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Neratinib for Metastatic Breast Cancer

Adam Brufsky,MD
Published: Tuesday, Feb 07, 2017



Adam Brufsky, MD, PhD: The other fascinating thing about these tyrosine kinase inhibitors, in particular, neratinib—which is one of the first of many kinds of next-generation tyrosine kinase inhibitors after lapatinib—is that they really do seem to have activity in HER2-positive metastatic disease. There was a trial, NEfERT-T, that was published in Lancet Oncology almost 1 year ago now, where women with first-line metastatic HER2-positive breast cancer were randomized to paclitaxel and trastuzumab or paclitaxel and neratinib.

And in fact, their progression-free survival was identical, which means, already, neratinib is better than lapatinib up front because lapatinib was not comparable to trastuzumab up front. But the fascinating thing about this trial is, the incidence of brain metastases as a sign of progression was dramatically reduced, I think probably from like 30% down to 10%, if I remember the data correctly. But clearly, it was a substantial reduction in the brain metastases. And given that, I think that’s really interesting because the drug penetrates the CNS and it seems to have activity, potentially as a single agent, because the paclitaxel doesn’t get into the brain as far as we know.

So, these were really, really interesting data because brain metastases seem to be the biggest problem, or one of the big problems right now, with women eventually dying of metastatic HER2-positive breast cancer. And if we could somehow push out the incidence for progression of those brain metastases a couple of years, I think we’ve made another major advance.

The other thing that’s really cool about neratinib is that—now that we’re doing genome sequencing, exome sequencing of tumors, either through the Guardant Assay, Foundation One, or something else—we’re finding that a certain percentage of women with metastatic breast cancer that’s HER2-negative tend to have activating mutations of the HER2 protein, the internal tyrosine kinase domain. And clearly, because drugs, like neratinib in particular, seem to be irreversible inactivators of this, they seem to have a lot of activity. We don’t know the incidence; some people claim it’s about 1% to 2%. In terms of lobular cancer, it may be as high as 10%, if not higher, of these progressive metastatic patients. And, therefore, we may have a drug that has activity. In fact, there’s currently a phase II clinical trial called SUMMIT, where women with HER2-negative metastatic breast cancer who have a tyrosine kinase-activating domain mutation are given lapatinib and, in some cases, lapatinib with fulvestrant. And even women who had progressed on fulvestrant seemed to actually respond to this combination therapy.

So, it’s really, really interesting. And if this data does pan out, it may be one of the reasons, potentially in the future, that we may have to do some of these exome sequencing, do the next-generation sequencing assays, on women with progressive metastatic breast cancer. I think these are really interesting things that have come out that are on the side of the big data, which are the data that are really going to, I think, lead to the approval by the FDA.

 
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Adam Brufsky, MD, PhD: The other fascinating thing about these tyrosine kinase inhibitors, in particular, neratinib—which is one of the first of many kinds of next-generation tyrosine kinase inhibitors after lapatinib—is that they really do seem to have activity in HER2-positive metastatic disease. There was a trial, NEfERT-T, that was published in Lancet Oncology almost 1 year ago now, where women with first-line metastatic HER2-positive breast cancer were randomized to paclitaxel and trastuzumab or paclitaxel and neratinib.

And in fact, their progression-free survival was identical, which means, already, neratinib is better than lapatinib up front because lapatinib was not comparable to trastuzumab up front. But the fascinating thing about this trial is, the incidence of brain metastases as a sign of progression was dramatically reduced, I think probably from like 30% down to 10%, if I remember the data correctly. But clearly, it was a substantial reduction in the brain metastases. And given that, I think that’s really interesting because the drug penetrates the CNS and it seems to have activity, potentially as a single agent, because the paclitaxel doesn’t get into the brain as far as we know.

So, these were really, really interesting data because brain metastases seem to be the biggest problem, or one of the big problems right now, with women eventually dying of metastatic HER2-positive breast cancer. And if we could somehow push out the incidence for progression of those brain metastases a couple of years, I think we’ve made another major advance.

The other thing that’s really cool about neratinib is that—now that we’re doing genome sequencing, exome sequencing of tumors, either through the Guardant Assay, Foundation One, or something else—we’re finding that a certain percentage of women with metastatic breast cancer that’s HER2-negative tend to have activating mutations of the HER2 protein, the internal tyrosine kinase domain. And clearly, because drugs, like neratinib in particular, seem to be irreversible inactivators of this, they seem to have a lot of activity. We don’t know the incidence; some people claim it’s about 1% to 2%. In terms of lobular cancer, it may be as high as 10%, if not higher, of these progressive metastatic patients. And, therefore, we may have a drug that has activity. In fact, there’s currently a phase II clinical trial called SUMMIT, where women with HER2-negative metastatic breast cancer who have a tyrosine kinase-activating domain mutation are given lapatinib and, in some cases, lapatinib with fulvestrant. And even women who had progressed on fulvestrant seemed to actually respond to this combination therapy.

So, it’s really, really interesting. And if this data does pan out, it may be one of the reasons, potentially in the future, that we may have to do some of these exome sequencing, do the next-generation sequencing assays, on women with progressive metastatic breast cancer. I think these are really interesting things that have come out that are on the side of the big data, which are the data that are really going to, I think, lead to the approval by the FDA.

 
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