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HER2+ Breast Cancer: Neratinibs Role as Adjuvant Therapy

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:
We have to talk about neratinib, OK? Because we’re going to change what we’re doing with that. So the ExteNET trial overall was positive, with 2.5% improvement in invasive disease-free survival [DFS] when giving 1 year of neratinib after finishing up your year of trastuzumab, and you didn’t want to wait too long. If you started within a year, you had a better outcome than waiting a year off of everything. You started it and then took your year of neratinib, 240 mg daily with prophylaxis against diarrhea, of course, which is the loperamide. The colestipol is looking really good.

But in the ER [estrogen receptor]-positive population, it was a larger delta of 5% that really held up over time. At San Antonio this year [2018], Michael Gnant, MD, and Frankie Ann Holmes, MD, have a nice poster looking at the one-third of patients in ExteNET who had preoperative therapy, had residual disease, and then were randomized, and the delta is even bigger there because you’re enriching for those. And this is the ER-positive group. It was big. It was like 8 percentage points of absolute improvement there. So that’s pretty good.

So in the ER-negative, HER2 [human epidermal growth factor receptor 2]-positive disease, initially there were those data where the curves came apart and it looked pretty good for a while, and then they came back together as soon as the patient stopped the therapy. But, there was a poster at ASCO [American Society of Clinical Oncology] this year [2018] that looked specifically at patients who had ER-negative, HER2-positive disease that started within 6 months of finishing up their trastuzumab. The curves split apart. It was 2.5% and they stayed apart. It didn’t come right back. So it was a lesser magnitude of benefit but at least it made more sense that it was maintained.             

Now maybe if you enriched as well for patients who had preoperative therapy, who still had considerable residual disease with ER-negative, HER-positive, you would see that the higher the risk, the hazard ratio will translate into a greater absolute benefit.

So let’s just go through each of us; now we’re going to be using T-DM1 [trastuzumab emtansine] for patients who don’t have a path CR [pathologic complete response] because T-DM1 was studied just in that population. That fits our current practice. We’re mostly giving preoperative therapy to the high-risk patients. So now we’re going to finish up the T-DM1 and then, for patients who are on endocrine therapy, who are you going to think about neratinib for, recognizing it’s a lot of therapy, but also recognizing the stakes are very high, of course? So how about you, Aditya?

Aditya Bardia, MD, MPH: I think as I look at the subset analysis of ExteNET, the biggest benefit was seen in the ER-positive, HER2-positive setting. And coming back to what Heather was saying earlier, patients can have later recurrence, especially the tumors that are ER-positive and HER2-positive. So if you just focus at 3-year disease-free survival or 5-year disease-free survival, that might not be sufficient, especially for that group. So if I have a young patient with ER-positive, HER2-positive disease, that is a patient I would consider neratinib for, even after T-DM1.

Joyce O’Shaughnessy, MD: How about you, Ruth?

Ruth O'Regan, MD: Well as you know, I’m a big believer in this cross talk between the HER2 and ER pathways. And as Adam alluded to earlier, I think the fact that there’s a subset of ER-positive, HER2 positive cancers that are luminal A is a very important thing to take into account. And we don’t have that from ExteNET. But I do think, it’s like Aditya said, if I had somebody who was high-risk that was ER-positive, HER2-positive, I would talk about neratinib, even if they had T-DM1.

Heather L. McArthur, MD, MPH: So you’ve been giving it after trastuzumab/pertuzumab, because ExteNET doesn’t address that population.

Adam M. Brufsky, MD, PhD: So ER-positive was substantial because remember, 50% of the ER-positive population is going to have residual disease. So it’s a question….

Heather L. McArthur, MD, MPH: I believe it speaks to your beliefs about whether you think it’s relevant therapy for your high-risk, particularly ER-positive, patients. Because if it is true that you believe even after HP [trastuzumab/pertuzumab] someone warrants neratinib, that same argument should carry over to the T-DM1 treated patient.

Adam M. Brufsky, MD, PhD: For me it will. I think that RCB2 or 3, definitely with ER-positive, will get both. T-DM1 for a year and then neratinib for a year. Again, with no more pertuzumab after.

Joyce O’Shaughnessy, MD: Good treaters, I like this.

Adam M. Brufsky, MD, PhD: That’s what I would do. What would you guys do, what would you have?

Heather L. McArthur, MD, MPH: I think time will tell. We need the experience under our belt, too, to see what patients can actually tolerate because we are talking about maybe AC-THP [doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab] neoadjuvant therapy, then T-DM1 after that for 14 cycles, and then a year of neratinib. That’s a lot of treatment.

Joyce O’Shaughnessy, MD: A lot of treatment. And by the time ExteNET came up, a standard of care had changed. It now included pertuzumab. So we had to take that leap of faith that there’s no cross resistance by hitting the tyrosine kinase end of HER2 and doing pan HER2 inhibition. But that made sense to us in our data in the metastatic setting in patients who had had HP, who had had CLEOPATRA-like taxane, trastuzumab, pertuzumab and then received in phase II trials of T-DM1 plus neratinib. It’s  very active. There are very high response rates, higher than we see with either one alone suggesting that after pertuzumab, neratinib was adding benefit. You know what I mean? Inferential. But we made that leap and we’re going to have to make the same leap with KATHERINE because it’s only a small percentage who had the pertuzumab. So now we’re making 2 leaps in that neratinib would be non-cross resistant with both pertuzumab and T-DM1. But talk a little about this cross talk that is persuasive to your group.

Ruth O'Regan, MD: Well, it’s the part about preclinical data saying that if you’ve blocked the HER2 pathway, the ER pathway becomes more active and vice versa. So biologically I think the results of ExteNET actually make sense where in the placebo arm where you’re taking away the HER2 inhibition, you’re allowing that to act as a resistance mechanism. And biologically I think that makes some sense. I would like it if we knew whether they were luminal A or luminal B patients who were benefiting. I don’t think we’ll really get those data. So that’s what I think makes the most sense.

What’s interesting though is why the tyrosine kinase inhibitor works but trastuzumab didn’t work in that setting. But we would assume the fact that because they’ve been on trastuzumab for a while, maybe some of them were resistant. So that’s my thought, I don’t know if it’s true. It’s totally hypothesis and we’re trying to work to do a trial where we would actually give a couple of weeks of either endocrine therapy or HER2-directed therapy for these triple positive cancers and see what happens to the other pathway. I think that’s the way that you would actually address that.

Joyce O’Shaughnessy, MD: Yes. It makes you think about giving neratinib plus good endocrine therapy up front as a possibility. It’s interesting. I think we’re all on the same page with that, and that’s going to hopefully bring the long-term disease-free survival rates up even higher in this disease. And then hopefully there will be some de-escalation too, maybe at the lower risk end of things. But in the higher risk setting, we have more and more tools, certainly.

Tiffany A. Traina, MD: You wonder what to do in the first-line setting for metastatic disease then after somebody has been exposed to HP and T-DM1.

Adam M. Brufsky, MD, PhD: I feel like there won’t be a lot of people.

Joyce O’Shaughnessy, MD: And it may be a while. Maybe they could go back to CLEOPATRA.

Ruth O'Regan, MD: Actually I have to say I haven’t thought about. What do you give those patients then?

Adam M. Brufsky, MD, PhD: Well we’re down now to 1 in 20; we’re now at 95% or over 90% of 5 to 10 years of DFS, you know?

Tiffany A. Traina, MD: It takes a long time to happen.

Transcript Edited for Clarity

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Transcript:

Joyce O’Shaughnessy, MD:
We have to talk about neratinib, OK? Because we’re going to change what we’re doing with that. So the ExteNET trial overall was positive, with 2.5% improvement in invasive disease-free survival [DFS] when giving 1 year of neratinib after finishing up your year of trastuzumab, and you didn’t want to wait too long. If you started within a year, you had a better outcome than waiting a year off of everything. You started it and then took your year of neratinib, 240 mg daily with prophylaxis against diarrhea, of course, which is the loperamide. The colestipol is looking really good.

But in the ER [estrogen receptor]-positive population, it was a larger delta of 5% that really held up over time. At San Antonio this year [2018], Michael Gnant, MD, and Frankie Ann Holmes, MD, have a nice poster looking at the one-third of patients in ExteNET who had preoperative therapy, had residual disease, and then were randomized, and the delta is even bigger there because you’re enriching for those. And this is the ER-positive group. It was big. It was like 8 percentage points of absolute improvement there. So that’s pretty good.

So in the ER-negative, HER2 [human epidermal growth factor receptor 2]-positive disease, initially there were those data where the curves came apart and it looked pretty good for a while, and then they came back together as soon as the patient stopped the therapy. But, there was a poster at ASCO [American Society of Clinical Oncology] this year [2018] that looked specifically at patients who had ER-negative, HER2-positive disease that started within 6 months of finishing up their trastuzumab. The curves split apart. It was 2.5% and they stayed apart. It didn’t come right back. So it was a lesser magnitude of benefit but at least it made more sense that it was maintained.             

Now maybe if you enriched as well for patients who had preoperative therapy, who still had considerable residual disease with ER-negative, HER-positive, you would see that the higher the risk, the hazard ratio will translate into a greater absolute benefit.

So let’s just go through each of us; now we’re going to be using T-DM1 [trastuzumab emtansine] for patients who don’t have a path CR [pathologic complete response] because T-DM1 was studied just in that population. That fits our current practice. We’re mostly giving preoperative therapy to the high-risk patients. So now we’re going to finish up the T-DM1 and then, for patients who are on endocrine therapy, who are you going to think about neratinib for, recognizing it’s a lot of therapy, but also recognizing the stakes are very high, of course? So how about you, Aditya?

Aditya Bardia, MD, MPH: I think as I look at the subset analysis of ExteNET, the biggest benefit was seen in the ER-positive, HER2-positive setting. And coming back to what Heather was saying earlier, patients can have later recurrence, especially the tumors that are ER-positive and HER2-positive. So if you just focus at 3-year disease-free survival or 5-year disease-free survival, that might not be sufficient, especially for that group. So if I have a young patient with ER-positive, HER2-positive disease, that is a patient I would consider neratinib for, even after T-DM1.

Joyce O’Shaughnessy, MD: How about you, Ruth?

Ruth O'Regan, MD: Well as you know, I’m a big believer in this cross talk between the HER2 and ER pathways. And as Adam alluded to earlier, I think the fact that there’s a subset of ER-positive, HER2 positive cancers that are luminal A is a very important thing to take into account. And we don’t have that from ExteNET. But I do think, it’s like Aditya said, if I had somebody who was high-risk that was ER-positive, HER2-positive, I would talk about neratinib, even if they had T-DM1.

Heather L. McArthur, MD, MPH: So you’ve been giving it after trastuzumab/pertuzumab, because ExteNET doesn’t address that population.

Adam M. Brufsky, MD, PhD: So ER-positive was substantial because remember, 50% of the ER-positive population is going to have residual disease. So it’s a question….

Heather L. McArthur, MD, MPH: I believe it speaks to your beliefs about whether you think it’s relevant therapy for your high-risk, particularly ER-positive, patients. Because if it is true that you believe even after HP [trastuzumab/pertuzumab] someone warrants neratinib, that same argument should carry over to the T-DM1 treated patient.

Adam M. Brufsky, MD, PhD: For me it will. I think that RCB2 or 3, definitely with ER-positive, will get both. T-DM1 for a year and then neratinib for a year. Again, with no more pertuzumab after.

Joyce O’Shaughnessy, MD: Good treaters, I like this.

Adam M. Brufsky, MD, PhD: That’s what I would do. What would you guys do, what would you have?

Heather L. McArthur, MD, MPH: I think time will tell. We need the experience under our belt, too, to see what patients can actually tolerate because we are talking about maybe AC-THP [doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab] neoadjuvant therapy, then T-DM1 after that for 14 cycles, and then a year of neratinib. That’s a lot of treatment.

Joyce O’Shaughnessy, MD: A lot of treatment. And by the time ExteNET came up, a standard of care had changed. It now included pertuzumab. So we had to take that leap of faith that there’s no cross resistance by hitting the tyrosine kinase end of HER2 and doing pan HER2 inhibition. But that made sense to us in our data in the metastatic setting in patients who had had HP, who had had CLEOPATRA-like taxane, trastuzumab, pertuzumab and then received in phase II trials of T-DM1 plus neratinib. It’s  very active. There are very high response rates, higher than we see with either one alone suggesting that after pertuzumab, neratinib was adding benefit. You know what I mean? Inferential. But we made that leap and we’re going to have to make the same leap with KATHERINE because it’s only a small percentage who had the pertuzumab. So now we’re making 2 leaps in that neratinib would be non-cross resistant with both pertuzumab and T-DM1. But talk a little about this cross talk that is persuasive to your group.

Ruth O'Regan, MD: Well, it’s the part about preclinical data saying that if you’ve blocked the HER2 pathway, the ER pathway becomes more active and vice versa. So biologically I think the results of ExteNET actually make sense where in the placebo arm where you’re taking away the HER2 inhibition, you’re allowing that to act as a resistance mechanism. And biologically I think that makes some sense. I would like it if we knew whether they were luminal A or luminal B patients who were benefiting. I don’t think we’ll really get those data. So that’s what I think makes the most sense.

What’s interesting though is why the tyrosine kinase inhibitor works but trastuzumab didn’t work in that setting. But we would assume the fact that because they’ve been on trastuzumab for a while, maybe some of them were resistant. So that’s my thought, I don’t know if it’s true. It’s totally hypothesis and we’re trying to work to do a trial where we would actually give a couple of weeks of either endocrine therapy or HER2-directed therapy for these triple positive cancers and see what happens to the other pathway. I think that’s the way that you would actually address that.

Joyce O’Shaughnessy, MD: Yes. It makes you think about giving neratinib plus good endocrine therapy up front as a possibility. It’s interesting. I think we’re all on the same page with that, and that’s going to hopefully bring the long-term disease-free survival rates up even higher in this disease. And then hopefully there will be some de-escalation too, maybe at the lower risk end of things. But in the higher risk setting, we have more and more tools, certainly.

Tiffany A. Traina, MD: You wonder what to do in the first-line setting for metastatic disease then after somebody has been exposed to HP and T-DM1.

Adam M. Brufsky, MD, PhD: I feel like there won’t be a lot of people.

Joyce O’Shaughnessy, MD: And it may be a while. Maybe they could go back to CLEOPATRA.

Ruth O'Regan, MD: Actually I have to say I haven’t thought about. What do you give those patients then?

Adam M. Brufsky, MD, PhD: Well we’re down now to 1 in 20; we’re now at 95% or over 90% of 5 to 10 years of DFS, you know?

Tiffany A. Traina, MD: It takes a long time to happen.

Transcript Edited for Clarity
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