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Immunotherapy for TNBC

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Friday, Sep 02, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on just to talk briefly on “topic A.” We’ve kind of hinted at it, immunotherapy for triple-negative breast cancer. Is it going to be as good as it is now for our colleagues in the melanoma and lung fields, or no?

Carlos L. Arteaga, MD: Probably not.

Adam M. Brufsky, MD, PhD: As it stands now, as immunotherapy stands now?

Carlos L. Arteaga, MD: If you look at the predictive biomarkers for the way these checkpoint inhibitors work, PD-1 and PD-L1 may not be the panacea. The best data, to my knowledge, are those on mutational load, and if you look at the TCGA (The Cancer Genome Atlas) data, it’s very clear that breast is not one of the most mutated tumors; it’s not a hypermutator. There may be some hypermutators there; we have to find them. Then you look at melanoma—small cell, bladder, non–small cell—those are the ones that are encumbered by a lot of alterations, giving you the broad neoantigen expression that is a marker for sensitivity to these checkpoint inhibitors. It doesn’t mean to say that there’s not a subgroup of patients with breast cancer that should respond to these; we just have to find them. I don’t anticipate it’s going to be as good as in melanoma, or non–small cell lung cancer or bladder cancer.

Adam M. Brufsky, MD, PhD: So, is there any way to make it better though? Could we increase, somehow, the microenvironment? I know, from example, from your institution, there are colleagues exploiting MEK inhibitors to somehow improve MHC (major histocompatibility complex) expression, PD-L1 expression. Is that a possibility?

Carlos L. Arteaga, MD: It is. There’s several approaches. One is to identify that predictive biomarker that gives you some odds of benefit to these therapies. Second, move it to the micrometastatic setting. Those patients have residual disease after neoadjuvant therapy, where the standard of care may be observation and then you can deploy them in that setting. And the other one would be rational combinations with molecularly targeted therapies, but, again, for which we don’t have a lot of mechanistic data. It could be that some of these molecular targeted therapies inhibit the action of these checkpoint inhibitors.

Sunil Verma, MD, MSEd, FRCPC: What’s been interesting in the molecular-targeted realm to date is when there is an identifiable mutation. Those patients don’t tend to have the degree of heterogeneity and mutational load. I’m looking at EGFR mutation–positive breast cancer or ALK mutation–positive lung cancer where they don’t drive as big a benefit from immunotherapy. It’s really that sort of dirty complex disease, like triple-negative breast cancer, which is really struck for it.

Adam M. Brufsky, MD, PhD: For non-HPV head and neck cancer or whatever.

Sunil Verma, MD, MSEd, FRCPC: So, what is the right combination? I think probably the most interesting data in this field is the combination of nab-paclitaxel plus the checkpoint inhibitors, which Sylvia Adams, I think she presented that.

Joyce A. O’Shaughnessy, MD: Atezolizumab, yes.

Adam M. Brufsky, MD, PhD: There’s another updated abstract here.

Sunil Verma, MD, MSEd, FRCPC: That’s right, where you’re seeing a response rate in the 70%-plus range in the combination. I think it may well be that you need the chemotherapy to create that potentiation of immune effect or activation of immune response that could be then potentiated by this checkpoint inhibitor. That combination will likely be very interesting. And there are so many planned neoadjuvant, adjuvant trials where we are waiting for some of this direction to see if it should be all-comers or if it should be in a defined subtype or biomarker, and which subtype that we can really see which patients are going to get the benefit.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on just to talk briefly on “topic A.” We’ve kind of hinted at it, immunotherapy for triple-negative breast cancer. Is it going to be as good as it is now for our colleagues in the melanoma and lung fields, or no?

Carlos L. Arteaga, MD: Probably not.

Adam M. Brufsky, MD, PhD: As it stands now, as immunotherapy stands now?

Carlos L. Arteaga, MD: If you look at the predictive biomarkers for the way these checkpoint inhibitors work, PD-1 and PD-L1 may not be the panacea. The best data, to my knowledge, are those on mutational load, and if you look at the TCGA (The Cancer Genome Atlas) data, it’s very clear that breast is not one of the most mutated tumors; it’s not a hypermutator. There may be some hypermutators there; we have to find them. Then you look at melanoma—small cell, bladder, non–small cell—those are the ones that are encumbered by a lot of alterations, giving you the broad neoantigen expression that is a marker for sensitivity to these checkpoint inhibitors. It doesn’t mean to say that there’s not a subgroup of patients with breast cancer that should respond to these; we just have to find them. I don’t anticipate it’s going to be as good as in melanoma, or non–small cell lung cancer or bladder cancer.

Adam M. Brufsky, MD, PhD: So, is there any way to make it better though? Could we increase, somehow, the microenvironment? I know, from example, from your institution, there are colleagues exploiting MEK inhibitors to somehow improve MHC (major histocompatibility complex) expression, PD-L1 expression. Is that a possibility?

Carlos L. Arteaga, MD: It is. There’s several approaches. One is to identify that predictive biomarker that gives you some odds of benefit to these therapies. Second, move it to the micrometastatic setting. Those patients have residual disease after neoadjuvant therapy, where the standard of care may be observation and then you can deploy them in that setting. And the other one would be rational combinations with molecularly targeted therapies, but, again, for which we don’t have a lot of mechanistic data. It could be that some of these molecular targeted therapies inhibit the action of these checkpoint inhibitors.

Sunil Verma, MD, MSEd, FRCPC: What’s been interesting in the molecular-targeted realm to date is when there is an identifiable mutation. Those patients don’t tend to have the degree of heterogeneity and mutational load. I’m looking at EGFR mutation–positive breast cancer or ALK mutation–positive lung cancer where they don’t drive as big a benefit from immunotherapy. It’s really that sort of dirty complex disease, like triple-negative breast cancer, which is really struck for it.

Adam M. Brufsky, MD, PhD: For non-HPV head and neck cancer or whatever.

Sunil Verma, MD, MSEd, FRCPC: So, what is the right combination? I think probably the most interesting data in this field is the combination of nab-paclitaxel plus the checkpoint inhibitors, which Sylvia Adams, I think she presented that.

Joyce A. O’Shaughnessy, MD: Atezolizumab, yes.

Adam M. Brufsky, MD, PhD: There’s another updated abstract here.

Sunil Verma, MD, MSEd, FRCPC: That’s right, where you’re seeing a response rate in the 70%-plus range in the combination. I think it may well be that you need the chemotherapy to create that potentiation of immune effect or activation of immune response that could be then potentiated by this checkpoint inhibitor. That combination will likely be very interesting. And there are so many planned neoadjuvant, adjuvant trials where we are waiting for some of this direction to see if it should be all-comers or if it should be in a defined subtype or biomarker, and which subtype that we can really see which patients are going to get the benefit.

Transcript Edited for Clarity
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