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Immunotherapy for Triple-Negative Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, FACP, University of Pittsburgh School of Medicine; Francisco Esteva, MD, PhD, Langone Medical Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Lee Schwartzberg, MD, FACP, The University of Texas Health Science Center
Published: Monday, Apr 09, 2018



Transcript: 

Adam M. Brufsky, MD, PhD, FACP: Let’s save this last little bit for a topic that I wish we had more time on, but we’re running toward the end here, and that is immunotherapy for triple-negative breast cancer and breast cancer in general. I’m not saying it’s unfortunate because I have Hope Rugo sitting next to me, who’s a big immunotherapist, but I think we all would have hoped that we would have gotten more bang for the buck like our colleagues in melanoma care.

Hope S. Rugo, MD: Well, I think we are getting bang for the buck finally.

Adam M. Brufsky, MD, PhD, FACP: Why don’t you tell us about that. Tell us about immunotherapy. What’s the latest immunotherapy data?

Hope S. Rugo, MD: I think it makes perfect sense, and it fits all into everything we know, which is that as the tumor progresses, it starts to press on the host’s immune system more and more. What happens is with immunotherapy for breast cancer, because it’s not a very immunogenic disease, it’s really important to do it early. We saw a doubling or tripling of pathologic complete response rates in the neoadjuvant I-SPY trial. In the first-line trials of PD-L1–positive tumors, in KEYNOTE as well as in the atezolizumab trial that focused on patients with PD-L1–positive disease, we’re seeing response rates just under 25%. What’s really important about those response rates is that responders do really well. As you look at those curves and patients are sitting out there with responses out past 2 years, these are patients with triple-negative breast cancer. That’s exciting. We’ve also seen some data from Sherene Loi looking at our KEYNOTE trial with TILs and some data from other studies as well.

Adam M. Brufsky, MD, PhD, FACP: That’s tumor-infiltrating lymphocytes, just so people know.

Hope S. Rugo, MD: High tumor-infiltrating lymphocytes, and it’s not any big scientific definition of how many; it’s more than 50%. You say, “OK, I have this many, it’s the ones who are in the top half,” and those patients also responded. It makes perfect sense. You get less TILs as the cancer progresses. What we should be doing next is—we’re, of course, already doing it, and we’ll see data reported, I think in the near future—using agents that can try to help the immune system for patients whose own immune system may be lagging behind. But we’re going to have to do that early. For neoadjuvant therapy, there are 2 phase III trials, there are adjuvant trials, and then in the first-line metastatic setting, in giving chemotherapy with checkpoint inhibitors, we’ve seen that we increase TILs, tumor-infiltrating lymphocytes, and hope that may result in improved responses and response duration. Then, we’re looking at immune agonists. So, there are a lot of different combinations that are being looked at, even with PARP inhibitors, in early trials.

Adam M. Brufsky, MD, PhD, FACP: I like the double DNA strand immune response. I think it’s a great preclinical idea.

Hope S. Rugo, MD: There are also immune agonists. There are drugs that actually stimulate the immune system and are known to do that and are combined with checkpoint inhibitors, with some encouraging data in the diseases that are most responsive. We have a TBCRC (Translational Breast Cancer Research Consortium) trial where we’re actually looking at 2 different immune agonists as well as a MEK inhibitor. And you’re involved in a MEK inhibitor trial as well where there are great preclinical data.

Adam M. Brufsky, MD, PhD, FACP: With cobimetinib.

Hope S. Rugo, MD: I think that we’re looking at an explosion of studies now with a lot of excitement. Hopefully we’ll be able to hone to try and figure out who’s going to respond and how we can best capitalize on that.

Lee Schwartzberg, MD, FACP: The problem is that we don’t have a biomarker yet. PD-L1 is lowly expressed in breast cancer compared with some other tumors, and it’s a decent biomarker, but it’s not great. I think generally, and especially in ER-positive disease, breast cancer is not an inflamed hot tumor. But the neoadjuvant data from I-SPY are really very impressive.

Adam M. Brufsky, MD, PhD, FACP: That trial was very impressive.

Hope S. Rugo, MD: And in ER-positive disease.

Adam M. Brufsky, MD, PhD, FACP: The neoadjuvant data were very impressive. Before we go to the extremely informative part of this, and that is the summary, we have sacituzumab. I think we had talked about how we’ve been looking for antibody-drug conjugates for a long time, and we seem to have a really exciting one in HER2 beyond T-DM1, and I’m going to call that TrasD. Now we have sacituzumab. Do you want to talk about sacituzumab?

Komal Jhaveri, MD, FACP: We’re definitely getting excited, as we said, about antibody-drug conjugates. I think we spoke about how it has the components of an antibody in a payload. I think identifying the right target beyond HER2 has been something that has been very interesting to look at. In this case with sacituzumab, the target that they’re looking at is a protein called TROP2, which is a surface glycoprotein that is expressed in more than 90% of triple-negative breast cancers. These were very impressive data that Aditya Bardia presented from Dana-Farber looking at third-line treatment in metastatic triple-negative breast cancer, where we know the response rates are not beyond 20% at the very best. In this patient population, about 110 patients I believe, the response rates were impressive at 34%, with a median progression-free survival of 5-and-a-half months. This drug also has a breakthrough FDA designation for the same reason, so I think these are exciting data. The overall survival is similar to what we saw with the EMBRACE trial, with 13 months. So, I think it’s a great drug; it sounds like it has good efficacy that we’re seeing in the third-line setting. It’s very encouraging for our patients.

Hope S. Rugo, MD: A phase III trial is now opening with up to 5 lines of prior therapy, which is great.

Adam M. Brufsky, MD, PhD, FACP: It’s against physician’s choice. It’s a great trial, very similar to the EMBRACE design. I think it’s a great design. It really is for an area where there’s a totally unmet need.

Hope S. Rugo, MD: And it’s pretty well tolerated.

Adam M. Brufsky, MD, PhD, FACP: It is very well tolerated.

Komal Jhaveri, MD, FACP: It is very well tolerated, yes.

Lee Schwartzberg, MD, FACP: New delivery systems for chemotherapy still have a role in this new world where immunotherapy is coming.

Hope S. Rugo, MD: It’s exciting.

Komal Jhaveri, MD, FACP: Absolutely. The response rates are impressive.

Adam M. Brufsky, MD, PhD, FACP: We’ve got to think about the antigen that we’re using, and payload-to-antibody ratios are going to be very important.

Komal Jhaveri, MD, FACP: Absolutely.

Francisco Esteva, MD, PhD: And hopefully in the future, we will not refer to it as triple-negative breast cancer, which means nothing.

Adam M. Brufsky, MD, PhD, FACP: Exactly. We didn’t even discuss that point.

Lee Schwartzberg, MD, FACP: A very good point.

Komal Jhaveri, MD, FACP: Exactly.

Hope S. Rugo, MD: Absolutely.

Transcript Edited for Clarity 

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Transcript: 

Adam M. Brufsky, MD, PhD, FACP: Let’s save this last little bit for a topic that I wish we had more time on, but we’re running toward the end here, and that is immunotherapy for triple-negative breast cancer and breast cancer in general. I’m not saying it’s unfortunate because I have Hope Rugo sitting next to me, who’s a big immunotherapist, but I think we all would have hoped that we would have gotten more bang for the buck like our colleagues in melanoma care.

Hope S. Rugo, MD: Well, I think we are getting bang for the buck finally.

Adam M. Brufsky, MD, PhD, FACP: Why don’t you tell us about that. Tell us about immunotherapy. What’s the latest immunotherapy data?

Hope S. Rugo, MD: I think it makes perfect sense, and it fits all into everything we know, which is that as the tumor progresses, it starts to press on the host’s immune system more and more. What happens is with immunotherapy for breast cancer, because it’s not a very immunogenic disease, it’s really important to do it early. We saw a doubling or tripling of pathologic complete response rates in the neoadjuvant I-SPY trial. In the first-line trials of PD-L1–positive tumors, in KEYNOTE as well as in the atezolizumab trial that focused on patients with PD-L1–positive disease, we’re seeing response rates just under 25%. What’s really important about those response rates is that responders do really well. As you look at those curves and patients are sitting out there with responses out past 2 years, these are patients with triple-negative breast cancer. That’s exciting. We’ve also seen some data from Sherene Loi looking at our KEYNOTE trial with TILs and some data from other studies as well.

Adam M. Brufsky, MD, PhD, FACP: That’s tumor-infiltrating lymphocytes, just so people know.

Hope S. Rugo, MD: High tumor-infiltrating lymphocytes, and it’s not any big scientific definition of how many; it’s more than 50%. You say, “OK, I have this many, it’s the ones who are in the top half,” and those patients also responded. It makes perfect sense. You get less TILs as the cancer progresses. What we should be doing next is—we’re, of course, already doing it, and we’ll see data reported, I think in the near future—using agents that can try to help the immune system for patients whose own immune system may be lagging behind. But we’re going to have to do that early. For neoadjuvant therapy, there are 2 phase III trials, there are adjuvant trials, and then in the first-line metastatic setting, in giving chemotherapy with checkpoint inhibitors, we’ve seen that we increase TILs, tumor-infiltrating lymphocytes, and hope that may result in improved responses and response duration. Then, we’re looking at immune agonists. So, there are a lot of different combinations that are being looked at, even with PARP inhibitors, in early trials.

Adam M. Brufsky, MD, PhD, FACP: I like the double DNA strand immune response. I think it’s a great preclinical idea.

Hope S. Rugo, MD: There are also immune agonists. There are drugs that actually stimulate the immune system and are known to do that and are combined with checkpoint inhibitors, with some encouraging data in the diseases that are most responsive. We have a TBCRC (Translational Breast Cancer Research Consortium) trial where we’re actually looking at 2 different immune agonists as well as a MEK inhibitor. And you’re involved in a MEK inhibitor trial as well where there are great preclinical data.

Adam M. Brufsky, MD, PhD, FACP: With cobimetinib.

Hope S. Rugo, MD: I think that we’re looking at an explosion of studies now with a lot of excitement. Hopefully we’ll be able to hone to try and figure out who’s going to respond and how we can best capitalize on that.

Lee Schwartzberg, MD, FACP: The problem is that we don’t have a biomarker yet. PD-L1 is lowly expressed in breast cancer compared with some other tumors, and it’s a decent biomarker, but it’s not great. I think generally, and especially in ER-positive disease, breast cancer is not an inflamed hot tumor. But the neoadjuvant data from I-SPY are really very impressive.

Adam M. Brufsky, MD, PhD, FACP: That trial was very impressive.

Hope S. Rugo, MD: And in ER-positive disease.

Adam M. Brufsky, MD, PhD, FACP: The neoadjuvant data were very impressive. Before we go to the extremely informative part of this, and that is the summary, we have sacituzumab. I think we had talked about how we’ve been looking for antibody-drug conjugates for a long time, and we seem to have a really exciting one in HER2 beyond T-DM1, and I’m going to call that TrasD. Now we have sacituzumab. Do you want to talk about sacituzumab?

Komal Jhaveri, MD, FACP: We’re definitely getting excited, as we said, about antibody-drug conjugates. I think we spoke about how it has the components of an antibody in a payload. I think identifying the right target beyond HER2 has been something that has been very interesting to look at. In this case with sacituzumab, the target that they’re looking at is a protein called TROP2, which is a surface glycoprotein that is expressed in more than 90% of triple-negative breast cancers. These were very impressive data that Aditya Bardia presented from Dana-Farber looking at third-line treatment in metastatic triple-negative breast cancer, where we know the response rates are not beyond 20% at the very best. In this patient population, about 110 patients I believe, the response rates were impressive at 34%, with a median progression-free survival of 5-and-a-half months. This drug also has a breakthrough FDA designation for the same reason, so I think these are exciting data. The overall survival is similar to what we saw with the EMBRACE trial, with 13 months. So, I think it’s a great drug; it sounds like it has good efficacy that we’re seeing in the third-line setting. It’s very encouraging for our patients.

Hope S. Rugo, MD: A phase III trial is now opening with up to 5 lines of prior therapy, which is great.

Adam M. Brufsky, MD, PhD, FACP: It’s against physician’s choice. It’s a great trial, very similar to the EMBRACE design. I think it’s a great design. It really is for an area where there’s a totally unmet need.

Hope S. Rugo, MD: And it’s pretty well tolerated.

Adam M. Brufsky, MD, PhD, FACP: It is very well tolerated.

Komal Jhaveri, MD, FACP: It is very well tolerated, yes.

Lee Schwartzberg, MD, FACP: New delivery systems for chemotherapy still have a role in this new world where immunotherapy is coming.

Hope S. Rugo, MD: It’s exciting.

Komal Jhaveri, MD, FACP: Absolutely. The response rates are impressive.

Adam M. Brufsky, MD, PhD, FACP: We’ve got to think about the antigen that we’re using, and payload-to-antibody ratios are going to be very important.

Komal Jhaveri, MD, FACP: Absolutely.

Francisco Esteva, MD, PhD: And hopefully in the future, we will not refer to it as triple-negative breast cancer, which means nothing.

Adam M. Brufsky, MD, PhD, FACP: Exactly. We didn’t even discuss that point.

Lee Schwartzberg, MD, FACP: A very good point.

Komal Jhaveri, MD, FACP: Exactly.

Hope S. Rugo, MD: Absolutely.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Breast CancerJul 31, 20181.0
Community Practice Connections™: Medical Crossfire®: Translating Lessons Learned with PARP Inhibition to the Treatment of Breast Cancer—Expert Exchanges on Novel Strategies to Personalize CareAug 29, 20181.5
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