Select Topic:
Browse by Series:

Neratinib in HER2+ 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 16, 2016



Transcript:

Adam M. Brufsky, MD, PhD:
Again, we were talking about tyrosine kinase inhibitors. Over the years, lapatinib has been somewhat disappointing to some of us. Now, along comes a variety of tyrosine kinase inhibitors, particularly neratinib—which a lot of us, for a long time, thought was equivalent to lapatinib, except with more diarrhea. But I think there has been a lot of very exciting and interesting studies that have come up over the last few years. One of them is the NEfERTT trial. Can you explain that to us, Ahmad?

Ahmad Awada, MD, PhD: I think before I go to this trial, I would like to put the study in the context of the neratinib program. As a single-agent therapy in trastuzumab-naïve patients, this drug gave up to 45% objective response rate. In patients pretreated with trastuzumab, there is up to 25% objective response rate. There are many combinations, including the combination of weekly paclitaxel with neratinib, which was compared to weekly paclitaxel with trastuzumab in the NEfERTT trial. This trial showed exactly that both arms are superimposable in terms of progression-free survival and objective response rate, as well. But what’s really interesting is this trial, because it was laid to look at the CNS event in each arm for the trial. And what we showed was that in the weekly paclitaxel arm with trastuzumab, we had 40 events. In the weekly paclitaxel-with-neratinib arm, we had 20 events. So, that means the incidence of CNS event was reduced by 50%. And that’s really very important information, knowing the bulk of this problem of brain metastases in HER2 disease.

Adam M. Brufsky, MD, PhD: Right. I think it is the major issue, one of the major issues we have.

Ahmad Awada, MD, PhD: It’s really important to look, to go back to this, and to try to really show the importance of this drug in preventing and/or delaying the appearance of a CNS event in the evolution of HER2+ disease.

Adam M. Brufsky, MD, PhD: Right. I’m very excited by this. Even though trastuzumab/taxane, by themselves as a doublet, is not the standard of care anymore, the fact that lapatinib/neratinib and a taxane had equivalent response has never really been seen. You know all the data from lapatinib, MA.31, showing inferiority. The second-line trials had to be stopped with lapatinib because of inferiority in systemic disease. And you have that, as well as the decrease in brain metastases in a randomized first-line trial. I think that is actually fairly interesting.

Ahmad Awada, MD, PhD: Very quick remark about the CNS events because of brain metastasis, meningitis, and so on. I think it’s really important to look to drugs. It would be difficult to discover drugs that shrink, let’s say, a brain metastasis and really pretreat it by systemic disease, as well by local therapy. But I think it’s really important to look for drugs that could prevent or delay the appearance of this. And from our study, this could be happening with neratinib. So, it’s important to confirm that. And in our program, we are looking to this important, let’s say, endpoint, delaying or preventing the appearance of a CNS event.

Adam M. Brufsky, MD, PhD: So, Hope, this drug was developed. The first actual indication for approval is going to be, it looks like, in the post-trastuzumab adjuvant setting. Can you talk about ExteNET?

Hope S. Rugo, MD: It’s such an interesting progression. Usually what happens is we get really excited about something and then our excitement wanes over time, right? And you could even go back to bone marrow transplant for breast cancer. This is exactly the opposite, where the initial data from neratinib seemed like it was a really toxic drug. It caused a lot of diarrhea compared to lapatinib, and so we weren’t all that excited. Then, we saw the data from the TEACH trial that suggested that when you added lapatinib in the adjuvant setting in patients who were further out from their HER2+ early stage diagnosis, that you didn’t really benefit patients—so toxicity without much benefit. Neratinib, however, has this intriguing data, and I actually have become extremely interested in it. And it’s, as I say, from not too excited to very excited.

The neratinib is a potent irreversible pan-HER inhibitor that inhibits HER2, HER1, EGFR, and HER4. And, in the ExteNET trial, the idea originally was very much like TEACH, which was to add it on after somebody had completed a year of adjuvant trastuzumab for 1 more year. Remember, when that study was developed, we didn’t know the results of HERA, which showed that the continued trastuzumab didn’t benefit patients as a whole. But, we did, over time, know the results of TEACH. So, what happened was you got some negative data from the metastatic setting because of toxicity, I presume, and maybe designs that weren’t perfect, dosing, and toxicity management that was delayed. The drug was shuffled along from one company to another to now its current owner, Puma.

What first ended up happening over the course of ExteNET was they reduced the number of patients, saying, “Okay, we’re going to cut our losses.” Very clever and this was, I think, a critical move. The idea was to expand the population of patients so that you increased the risk of relapse. So, you took patients who had higher-risk disease, bigger tumors, positive nodes, and residual disease after neoadjuvant chemotherapy. That was really important. And then they changed the endpoint to a clinically important endpoint, which was invasive disease-free survival as opposed to just looking at any event. In the MA-17R trial, you reduced contralateral new breast cancers, but that may not be a reason to extend your adjuvant hormone therapy.

That was really important. And then when Puma picked it up and saw the positive results from the neoadjuvant I-SPY trial published this year in the New England Journal of Medicine—showing that if you looked at a similar design to NEfERTT, which was looking at neratinib and paclitaxel versus trastuzumab and paclitaxel, and showing that the estimated or potential pCR rates were higher in the neratinib arm—that led to wanting to follow these patients longer. So, they changed the follow-up from 2 years to 5 years.

So, what results did we get? The initial data, if you just think about 3-year invasive disease-free survival, that came out said, “Oh, there’s a little more than a 2% difference in invasive disease-free survival.” We’re like, “Oh, almost 100% diarrhea rate, 30% grade 3, mostly it’s grade 3, and if it’s only 2.5%, is it worth it?” Then, you look at the pre-planned subset analysis, at ER+ disease, and if you see that you can then double that number, it’s over 4% in patients who had ER+ disease. We went back and looked at patients who had centrally confirmed HER2+ disease, which is really important, and ER+ disease. Particularly, if you look at the patients who were treated within a year of finishing their adjuvant trastuzumab, you could see more than a 7% improvement in disease-free survival in ER+ disease, invasive disease-free survival. And that’s better than we see with adjuvant chemotherapy, so that’s actually quite impressive. Actually, the FDA asked them to do an interim 5-year analysis, although they don’t have the number of events for the final analysis. That’s public, and it shows, again, a 7% improvement in ER+ disease, centrally confirmed HER2 with this interim 5-year invasive disease-free survival analysis.

You could still ask, “Well, what’s your quality of life in that setting?” But it turns out you can reduce grade 3+ diarrhea to about 17% with intensive prophylaxis with loperamide. And the control trial is now looking at patients, similar to ExteNET, and looking at a number of approaches, not just the loperamide, but figuring that if you take loperamide, patients don’t like it much; they get diarrhea alternating with constipation. But also looking at an oral nonabsorbable steroid and some other approaches, we, at UCSF, particularly my colleague, Joe Chen, are looking at an herbal agent that reduces secretory diarrhea (since this is secretory). And then, I think the last thing about this that’s interesting about toxicity is that the toxicity is all up front, which is pretty helpful. It’s not like seeing neuropathy that gets worse and worse over time. You get it right up front in the first few days, and once you’ve gotten past a month, your chances of getting significant diarrhea go way, way down. So, it’s something that patients can learn how to manage, and it would be very exciting if long term we see less, or no CNS metastases in these patients, too. To me, it’s a real advance and exciting.

Transcript Edited for Clarity

Slider Left
Slider Right


Transcript:

Adam M. Brufsky, MD, PhD:
Again, we were talking about tyrosine kinase inhibitors. Over the years, lapatinib has been somewhat disappointing to some of us. Now, along comes a variety of tyrosine kinase inhibitors, particularly neratinib—which a lot of us, for a long time, thought was equivalent to lapatinib, except with more diarrhea. But I think there has been a lot of very exciting and interesting studies that have come up over the last few years. One of them is the NEfERTT trial. Can you explain that to us, Ahmad?

Ahmad Awada, MD, PhD: I think before I go to this trial, I would like to put the study in the context of the neratinib program. As a single-agent therapy in trastuzumab-naïve patients, this drug gave up to 45% objective response rate. In patients pretreated with trastuzumab, there is up to 25% objective response rate. There are many combinations, including the combination of weekly paclitaxel with neratinib, which was compared to weekly paclitaxel with trastuzumab in the NEfERTT trial. This trial showed exactly that both arms are superimposable in terms of progression-free survival and objective response rate, as well. But what’s really interesting is this trial, because it was laid to look at the CNS event in each arm for the trial. And what we showed was that in the weekly paclitaxel arm with trastuzumab, we had 40 events. In the weekly paclitaxel-with-neratinib arm, we had 20 events. So, that means the incidence of CNS event was reduced by 50%. And that’s really very important information, knowing the bulk of this problem of brain metastases in HER2 disease.

Adam M. Brufsky, MD, PhD: Right. I think it is the major issue, one of the major issues we have.

Ahmad Awada, MD, PhD: It’s really important to look, to go back to this, and to try to really show the importance of this drug in preventing and/or delaying the appearance of a CNS event in the evolution of HER2+ disease.

Adam M. Brufsky, MD, PhD: Right. I’m very excited by this. Even though trastuzumab/taxane, by themselves as a doublet, is not the standard of care anymore, the fact that lapatinib/neratinib and a taxane had equivalent response has never really been seen. You know all the data from lapatinib, MA.31, showing inferiority. The second-line trials had to be stopped with lapatinib because of inferiority in systemic disease. And you have that, as well as the decrease in brain metastases in a randomized first-line trial. I think that is actually fairly interesting.

Ahmad Awada, MD, PhD: Very quick remark about the CNS events because of brain metastasis, meningitis, and so on. I think it’s really important to look to drugs. It would be difficult to discover drugs that shrink, let’s say, a brain metastasis and really pretreat it by systemic disease, as well by local therapy. But I think it’s really important to look for drugs that could prevent or delay the appearance of this. And from our study, this could be happening with neratinib. So, it’s important to confirm that. And in our program, we are looking to this important, let’s say, endpoint, delaying or preventing the appearance of a CNS event.

Adam M. Brufsky, MD, PhD: So, Hope, this drug was developed. The first actual indication for approval is going to be, it looks like, in the post-trastuzumab adjuvant setting. Can you talk about ExteNET?

Hope S. Rugo, MD: It’s such an interesting progression. Usually what happens is we get really excited about something and then our excitement wanes over time, right? And you could even go back to bone marrow transplant for breast cancer. This is exactly the opposite, where the initial data from neratinib seemed like it was a really toxic drug. It caused a lot of diarrhea compared to lapatinib, and so we weren’t all that excited. Then, we saw the data from the TEACH trial that suggested that when you added lapatinib in the adjuvant setting in patients who were further out from their HER2+ early stage diagnosis, that you didn’t really benefit patients—so toxicity without much benefit. Neratinib, however, has this intriguing data, and I actually have become extremely interested in it. And it’s, as I say, from not too excited to very excited.

The neratinib is a potent irreversible pan-HER inhibitor that inhibits HER2, HER1, EGFR, and HER4. And, in the ExteNET trial, the idea originally was very much like TEACH, which was to add it on after somebody had completed a year of adjuvant trastuzumab for 1 more year. Remember, when that study was developed, we didn’t know the results of HERA, which showed that the continued trastuzumab didn’t benefit patients as a whole. But, we did, over time, know the results of TEACH. So, what happened was you got some negative data from the metastatic setting because of toxicity, I presume, and maybe designs that weren’t perfect, dosing, and toxicity management that was delayed. The drug was shuffled along from one company to another to now its current owner, Puma.

What first ended up happening over the course of ExteNET was they reduced the number of patients, saying, “Okay, we’re going to cut our losses.” Very clever and this was, I think, a critical move. The idea was to expand the population of patients so that you increased the risk of relapse. So, you took patients who had higher-risk disease, bigger tumors, positive nodes, and residual disease after neoadjuvant chemotherapy. That was really important. And then they changed the endpoint to a clinically important endpoint, which was invasive disease-free survival as opposed to just looking at any event. In the MA-17R trial, you reduced contralateral new breast cancers, but that may not be a reason to extend your adjuvant hormone therapy.

That was really important. And then when Puma picked it up and saw the positive results from the neoadjuvant I-SPY trial published this year in the New England Journal of Medicine—showing that if you looked at a similar design to NEfERTT, which was looking at neratinib and paclitaxel versus trastuzumab and paclitaxel, and showing that the estimated or potential pCR rates were higher in the neratinib arm—that led to wanting to follow these patients longer. So, they changed the follow-up from 2 years to 5 years.

So, what results did we get? The initial data, if you just think about 3-year invasive disease-free survival, that came out said, “Oh, there’s a little more than a 2% difference in invasive disease-free survival.” We’re like, “Oh, almost 100% diarrhea rate, 30% grade 3, mostly it’s grade 3, and if it’s only 2.5%, is it worth it?” Then, you look at the pre-planned subset analysis, at ER+ disease, and if you see that you can then double that number, it’s over 4% in patients who had ER+ disease. We went back and looked at patients who had centrally confirmed HER2+ disease, which is really important, and ER+ disease. Particularly, if you look at the patients who were treated within a year of finishing their adjuvant trastuzumab, you could see more than a 7% improvement in disease-free survival in ER+ disease, invasive disease-free survival. And that’s better than we see with adjuvant chemotherapy, so that’s actually quite impressive. Actually, the FDA asked them to do an interim 5-year analysis, although they don’t have the number of events for the final analysis. That’s public, and it shows, again, a 7% improvement in ER+ disease, centrally confirmed HER2 with this interim 5-year invasive disease-free survival analysis.

You could still ask, “Well, what’s your quality of life in that setting?” But it turns out you can reduce grade 3+ diarrhea to about 17% with intensive prophylaxis with loperamide. And the control trial is now looking at patients, similar to ExteNET, and looking at a number of approaches, not just the loperamide, but figuring that if you take loperamide, patients don’t like it much; they get diarrhea alternating with constipation. But also looking at an oral nonabsorbable steroid and some other approaches, we, at UCSF, particularly my colleague, Joe Chen, are looking at an herbal agent that reduces secretory diarrhea (since this is secretory). And then, I think the last thing about this that’s interesting about toxicity is that the toxicity is all up front, which is pretty helpful. It’s not like seeing neuropathy that gets worse and worse over time. You get it right up front in the first few days, and once you’ve gotten past a month, your chances of getting significant diarrhea go way, way down. So, it’s something that patients can learn how to manage, and it would be very exciting if long term we see less, or no CNS metastases in these patients, too. To me, it’s a real advance and exciting.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections: 15th Annual International Congress on the Future of Breast Cancer®Oct 06, 20172.0
Medical Crossfire®: Leveraging New Evidence in the Context of Evolving Early-Stage Treatment Standards in HER2-Positive Breast CancerJan 30, 20181.5
Publication Bottom Border
Border Publication