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Treating HER2+ mBC: Immunotherapy and TKIs

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Ian E. Krop, MD, PhD, Harvard Medical School; Joyce A. O'Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Debu Tripathy, MD, The University of Texas MD Anderson Cancer Center
Published: Friday, Feb 21, 2020



Transcript:

Debu Tripathy, MD: Hope, I want to ask you a question specifically about margetuximab but also the broader issue of immunotherapy in the HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer space, because we’ve all been impressed with the fact that there is almost certainly a big immune effect going on just with the standard antibodies we’ve been using. What are the future plans and your thoughts about margetuximab, in general, with the immune system and then some of these other trials that are going on exploring the role of checkpoint inhibitors?

Hope S. Rugo, MD: Well, margetuximab is an interesting agent. It clearly has enhanced immune activity, and there may be a subset of patients who represent a very large group of patients within the world and carry the F allele, the low-affinity CD16, the IgG Fc receptor that may benefit specifically from margetuximab. Where, and in what line of therapy, can we talk about 2 drugs that are already going to get approved, and we don’t know where to put them in sequencing? With margetuximab, we definitely don’t know.

Actually, Ian has developed a neoadjuvant trial that will focus on people who have the F allele. To me, that’s going to be a really important end point, because looking at pCR [pathologic complete response] in those patients, they have high pCRs, but there’s some improvement we can make. These patients will have a more intact immune system. It’s going to be really interesting to see what happens. Margetuximab can be combined with other immune active agents, which I think will be interesting as well. They have a LAG3 antagonist. There are ways maybe to further enhance the immunity, but I think it’s going to have to win as a single agent with chemotherapy before it’s added to other antibodies.

Adam M. Brufsky, MD, PhD: I like the fact that we’ve been debating this for how many years, that there’s really immune activity from trastuzumab. We’ve talked about and argued through clinical trial data here, but this is the first real proof of concept in a large trial that it’s true. That’s the beauty of this study.

Hope S. Rugo, MD: Our next step is to go on and combine HER2-targeted therapy with immunotherapy. I wondered some time ago—when all these studies popped up about whether it was really making sense, because now we’ve got all these new agents. Actually, there are quite a number of trials adding or substituting agents with checkpoint inhibitors, so it will be interesting to see what happens. They’re neoadjuvant and they’re metastatic. There are a bunch of trials going on. How we’re going to fit all this together is interesting because we really have a disease subset that’s a minority of our patients. Most of them do really well, and we have lots of drugs that are active.

Adam M. Brufsky, MD, PhD: So the…neoadjuvant study, is that restricted to F allele?

Ian E. Krop, MD, PhD: Yes.

Adam M. Brufsky, MD, PhD: And it’s in TBCRC [Translational Breast Cancer Research Symposium], it’s not a global study?

Ian E. Krop, MD, PhD: Right, it’s a TBCRC study.

Hope S. Rugo, MD: A Consortium trial.

Adam M. Brufsky, MD, PhD: Consortium, right.

Debu Tripathy, MD: To end this section, I’d like to go back to our kinase inhibitor discussion. We’ve got the NALA trial showing a benefit of neratinib, and then there’s others, pyrotinib, but it’s not being tested widely here but was developed in China and tested there. Any comments that you all have?

Hope S. Rugo, MD: Some people were trastuzumab-naїve in that population.

Adam M. Brufsky, MD, PhD: They were trastuzumab naїve. That’s part of the problem with the pyrotinib study. Again, we have all these agents, and they all kind of do the same thing. They have different tolerabilities. I think it’s really the PK [pharmacokinetics] argument here with these agents. I think that sure, there’s actually an agent called poziotinib and a very elegant paper in Nature in preclinical data. It overcomes certain gatekeeper mutations to the pocket, the HER2 tyrosine kinase pocket. There may be some in poziotinib, but it is incredibly toxic. It’s an IC50 [half maximal inhibitory concentration] for an EGF of like 3 nanomolars, so that’s really toxic, and the rash and diarrhea are pretty nasty. It’s controllable.

Hope S. Rugo, MD: Pyrotinib caused diarrhea too.

Adam M. Brufsky, MD, PhD: Pyrotinib did too.

Hope S. Rugo, MD: My thought on pyrotinib was that in the Chinese population—where the access to trastuzumab has been dismal because everybody has to pay out of pocket, even with biosimilars—it’s been difficult having a homemade drug that works in HER2-positive disease.

Adam M. Brufsky, MD, PhD: That’s my point. My point is that the concept is a good one. Because it’s a global problem, where we use which tyrosine kinase is going to really depend on what the payer mix is and what the resources are.

Joyce A. O’Shaughnessy, MD: I just want to say a word about neratinib in the HER2 mutations, because we are finding it’s really getting a lot of traction, particularly with fulvestrant. In the plasmaMATCH trial, in the HER2-amplified population, 14% of those had activating mutations in HER2, which is really interesting, as a mechanism of escape.

Hope S. Rugo, MD: Even the triple negative patients responded to neratinib alone in plasmaMATCH, which is really interesting.

Ian E. Krop, MD, PhD: It shows that these are real driver mutations.

Joyce A. O’Shaughnessy, MD: Yes.

Adam M. Brufsky, MD, PhD: Absolutely.

Joyce A. O’Shaughnessy, MD: Super fascinating. So that’s something, I think there are enough data out there right now…

Hope S. Rugo, MD: I agree.

Joyce A. O’Shaughnessy, MD: …that if we find a HER2-activating mutation…

Hope S. Rugo, MD: We should give that…

Adam M. Brufsky, MD, PhD: Compensated for the TKI [tyrosine kinase inhibitor].

Debu Tripathy, MD: Absolutely. What I learned is that you also need to look at it in patients progressing on HER2 therapy. We’ve always thought of this mostly in ER [estrogen receptor] positive.

Adam M. Brufsky, MD, PhD: But do you sequence those patients?

Debu Tripathy, MD: Yes, I do. I sequence those patients. Now we need to start looking for PIK3CA mutations. This is more for clinical trials because there are trials now that are going to explore that. I do think those patients also have targetable lesions, although admittedly, based on our discussion here, they certainly have options that will soon be standard and available. So that’s really good news.

Ian E. Krop, MD, PhD: I was just going to say, certainly back to this TKI issue, do you think there’s any likelihood that patients who progress on tucatinib, which we all agree is going to be moved up, are they still potentially…

Hope S. Rugo, MD: …would get neratinib.

Ian E. Krop, MD, PhD: Right, are they still potentially sensitive to neratinib?

Adam M. Brufsky, MD, PhD: Or poziotinib?

Ian E. Krop, MD, PhD: Yeah.

Adam M. Brufsky, MD, PhD: Absolutely.

Joyce A. O’Shaughnessy, MD: Yeah, good point.

Ian E. Krop, MD, PhD: That’s worth thinking about.

Adam M. Brufsky, MD, PhD: Again, that’s going to be some clinical trial design at some point.

Transcript Edited for Clarity

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Transcript:

Debu Tripathy, MD: Hope, I want to ask you a question specifically about margetuximab but also the broader issue of immunotherapy in the HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer space, because we’ve all been impressed with the fact that there is almost certainly a big immune effect going on just with the standard antibodies we’ve been using. What are the future plans and your thoughts about margetuximab, in general, with the immune system and then some of these other trials that are going on exploring the role of checkpoint inhibitors?

Hope S. Rugo, MD: Well, margetuximab is an interesting agent. It clearly has enhanced immune activity, and there may be a subset of patients who represent a very large group of patients within the world and carry the F allele, the low-affinity CD16, the IgG Fc receptor that may benefit specifically from margetuximab. Where, and in what line of therapy, can we talk about 2 drugs that are already going to get approved, and we don’t know where to put them in sequencing? With margetuximab, we definitely don’t know.

Actually, Ian has developed a neoadjuvant trial that will focus on people who have the F allele. To me, that’s going to be a really important end point, because looking at pCR [pathologic complete response] in those patients, they have high pCRs, but there’s some improvement we can make. These patients will have a more intact immune system. It’s going to be really interesting to see what happens. Margetuximab can be combined with other immune active agents, which I think will be interesting as well. They have a LAG3 antagonist. There are ways maybe to further enhance the immunity, but I think it’s going to have to win as a single agent with chemotherapy before it’s added to other antibodies.

Adam M. Brufsky, MD, PhD: I like the fact that we’ve been debating this for how many years, that there’s really immune activity from trastuzumab. We’ve talked about and argued through clinical trial data here, but this is the first real proof of concept in a large trial that it’s true. That’s the beauty of this study.

Hope S. Rugo, MD: Our next step is to go on and combine HER2-targeted therapy with immunotherapy. I wondered some time ago—when all these studies popped up about whether it was really making sense, because now we’ve got all these new agents. Actually, there are quite a number of trials adding or substituting agents with checkpoint inhibitors, so it will be interesting to see what happens. They’re neoadjuvant and they’re metastatic. There are a bunch of trials going on. How we’re going to fit all this together is interesting because we really have a disease subset that’s a minority of our patients. Most of them do really well, and we have lots of drugs that are active.

Adam M. Brufsky, MD, PhD: So the…neoadjuvant study, is that restricted to F allele?

Ian E. Krop, MD, PhD: Yes.

Adam M. Brufsky, MD, PhD: And it’s in TBCRC [Translational Breast Cancer Research Symposium], it’s not a global study?

Ian E. Krop, MD, PhD: Right, it’s a TBCRC study.

Hope S. Rugo, MD: A Consortium trial.

Adam M. Brufsky, MD, PhD: Consortium, right.

Debu Tripathy, MD: To end this section, I’d like to go back to our kinase inhibitor discussion. We’ve got the NALA trial showing a benefit of neratinib, and then there’s others, pyrotinib, but it’s not being tested widely here but was developed in China and tested there. Any comments that you all have?

Hope S. Rugo, MD: Some people were trastuzumab-naїve in that population.

Adam M. Brufsky, MD, PhD: They were trastuzumab naїve. That’s part of the problem with the pyrotinib study. Again, we have all these agents, and they all kind of do the same thing. They have different tolerabilities. I think it’s really the PK [pharmacokinetics] argument here with these agents. I think that sure, there’s actually an agent called poziotinib and a very elegant paper in Nature in preclinical data. It overcomes certain gatekeeper mutations to the pocket, the HER2 tyrosine kinase pocket. There may be some in poziotinib, but it is incredibly toxic. It’s an IC50 [half maximal inhibitory concentration] for an EGF of like 3 nanomolars, so that’s really toxic, and the rash and diarrhea are pretty nasty. It’s controllable.

Hope S. Rugo, MD: Pyrotinib caused diarrhea too.

Adam M. Brufsky, MD, PhD: Pyrotinib did too.

Hope S. Rugo, MD: My thought on pyrotinib was that in the Chinese population—where the access to trastuzumab has been dismal because everybody has to pay out of pocket, even with biosimilars—it’s been difficult having a homemade drug that works in HER2-positive disease.

Adam M. Brufsky, MD, PhD: That’s my point. My point is that the concept is a good one. Because it’s a global problem, where we use which tyrosine kinase is going to really depend on what the payer mix is and what the resources are.

Joyce A. O’Shaughnessy, MD: I just want to say a word about neratinib in the HER2 mutations, because we are finding it’s really getting a lot of traction, particularly with fulvestrant. In the plasmaMATCH trial, in the HER2-amplified population, 14% of those had activating mutations in HER2, which is really interesting, as a mechanism of escape.

Hope S. Rugo, MD: Even the triple negative patients responded to neratinib alone in plasmaMATCH, which is really interesting.

Ian E. Krop, MD, PhD: It shows that these are real driver mutations.

Joyce A. O’Shaughnessy, MD: Yes.

Adam M. Brufsky, MD, PhD: Absolutely.

Joyce A. O’Shaughnessy, MD: Super fascinating. So that’s something, I think there are enough data out there right now…

Hope S. Rugo, MD: I agree.

Joyce A. O’Shaughnessy, MD: …that if we find a HER2-activating mutation…

Hope S. Rugo, MD: We should give that…

Adam M. Brufsky, MD, PhD: Compensated for the TKI [tyrosine kinase inhibitor].

Debu Tripathy, MD: Absolutely. What I learned is that you also need to look at it in patients progressing on HER2 therapy. We’ve always thought of this mostly in ER [estrogen receptor] positive.

Adam M. Brufsky, MD, PhD: But do you sequence those patients?

Debu Tripathy, MD: Yes, I do. I sequence those patients. Now we need to start looking for PIK3CA mutations. This is more for clinical trials because there are trials now that are going to explore that. I do think those patients also have targetable lesions, although admittedly, based on our discussion here, they certainly have options that will soon be standard and available. So that’s really good news.

Ian E. Krop, MD, PhD: I was just going to say, certainly back to this TKI issue, do you think there’s any likelihood that patients who progress on tucatinib, which we all agree is going to be moved up, are they still potentially…

Hope S. Rugo, MD: …would get neratinib.

Ian E. Krop, MD, PhD: Right, are they still potentially sensitive to neratinib?

Adam M. Brufsky, MD, PhD: Or poziotinib?

Ian E. Krop, MD, PhD: Yeah.

Adam M. Brufsky, MD, PhD: Absolutely.

Joyce A. O’Shaughnessy, MD: Yeah, good point.

Ian E. Krop, MD, PhD: That’s worth thinking about.

Adam M. Brufsky, MD, PhD: Again, that’s going to be some clinical trial design at some point.

Transcript Edited for Clarity
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