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Neoadjuvant Lapatinib in HER2+ Early 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: Friday, Dec 02, 2016



Transcript:

Adam M. Brufsky, MD, PhD:
There’s one outlier to this, and I’m really curious about it. Because this is, I think, a trial, NSABP-41, Hope, where they did get all the therapy up front, did have a small pCR benefit. And, in fact, I believe the data reported at ASCO actually added disease-free survival benefit (DFS) to the addition of lapatinib, did it not?

Hope S. Rugo, MD: No. There’s one study, interestingly in the neoadjuvant setting, that suggested some DFS benefit in the ER-positive subset, and that’s actually the German trial, GeparQuinto. That suggested that potentially continuing lapatinib with hormone therapy, because we start the hormone therapy after surgery and radiation, might have some advantage. This is intriguing given the data that I know we’ll talk about with neratinib, another oral tyrosine kinase inhibitor, because I think there may be something there. But, otherwise, there wasn’t. For B41, it’s an interesting question because we also have the lapatinib data from the CALGB trial that Lisa Carey published quite recently. And that one mainly, I think, has really helped a lot in terms of biomarker data. But, in terms of the addition of lapatinib, it’s very hard to interpret any information. And with that one, the anthracycline also was given after. We don’t know, and I think there are a lot of issues there in terms of how people tolerate neoadjuvant therapy, how much they get, the ER-positive versus negative differential, etc.

Adam M. Brufsky, MD, PhD: Just before we move on to T-DM1 in the neoadjuvant setting, I just want to ask everybody, at least in the adjuvant and neoadjuvant setting, whether lapatinib does not have a future or has a future. I’ll start with Ahmad. Do you think lapatinib is done?

Ahmad Awada, MD, PhD: I think it will be difficult, following the result of the ALTTO trial, to support lapatinib in the neoadjuvant setting. But, for the other drugs, certainly for pertuzumab and for neratinib, we should wait on a little bit more data to call.

Adam M. Brufsky, MD, PhD: Gotcha. Hope?

Hope Rugo, MD: I agree. I think there is likely an ongoing benefit of lapatinib, at least until neratinib is approved for patients who have resistant disease. And I’ve certainly added it in people with early relapses on a trastuzumab/pertuzumab combination.

Adam M. Brufsky, MD, PhD: Michael?

Michael Untch, MD: Before giving a yes or no answer, which might be the simplest way to go, let me just recall what Hope was mentioning to with the Quinto study. Since I am the PI (principal investigator) of the Quinto study, the Quinto study is actually a negative study.

Adam M. Brufsky, MD, PhD: Could you explain, though, for the audience what the Quinto study was, in case people don’t know?

Michael Untch, MD: Absolutely, yes. So, the neoadjuvant portion of the Quinto study was the comparison of lapatinib with trastuzumab and with the double combination. Now, the problem of Quinto is that it gave us a very nice hypothesis for the future—but I’m going to end up speaking of neratinib—because in the Quinto study, actually, we gave 6 months of neoadjuvant therapy. And after 6 months of neoadjuvant therapy, the lapatinib component or the lapatinib arm was inferior. That was number 1. Number 2, all patients received 12 months’ standard therapy with trastuzumab after surgery. So, actually, the patients in the lapatinib arm ended with 18 months of treatment with a sequence of a tyrosine kinase inhibitor and trastuzumab. And those other patients in the standard arm had 18 months or one-and-a-half years of trastuzumab.

Now, we know that trastuzumab 2 years is not better than 1 year, and that was exactly the same result in our study. But, interestingly, the hormone receptor–positive patients had a survival benefit from the receptor tyrosine kinase inhibitor portion and trastuzumab. So, I was then looking through the literature, and I ended up with the ExteNET trial in which we see exactly the same effect. I think lapatinib was used in the wrong way when we designed the trials, and probably we should learn from the neratinib trial, which I think we are going to focus on in a moment.

Adam M. Brufsky, MD, PhD: We’ll talk about it in a few minutes, yes.

Michael Untch, MD: Okay. So, my answer is lapatinib, at the moment in the adjuvant and neoadjuvant setting, is a no because we are not using it. We have better options. And how to use an extension of anti-HER2 therapy is the story with neratinib.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
There’s one outlier to this, and I’m really curious about it. Because this is, I think, a trial, NSABP-41, Hope, where they did get all the therapy up front, did have a small pCR benefit. And, in fact, I believe the data reported at ASCO actually added disease-free survival benefit (DFS) to the addition of lapatinib, did it not?

Hope S. Rugo, MD: No. There’s one study, interestingly in the neoadjuvant setting, that suggested some DFS benefit in the ER-positive subset, and that’s actually the German trial, GeparQuinto. That suggested that potentially continuing lapatinib with hormone therapy, because we start the hormone therapy after surgery and radiation, might have some advantage. This is intriguing given the data that I know we’ll talk about with neratinib, another oral tyrosine kinase inhibitor, because I think there may be something there. But, otherwise, there wasn’t. For B41, it’s an interesting question because we also have the lapatinib data from the CALGB trial that Lisa Carey published quite recently. And that one mainly, I think, has really helped a lot in terms of biomarker data. But, in terms of the addition of lapatinib, it’s very hard to interpret any information. And with that one, the anthracycline also was given after. We don’t know, and I think there are a lot of issues there in terms of how people tolerate neoadjuvant therapy, how much they get, the ER-positive versus negative differential, etc.

Adam M. Brufsky, MD, PhD: Just before we move on to T-DM1 in the neoadjuvant setting, I just want to ask everybody, at least in the adjuvant and neoadjuvant setting, whether lapatinib does not have a future or has a future. I’ll start with Ahmad. Do you think lapatinib is done?

Ahmad Awada, MD, PhD: I think it will be difficult, following the result of the ALTTO trial, to support lapatinib in the neoadjuvant setting. But, for the other drugs, certainly for pertuzumab and for neratinib, we should wait on a little bit more data to call.

Adam M. Brufsky, MD, PhD: Gotcha. Hope?

Hope Rugo, MD: I agree. I think there is likely an ongoing benefit of lapatinib, at least until neratinib is approved for patients who have resistant disease. And I’ve certainly added it in people with early relapses on a trastuzumab/pertuzumab combination.

Adam M. Brufsky, MD, PhD: Michael?

Michael Untch, MD: Before giving a yes or no answer, which might be the simplest way to go, let me just recall what Hope was mentioning to with the Quinto study. Since I am the PI (principal investigator) of the Quinto study, the Quinto study is actually a negative study.

Adam M. Brufsky, MD, PhD: Could you explain, though, for the audience what the Quinto study was, in case people don’t know?

Michael Untch, MD: Absolutely, yes. So, the neoadjuvant portion of the Quinto study was the comparison of lapatinib with trastuzumab and with the double combination. Now, the problem of Quinto is that it gave us a very nice hypothesis for the future—but I’m going to end up speaking of neratinib—because in the Quinto study, actually, we gave 6 months of neoadjuvant therapy. And after 6 months of neoadjuvant therapy, the lapatinib component or the lapatinib arm was inferior. That was number 1. Number 2, all patients received 12 months’ standard therapy with trastuzumab after surgery. So, actually, the patients in the lapatinib arm ended with 18 months of treatment with a sequence of a tyrosine kinase inhibitor and trastuzumab. And those other patients in the standard arm had 18 months or one-and-a-half years of trastuzumab.

Now, we know that trastuzumab 2 years is not better than 1 year, and that was exactly the same result in our study. But, interestingly, the hormone receptor–positive patients had a survival benefit from the receptor tyrosine kinase inhibitor portion and trastuzumab. So, I was then looking through the literature, and I ended up with the ExteNET trial in which we see exactly the same effect. I think lapatinib was used in the wrong way when we designed the trials, and probably we should learn from the neratinib trial, which I think we are going to focus on in a moment.

Adam M. Brufsky, MD, PhD: We’ll talk about it in a few minutes, yes.

Michael Untch, MD: Okay. So, my answer is lapatinib, at the moment in the adjuvant and neoadjuvant setting, is a no because we are not using it. We have better options. And how to use an extension of anti-HER2 therapy is the story with neratinib.

Transcript Edited for Clarity
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