, at the end of 1 year, patients are usually tired with the anti-HER2 therapy and they feel great that they’ve completed all the trastuzumab. If they’re ER-positive, they just need to continue on an AI, and that’s more of an insurance policy. But here, to say that you need a second agent, that you have to continue for additional 1 year, I think that will play into the decision making.

Adam M. Brufsky, MD, PhD: Any comments?

Mark E. Robson, MD: We’re turning ER-positive breast cancer into a real chronic disease, which may be appropriate, but if you think about it from the patient’s perspective, it’s 2 years of anti-HER2 therapy plus/minus chemotherapy before it and then 5 to 10 years’ worth of anti-estrogen therapy. This is now something that’s going to be treated for.

Adam M. Brufsky, MD, PhD: Do you have a group that you would treat, Kim, with this?

Kimberly L. Blackwell, MD: If it gets approved, I will offer it to all of my patients.

Adam M. Brufsky, MD, PhD: Everybody, even someone who has a 1?

Kimberly L. Blackwell, MD: I will have an educated discussion because, you know what, it was the ER-positive patients that drive the benefit. In my patient population, when it gets down to that end of the year of Herceptin (trastuzumab), there’s this moment of—especially patients whose tumors melted away if they got neoadjuvant therapy—why don’t we continue it? I get asked that all the time, “Are you sure that this is all I need?” Diarrhea is a horrible, life-altering thing. We do have data with neratinib that you can control it. It reminds me of the CPT-11 days, where you just had to have a prophylactic schedule. We’ve given the drug in the patients with metastatic early disease, and they gotta have a diarrhea diary. Isn’t that clever? The nurses really love it. None of us likes talking about diarrhea. That takes 15 minutes.

Adam M. Brufsky, MD, PhD: But it’s a different kind of diarrhea, too, isn’t it? It’s not like the explosive type, just more stools; grade 3. More than 7 stools a day is grade 3 or something.

Kimberly L. Blackwell, MD: Yes, more than 6. Anyway, the bottom line is that, again—and it goes back to why we give trastuzumab to all HER2-positive patients for the most part—is that we now have 5 years of follow-up. At 2 years, I kind of scratched my head and said, “Oh, the curves are going to come back together; there’s something funky going on.” With 5 years of follow-up, the curves remain separated, so I can’t explain why it only works in ER-positive. But if the indication is for all HER2-positive early stage breast cancer, especially if we don’t see a survival detriment—we haven’t seen the survival, but the FDA is going to require that for label—I think you’re obligated to discuss it, just like you’re obligated to discuss continuing tamoxifen after 5 years and an AI after 5 years. Our patients do want to participate in that, and our job is to help them participate in these decisions. I’m going to have plenty of patients who say, “You’ve got to be crazy. You’re going to help 2 women and you’re going to give a 15-mg dose for diarrhea.” There will be patients that say that, but I will feel obligated to at least discuss it and document it in my note.

Adam M. Brufsky, MD, PhD: You practice in the city, Mark, where patients want very aggressive therapy. So, how do you feel about this?

Mark E. Robson, MD: Well, I think our practice is probably no different from yours, which is that it’s very variable. Some people do, some people don’t. If you take this group of patients that we talked about a little bit ago, small node-negative, HER2-positive tumors who are 96% to 98% likely to survive free of disease with a year’s worth of trastuzumab, it’s going to be pretty hard to sell another year of neratinib to those patients.

Adam M. Brufsky, MD, PhD: That’s why I was kind of surprised. Someone who comes in with a big tumor and a lot of it’s left-side, you give them chemotherapy. I would be more excited about doing that.

Mark E. Robson, MD: Right, or even the ones who come in with big tumor, node-positive disease and have a good initial response, you still might worry about that.

Kimberly L. Blackwell, MD: I’d be more enthusiastic about those. If that tumor melts away on HER2-based therapy, I’d be even more enthused. And in the patients that it doesn’t melt away, then I’d be less enthused. I think we have an in vivo sensitivity assay to which tumors are HER2-addicted. That’s my favorite term. But the reality is, when tumors melt away to trastuzumab or trastuzumab/pertuzumab, that’s [an] HER2-addicted tumor. We saw that from the lapatinib days. And hopefully one day, we will see the results of the APHINITY study. There was probably a lot of HER2 nonenriched or HER2 nonaddicted tumors in that study, and it clearly affects our ability to see the benefits of adding pertuzumab in the adjuvant setting. So, again, I practice very practically, which is I offer it. In the setting of neratinib, if they get diarrhea, and they don’t want to continue it, we stop it. Unless we see a survival detriment, there’s a lot of things that we do in medicine that require overtreatment of a population of patients. But for that individual patient sitting in front of me who I want to be able to say, “We’ve done everything within reason to prevent your breast cancer from coming back,” I think neratinib in that setting, if it’s approved and it’s not a huge financial burden to the patient, I’ll offer it.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
So, the next real question, though, getting to other things, we know that trastuzumab works really well, but now we have—it looks like it may get approval—a tyrosine kinase inhibitor. We have neratinib. And so, I’m curious about people’s thoughts about the ExteNET trial, where this is going, and the data that were presented at the San Antonio Breast Cancer Symposium about management of the diarrhea in the trial. What do people think? ExteNET was a trial where people had the standard therapy for their disease, and then within 1 year of finishing—so they could have had at least up to 2 years after getting their adjuvant chemotherapy—their adjuvant trastuzumab, they could be randomized to placebo or to neratinib. Everybody did really well, but there was a small yet significant benefit, as Kim was mentioning, in the ER-positive subgroup. There was probably like a 2% or 3% absolute benefit at 4 years in terms of disease-free survival. So, what do you think of ExteNET? Assuming it gets approved, would you use it and in what patients?

Aditya Bardia, MD, MPH: I think the data are a bit compelling for the ER-positive, HER2-positive group because that’s where you could really see the benefit. As Kim was mentioning earlier, there are, at least, a lot of preclinical data of this cross-talk between ER and HER2. So, you could make a case that potentially that’s why it’s working and we should be using it in this setting. The challenge is the potential toxicity, with the diarrhea being the most common side effect. And also, at the end of 1 year, patients are usually tired with the anti-HER2 therapy and they feel great that they’ve completed all the trastuzumab. If they’re ER-positive, they just need to continue on an AI, and that’s more of an insurance policy. But here, to say that you need a second agent, that you have to continue for additional 1 year, I think that will play into the decision making.

Adam M. Brufsky, MD, PhD: Any comments?

Mark E. Robson, MD: We’re turning ER-positive breast cancer into a real chronic disease, which may be appropriate, but if you think about it from the patient’s perspective, it’s 2 years of anti-HER2 therapy plus/minus chemotherapy before it and then 5 to 10 years’ worth of anti-estrogen therapy. This is now something that’s going to be treated for.

Adam M. Brufsky, MD, PhD: Do you have a group that you would treat, Kim, with this?

Kimberly L. Blackwell, MD: If it gets approved, I will offer it to all of my patients.

Adam M. Brufsky, MD, PhD: Everybody, even someone who has a 1?

Kimberly L. Blackwell, MD: I will have an educated discussion because, you know what, it was the ER-positive patients that drive the benefit. In my patient population, when it gets down to that end of the year of Herceptin (trastuzumab), there’s this moment of—especially patients whose tumors melted away if they got neoadjuvant therapy—why don’t we continue it? I get asked that all the time, “Are you sure that this is all I need?” Diarrhea is a horrible, life-altering thing. We do have data with neratinib that you can control it. It reminds me of the CPT-11 days, where you just had to have a prophylactic schedule. We’ve given the drug in the patients with metastatic early disease, and they gotta have a diarrhea diary. Isn’t that clever? The nurses really love it. None of us likes talking about diarrhea. That takes 15 minutes.

Adam M. Brufsky, MD, PhD: But it’s a different kind of diarrhea, too, isn’t it? It’s not like the explosive type, just more stools; grade 3. More than 7 stools a day is grade 3 or something.

Kimberly L. Blackwell, MD: Yes, more than 6. Anyway, the bottom line is that, again—and it goes back to why we give trastuzumab to all HER2-positive patients for the most part—is that we now have 5 years of follow-up. At 2 years, I kind of scratched my head and said, “Oh, the curves are going to come back together; there’s something funky going on.” With 5 years of follow-up, the curves remain separated, so I can’t explain why it only works in ER-positive. But if the indication is for all HER2-positive early stage breast cancer, especially if we don’t see a survival detriment—we haven’t seen the survival, but the FDA is going to require that for label—I think you’re obligated to discuss it, just like you’re obligated to discuss continuing tamoxifen after 5 years and an AI after 5 years. Our patients do want to participate in that, and our job is to help them participate in these decisions. I’m going to have plenty of patients who say, “You’ve got to be crazy. You’re going to help 2 women and you’re going to give a 15-mg dose for diarrhea.” There will be patients that say that, but I will feel obligated to at least discuss it and document it in my note.

Adam M. Brufsky, MD, PhD: You practice in the city, Mark, where patients want very aggressive therapy. So, how do you feel about this?

Mark E. Robson, MD: Well, I think our practice is probably no different from yours, which is that it’s very variable. Some people do, some people don’t. If you take this group of patients that we talked about a little bit ago, small node-negative, HER2-positive tumors who are 96% to 98% likely to survive free of disease with a year’s worth of trastuzumab, it’s going to be pretty hard to sell another year of neratinib to those patients.

Adam M. Brufsky, MD, PhD: That’s why I was kind of surprised. Someone who comes in with a big tumor and a lot of it’s left-side, you give them chemotherapy. I would be more excited about doing that.

Mark E. Robson, MD: Right, or even the ones who come in with big tumor, node-positive disease and have a good initial response, you still might worry about that.

Kimberly L. Blackwell, MD: I’d be more enthusiastic about those. If that tumor melts away on HER2-based therapy, I’d be even more enthused. And in the patients that it doesn’t melt away, then I’d be less enthused. I think we have an in vivo sensitivity assay to which tumors are HER2-addicted. That’s my favorite term. But the reality is, when tumors melt away to trastuzumab or trastuzumab/pertuzumab, that’s [an] HER2-addicted tumor. We saw that from the lapatinib days. And hopefully one day, we will see the results of the APHINITY study. There was probably a lot of HER2 nonenriched or HER2 nonaddicted tumors in that study, and it clearly affects our ability to see the benefits of adding pertuzumab in the adjuvant setting. So, again, I practice very practically, which is I offer it. In the setting of neratinib, if they get diarrhea, and they don’t want to continue it, we stop it. Unless we see a survival detriment, there’s a lot of things that we do in medicine that require overtreatment of a population of patients. But for that individual patient sitting in front of me who I want to be able to say, “We’ve done everything within reason to prevent your breast cancer from coming back,” I think neratinib in that setting, if it’s approved and it’s not a huge financial burden to the patient, I’ll offer it.

Transcript Edited for Clarity
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