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Immunotherapy for Triple-Negative Breast Cancer

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute; Carlos L. Arteaga, MD, Vanderbilt University; Jose Baselga, MD, PhD, Memorial Sloan Kettering Cancer Center; Kimberly Blackwell, MD, Duke Cancer Institute; Debu Tripathy, MD, University of Texas MD Anderson Cancer Center; Denise A. Yardley, MD, Sarah Cannon Research Institute; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Monday, Jul 31, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
Let me take the last couple of minutes and just end with immunotherapy for triple-negative breast cancer. Again, I’ll start with Carlos. We have some initial studies with immunotherapy. What are your thoughts so far?

Carlos L. Arteaga, MD: Well, my thoughts about immunotherapy are that we have some signals that it may work in a subgroup of patients with triple-negative breast cancer. I’m thinking of the study—reported by Rita Nanda and published in the Journal of Clinical Oncology—with pembrolizumab, which is a PD-L1 inhibitor that releases a checkpoint that, by that release, allows T cells to induce tumor cell death. There was about a 20% response rate. There’s a more recent study that’s going to be presented tomorrow that was a lot less impressive. My sense overall is that there is a subgroup of patients with triple-negative breast cancer who probably benefit from these drugs, but we need to do a better effort in identifying who they are.

Adam M. Brufsky, MD, PhD: It’s not going to be like melanoma or non–small cell lung cancer.

Carlos L. Arteaga, MD: It can be, it can be. And the mutational load, the neoantigen load, in these tumors is really telling you that. There’s a subgroup that looks like melanoma, but it’s a minority. PD-1 and PD-L1 staining are not really the biomarkers. We need more than that. So I think that I am skeptical at this point, and I would like to see more conversation between cancer immunologists and immunotherapists to come up with better combinations, which are better selectors of those tumors that are likely to respond.

Debu Tripathy, MD: We’re very interested in trying to make cold tumors hot, using toll-like receptors, OX40 agonists, and other things that will make the tumor more immunogenic. Because it’s clear that as it stands now with monotherapy with checkpoint inhibitors, only a minority are responding. Now, granted, some of these responses are long-lived, and in Rita Nanda’s follow-up presentation of the KEYNOTE study—the phase Ib study—there were some 2-year responders, but it’s a very small subset.

Adam M. Brufsky, MD, PhD: The other question I had is that I don’t think it’s that positive. I was just thinking about this a few days ago. How much breast cancer has MSI deficiency? Does any?

Debu Tripathy, MD: It’s low.

Adam M. Brufsky, MD, PhD: But it’s there, though. Could that be something? I think it’s probably too low for people to really…

Debu Tripathy, MD: There is an approval now.

Adam M. Brufsky, MD, PhD: There is. That’s what I was going to say; there’s an approval of pembrolizumab in MSI-high tumors.

Debu Tripathy, MD: MSI of any solid tumor.

José Baselga, MD, PhD: Actually, the study that led to the approval is fascinating because it’s the first approval that is based on everyone’s disease basis rather than on MSI.

Carlos L. Arteaga, MD: Tumor agnostic.

José Baselga, MD, PhD: I think there is something there. I think that we are not there in understanding all the determinants. For example, in triple-negative breast cancer, the role of TILs appears to be very important. We have all these German studies—the GeparSixto—that show that if you have lymphocytes in the tumor, you have a much better outcome. So I think that we need to learn what’s happening. To me, there is enough of a signal that there is something there. Remember, the first Herceptin paper that was coauthored by Debu and myself…

Adam M. Brufsky, MD, PhD: It’s 12%, right?

José Baselga, MD, PhD: Yes, 12%. I remember that when we presented the first time, there was 1 person who stood up and asked, “Why are you guys so excited about this?” By the way, it was a right comment, but there was a signal. So I think that we are in the same situation here. We need to understand what the terms of response are.

Kimberly L. Blackwell, MD: My hope and optimism for this space comes from the large randomized phase III studies, in particular the KEYNOTE trial. I wasn’t involved in the first-line study. It required biopsies to go on the study. So they required PD-L1 expression, or at least you had to submit the sample. And I think with that, we should be able to tease out who really might derive benefit.

Adam M. Brufsky, MD, PhD: I just hope we know the questions to ask of those samples. I just don’t know if we know the proper questions yet. It’s great that we have it, and I think at some point we’ll know, but do we really know the right questions to be asking?

José Baselga, MD, PhD: I think we begin to know. The point that Debu was mentioning about hot and cold—we can determine the mutational load. That’s going to be important. But most importantly, we’ve got to determine the interferon response signatures and whether those T cells engage or not. And we are beginning to develop assays.

Debu Tripathy, MD: There are some signatures as well as multiplex assays.

José Baselga, MD, PhD: Yes, including those signatures.

Adam M. Brufsky, MD, PhD: Plus, the IDO inhibitors that are trying to suppress T cells. There’s a lot of stuff out there that may be applicable to breast cancer.

Carlos L. Arteaga, MD: But there’s also a therapy that also may work, involving tumor cell nonautonomous mechanisms. The host is a bit determinant.

Adam M. Brufsky, MD, PhD: Right, a very big determinant.

Carlos L. Arteaga, MD: So, for example, it may well be that the therapies are absolutely wonderful in micrometastatic disease after neoadjuvant therapy but not in other settings. I don’t know of any other therapies where the host can be such an important determinant, right?

Adam M. Brufsky, MD, PhD: Right. I agree, and I think the host is extraordinarily complicated. Seriously, that is something that we talk about—all the genomics of the tumor. It’s a whole other area, the genetics of the host and the host response.

Debu Tripathy, MD: There are data in melanoma that the gut microbiome…

Adam M. Brufsky, MD, PhD: Right. There’s all this stuff, but we’ve only scratched the surface.

Debu Tripathy, MD: There’s the host, a difference. Did you want to make any comments about immunoconjugates?

Adam M. Brufsky, MD, PhD: Yes, I would. Let’s just talk a little bit about sacituzumab.

Debu Tripathy, MD: I think that’s an exciting area.

Adam M. Brufsky, MD, PhD: Debu, do you want to talk about that? Denise, do you have any comments about it?

Denise A. Yardley, MD: Yes, I’ve worked with glembatumumab, so I think for triple-negative disease, there are at least 2 exciting compounds on the horizon that are drug-antibody conjugates. And I think all of us are excited, based on our experience with therapeutic drug monitoring. There are different compounds, and I think that TROP-2-targeting sacituzumab has gotten recognition from the FDA and is moving into a phase III trial now. It’s interesting, because TROP-2 is a lot more prevalent in that triple-negative population.

Adam M. Brufsky, MD, PhD: Like 50% or 49%.

Denise A. Yardley, MD: Yes. So they’re not testing in that particular trial as they move forward. Glembatumumab we looked at in an all-comer breast trial, the EMERGE trial, and the signal for benefit from that drug-antibody conjugate that’s targeting the GPNMB receptor was most prevalent in triple-negative disease. From that trial, it was about 30% or 40%. What we’re seeing with the current trial, METRIC, is an excess of 50%, so that trial is actually selecting patients. You have to have greater than 25% on the tumor, and that is at the time of metastatic disease.

Adam M. Brufsky, MD, PhD: And how many patients do you have to screen?

Denise A. Yardley, MD: In that one, you’re screening almost 10 patients to get 6 or 7.

Adam M. Brufsky, MD, PhD: So it’s about 60%?

Denise A. Yardley, MD: Yes. It’s a lot higher in the METRIC trial. It’s about to close. It’s a 300-patient, phase II randomized trial that went up against capecitabine.

Adam M. Brufsky, MD, PhD: So not physician’s choice but against capecitabine?

Denise A. Yardley, MD: It’s against capecitabine, and so that will close. It’s very interesting to see the signal, because there is a signal in melanoma with glembatumumab that’s been very active. And in melanoma, the correlation is the rash, so the patients who get the rash tend to have the highest response in melanoma.

Adam M. Brufsky, MD, PhD: What’s the mechanism for the rash?

Denise A. Yardley, MD: They’re not sure. It’s not as prevalent.

Adam M. Brufsky, MD, PhD: Is it antigen in the skin?

Denise A. Yardley, MD: They think so in melanoma, but it has been less so in the patients with breast cancer, and we don’t know if that’s going to be a signal in the breast cancer population.

Kimberly L. Blackwell, MD: We do see it.

Adam M. Brufsky, MD, PhD: You were in the trial too?

Kimberly L. Blackwell, MD: Yes.

Denise A. Yardley, MD: And so in melanoma, I think their next trial had about an all-comer 11% response rate after checkpoint inhibitors. In the rash patients, it doubled to about 20%. So now they’re moving forward with a combination of a checkpoint inhibitor and glembatumumab. For the breast cancer trial, I think they will have data in the first quarter of 2018.

Adam M. Brufsky, MD, PhD: That would be great; we really need to see.

Transcript Edited for Clarity

Slider Left
Slider Right


Transcript:

Adam M. Brufsky, MD, PhD:
Let me take the last couple of minutes and just end with immunotherapy for triple-negative breast cancer. Again, I’ll start with Carlos. We have some initial studies with immunotherapy. What are your thoughts so far?

Carlos L. Arteaga, MD: Well, my thoughts about immunotherapy are that we have some signals that it may work in a subgroup of patients with triple-negative breast cancer. I’m thinking of the study—reported by Rita Nanda and published in the Journal of Clinical Oncology—with pembrolizumab, which is a PD-L1 inhibitor that releases a checkpoint that, by that release, allows T cells to induce tumor cell death. There was about a 20% response rate. There’s a more recent study that’s going to be presented tomorrow that was a lot less impressive. My sense overall is that there is a subgroup of patients with triple-negative breast cancer who probably benefit from these drugs, but we need to do a better effort in identifying who they are.

Adam M. Brufsky, MD, PhD: It’s not going to be like melanoma or non–small cell lung cancer.

Carlos L. Arteaga, MD: It can be, it can be. And the mutational load, the neoantigen load, in these tumors is really telling you that. There’s a subgroup that looks like melanoma, but it’s a minority. PD-1 and PD-L1 staining are not really the biomarkers. We need more than that. So I think that I am skeptical at this point, and I would like to see more conversation between cancer immunologists and immunotherapists to come up with better combinations, which are better selectors of those tumors that are likely to respond.

Debu Tripathy, MD: We’re very interested in trying to make cold tumors hot, using toll-like receptors, OX40 agonists, and other things that will make the tumor more immunogenic. Because it’s clear that as it stands now with monotherapy with checkpoint inhibitors, only a minority are responding. Now, granted, some of these responses are long-lived, and in Rita Nanda’s follow-up presentation of the KEYNOTE study—the phase Ib study—there were some 2-year responders, but it’s a very small subset.

Adam M. Brufsky, MD, PhD: The other question I had is that I don’t think it’s that positive. I was just thinking about this a few days ago. How much breast cancer has MSI deficiency? Does any?

Debu Tripathy, MD: It’s low.

Adam M. Brufsky, MD, PhD: But it’s there, though. Could that be something? I think it’s probably too low for people to really…

Debu Tripathy, MD: There is an approval now.

Adam M. Brufsky, MD, PhD: There is. That’s what I was going to say; there’s an approval of pembrolizumab in MSI-high tumors.

Debu Tripathy, MD: MSI of any solid tumor.

José Baselga, MD, PhD: Actually, the study that led to the approval is fascinating because it’s the first approval that is based on everyone’s disease basis rather than on MSI.

Carlos L. Arteaga, MD: Tumor agnostic.

José Baselga, MD, PhD: I think there is something there. I think that we are not there in understanding all the determinants. For example, in triple-negative breast cancer, the role of TILs appears to be very important. We have all these German studies—the GeparSixto—that show that if you have lymphocytes in the tumor, you have a much better outcome. So I think that we need to learn what’s happening. To me, there is enough of a signal that there is something there. Remember, the first Herceptin paper that was coauthored by Debu and myself…

Adam M. Brufsky, MD, PhD: It’s 12%, right?

José Baselga, MD, PhD: Yes, 12%. I remember that when we presented the first time, there was 1 person who stood up and asked, “Why are you guys so excited about this?” By the way, it was a right comment, but there was a signal. So I think that we are in the same situation here. We need to understand what the terms of response are.

Kimberly L. Blackwell, MD: My hope and optimism for this space comes from the large randomized phase III studies, in particular the KEYNOTE trial. I wasn’t involved in the first-line study. It required biopsies to go on the study. So they required PD-L1 expression, or at least you had to submit the sample. And I think with that, we should be able to tease out who really might derive benefit.

Adam M. Brufsky, MD, PhD: I just hope we know the questions to ask of those samples. I just don’t know if we know the proper questions yet. It’s great that we have it, and I think at some point we’ll know, but do we really know the right questions to be asking?

José Baselga, MD, PhD: I think we begin to know. The point that Debu was mentioning about hot and cold—we can determine the mutational load. That’s going to be important. But most importantly, we’ve got to determine the interferon response signatures and whether those T cells engage or not. And we are beginning to develop assays.

Debu Tripathy, MD: There are some signatures as well as multiplex assays.

José Baselga, MD, PhD: Yes, including those signatures.

Adam M. Brufsky, MD, PhD: Plus, the IDO inhibitors that are trying to suppress T cells. There’s a lot of stuff out there that may be applicable to breast cancer.

Carlos L. Arteaga, MD: But there’s also a therapy that also may work, involving tumor cell nonautonomous mechanisms. The host is a bit determinant.

Adam M. Brufsky, MD, PhD: Right, a very big determinant.

Carlos L. Arteaga, MD: So, for example, it may well be that the therapies are absolutely wonderful in micrometastatic disease after neoadjuvant therapy but not in other settings. I don’t know of any other therapies where the host can be such an important determinant, right?

Adam M. Brufsky, MD, PhD: Right. I agree, and I think the host is extraordinarily complicated. Seriously, that is something that we talk about—all the genomics of the tumor. It’s a whole other area, the genetics of the host and the host response.

Debu Tripathy, MD: There are data in melanoma that the gut microbiome…

Adam M. Brufsky, MD, PhD: Right. There’s all this stuff, but we’ve only scratched the surface.

Debu Tripathy, MD: There’s the host, a difference. Did you want to make any comments about immunoconjugates?

Adam M. Brufsky, MD, PhD: Yes, I would. Let’s just talk a little bit about sacituzumab.

Debu Tripathy, MD: I think that’s an exciting area.

Adam M. Brufsky, MD, PhD: Debu, do you want to talk about that? Denise, do you have any comments about it?

Denise A. Yardley, MD: Yes, I’ve worked with glembatumumab, so I think for triple-negative disease, there are at least 2 exciting compounds on the horizon that are drug-antibody conjugates. And I think all of us are excited, based on our experience with therapeutic drug monitoring. There are different compounds, and I think that TROP-2-targeting sacituzumab has gotten recognition from the FDA and is moving into a phase III trial now. It’s interesting, because TROP-2 is a lot more prevalent in that triple-negative population.

Adam M. Brufsky, MD, PhD: Like 50% or 49%.

Denise A. Yardley, MD: Yes. So they’re not testing in that particular trial as they move forward. Glembatumumab we looked at in an all-comer breast trial, the EMERGE trial, and the signal for benefit from that drug-antibody conjugate that’s targeting the GPNMB receptor was most prevalent in triple-negative disease. From that trial, it was about 30% or 40%. What we’re seeing with the current trial, METRIC, is an excess of 50%, so that trial is actually selecting patients. You have to have greater than 25% on the tumor, and that is at the time of metastatic disease.

Adam M. Brufsky, MD, PhD: And how many patients do you have to screen?

Denise A. Yardley, MD: In that one, you’re screening almost 10 patients to get 6 or 7.

Adam M. Brufsky, MD, PhD: So it’s about 60%?

Denise A. Yardley, MD: Yes. It’s a lot higher in the METRIC trial. It’s about to close. It’s a 300-patient, phase II randomized trial that went up against capecitabine.

Adam M. Brufsky, MD, PhD: So not physician’s choice but against capecitabine?

Denise A. Yardley, MD: It’s against capecitabine, and so that will close. It’s very interesting to see the signal, because there is a signal in melanoma with glembatumumab that’s been very active. And in melanoma, the correlation is the rash, so the patients who get the rash tend to have the highest response in melanoma.

Adam M. Brufsky, MD, PhD: What’s the mechanism for the rash?

Denise A. Yardley, MD: They’re not sure. It’s not as prevalent.

Adam M. Brufsky, MD, PhD: Is it antigen in the skin?

Denise A. Yardley, MD: They think so in melanoma, but it has been less so in the patients with breast cancer, and we don’t know if that’s going to be a signal in the breast cancer population.

Kimberly L. Blackwell, MD: We do see it.

Adam M. Brufsky, MD, PhD: You were in the trial too?

Kimberly L. Blackwell, MD: Yes.

Denise A. Yardley, MD: And so in melanoma, I think their next trial had about an all-comer 11% response rate after checkpoint inhibitors. In the rash patients, it doubled to about 20%. So now they’re moving forward with a combination of a checkpoint inhibitor and glembatumumab. For the breast cancer trial, I think they will have data in the first quarter of 2018.

Adam M. Brufsky, MD, PhD: That would be great; we really need to see.

Transcript Edited for Clarity
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