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Immunotherapy for TNBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Mark E. Robson, MD, Memorial Sloan Kettering Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Kimberly L. Blackwell, MD, Duke Cancer Institute
Published: Tuesday, Mar 28, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
The other group that I think we’re worried about with triple-negative breast cancer is the immune-infiltrated subgroup, the sicker subgroups of triple-negative breast cancer that we know about. Just to kind of reiterate, there’s the BL-1, BL-2—BL-1 is BRCA-positive—there’s the immune infiltrating subgroup that’s just a mesenchymal subgroup, and there’s an AR-positive subgroup. So, there’s all these other subgroups that we’re trying to figure out what to treat people with. I think a lot of people are very interested in this immune-infiltrated subgroup that has a lot of immune-infiltrated lymphocytes into it. That begs the question about immunotherapy in this patients. And so, Kim, where do you think immunotherapy is—the PD-1, PD-L1, the checkpoint inhibitors now?

Kimberly L. Blackwell, MD: First of all, I think the breast group is ready to catch up with the other solid tumors. We’re not used to being in second or third place in terms of drug development. So, beware, the breast cancer community is all behind enrolling patients very quickly to some of these checkpoint inhibitor trials. At least for me in triple-negative, I’m encouraging my patients to participate in the KEYNOTE studies and some of the single arm phase I/II studies where the checkpoint inhibitors are being compared. We have a first-line study, which is looking at Abraxane hypothetically as a good chemotherapy partner, because it doesn’t require steroids, plus or minus a PD-L1 inhibitor. And then, we have a second- through fourth-line trial, the KEYNOTE study, which is looking at randomization to chemotherapy alone versus the PD inhibitor alone. I think for, at least in my patient population, the triple-negative patients, I’m trying to steer them to either the first-line study where they have the opportunity or the second-line.

It’s interesting. We see the swimmer plots, we see the spaghetti plots. There’s definitely a signal in a population of patients. I don’t think we’ve figured out who those patients are, so, unfortunately, we’ve gone back to old-school clinical trial design, which is enroll a lot of people, standard of care versus the immuno-oncology agent. I remain excited about it, but somewhat guarded because there are a lot of patients that progress fairly quickly on these agents as well.

Aditya Bardia, MD, MPH: And I would build up on this. I agree. I think there is definitely excitement about immunotherapy and it works for a subset of patients. The challenge is I didn’t find that subset, and the interest. The first step is obviously to look at PD-1, but that might not be the answer. I think we need to consider other biomarkers. It could be mutation burden of the tumor. It could be other antigens that are expressed by the tumor, but that is what the field needs is predictive biomarkers that can predict who is going to benefit from immunotherapy.

Adam M. Brufsky, MD, PhD: The thing I wanted to ask before we move on to something else is this whole concept of mutational load. Like melanoma, lung cancer, bladder, head and neck, they seem to have very high mutational loads. And so, there are a lot of neoantigens when you do DNA sequencing. Just for the people in the audience, what you do is DNA sequencing. If there’s a lot of coding sequencing that has been changed—so there’s a lot of neoantigens that makes new proteins—you have higher levels of that in some of these other cancers that respond really well. And breast cancer doesn’t seem to have a very high mutational burden. Are people concerned about that in the development of immunotherapy for breast cancer?

Mark E. Robson, MD: That’s an open question. And even triple-negative, which does tend to be a little bit more genomically disrupted, is genomically disrupted by large gains and losses, which are not as likely to generate neoantigens or at least not typical.

Adam M. Brufsky, MD, PhD: I heard somewhere that the patients who are BRCA-positive, already come in with a DNA repair defect, seem to have more mutational load. Is that true?

Mark E. Robson, MD: Well, they have more but it’s a different kind of mutation. If you look at the types of mutations that are in the diseases that are most associated with response, they tend to be point mutations or small indels. And so, they’re generating abnormal proteins, which can be recognized, whereas in the homologous recombination deficient tumors, you’ve got big gains and losses.

Adam M. Brufsky, MD, PhD: Right, so you’re not getting these small point mutations.

Mark E. Robson, MD: Yes, so you’re not generating proteins.

Kimberly L. Blackwell, MD: I have a question. Has anyone used it off-label? Because this is the tempting thing for me.

Adam M. Brufsky, MD, PhD: You know, I didn’t think you could until a patient of mine actually told me you can.

Kimberly L. Blackwell, MD: Yes. There is a fairly vigorous drug replacement program. I’ve not done it, but for these women that are facing fourth- and fifth-line triple-negative breast cancer—where honestly, unless I’m going to give them CMF (cyclophosphamide, methotrexate and fluorouracil) or something, there isn’t a lot—if they don’t match in the MATCH study, which many of them don’t, triple-negative, that’s for me something that I’ve been contemplating. I haven’t done it yet, but I wish there were more trials in those fourth- and fifth-line settings. What we’re really limited to, at least in breast cancer right now, is the first- and the second-line. I sit through molecular tumor boards with my GI colleagues who get this high mutational burden even on the Foundation Medicine assay, which we haven’t talked about, and then they give it and the disease melts away. And I’m thinking, if I could figure out which of my breast cancer patients have that, it would be interesting. But I was just curious if anyone else had broken the law of off-label use and done it.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
The other group that I think we’re worried about with triple-negative breast cancer is the immune-infiltrated subgroup, the sicker subgroups of triple-negative breast cancer that we know about. Just to kind of reiterate, there’s the BL-1, BL-2—BL-1 is BRCA-positive—there’s the immune infiltrating subgroup that’s just a mesenchymal subgroup, and there’s an AR-positive subgroup. So, there’s all these other subgroups that we’re trying to figure out what to treat people with. I think a lot of people are very interested in this immune-infiltrated subgroup that has a lot of immune-infiltrated lymphocytes into it. That begs the question about immunotherapy in this patients. And so, Kim, where do you think immunotherapy is—the PD-1, PD-L1, the checkpoint inhibitors now?

Kimberly L. Blackwell, MD: First of all, I think the breast group is ready to catch up with the other solid tumors. We’re not used to being in second or third place in terms of drug development. So, beware, the breast cancer community is all behind enrolling patients very quickly to some of these checkpoint inhibitor trials. At least for me in triple-negative, I’m encouraging my patients to participate in the KEYNOTE studies and some of the single arm phase I/II studies where the checkpoint inhibitors are being compared. We have a first-line study, which is looking at Abraxane hypothetically as a good chemotherapy partner, because it doesn’t require steroids, plus or minus a PD-L1 inhibitor. And then, we have a second- through fourth-line trial, the KEYNOTE study, which is looking at randomization to chemotherapy alone versus the PD inhibitor alone. I think for, at least in my patient population, the triple-negative patients, I’m trying to steer them to either the first-line study where they have the opportunity or the second-line.

It’s interesting. We see the swimmer plots, we see the spaghetti plots. There’s definitely a signal in a population of patients. I don’t think we’ve figured out who those patients are, so, unfortunately, we’ve gone back to old-school clinical trial design, which is enroll a lot of people, standard of care versus the immuno-oncology agent. I remain excited about it, but somewhat guarded because there are a lot of patients that progress fairly quickly on these agents as well.

Aditya Bardia, MD, MPH: And I would build up on this. I agree. I think there is definitely excitement about immunotherapy and it works for a subset of patients. The challenge is I didn’t find that subset, and the interest. The first step is obviously to look at PD-1, but that might not be the answer. I think we need to consider other biomarkers. It could be mutation burden of the tumor. It could be other antigens that are expressed by the tumor, but that is what the field needs is predictive biomarkers that can predict who is going to benefit from immunotherapy.

Adam M. Brufsky, MD, PhD: The thing I wanted to ask before we move on to something else is this whole concept of mutational load. Like melanoma, lung cancer, bladder, head and neck, they seem to have very high mutational loads. And so, there are a lot of neoantigens when you do DNA sequencing. Just for the people in the audience, what you do is DNA sequencing. If there’s a lot of coding sequencing that has been changed—so there’s a lot of neoantigens that makes new proteins—you have higher levels of that in some of these other cancers that respond really well. And breast cancer doesn’t seem to have a very high mutational burden. Are people concerned about that in the development of immunotherapy for breast cancer?

Mark E. Robson, MD: That’s an open question. And even triple-negative, which does tend to be a little bit more genomically disrupted, is genomically disrupted by large gains and losses, which are not as likely to generate neoantigens or at least not typical.

Adam M. Brufsky, MD, PhD: I heard somewhere that the patients who are BRCA-positive, already come in with a DNA repair defect, seem to have more mutational load. Is that true?

Mark E. Robson, MD: Well, they have more but it’s a different kind of mutation. If you look at the types of mutations that are in the diseases that are most associated with response, they tend to be point mutations or small indels. And so, they’re generating abnormal proteins, which can be recognized, whereas in the homologous recombination deficient tumors, you’ve got big gains and losses.

Adam M. Brufsky, MD, PhD: Right, so you’re not getting these small point mutations.

Mark E. Robson, MD: Yes, so you’re not generating proteins.

Kimberly L. Blackwell, MD: I have a question. Has anyone used it off-label? Because this is the tempting thing for me.

Adam M. Brufsky, MD, PhD: You know, I didn’t think you could until a patient of mine actually told me you can.

Kimberly L. Blackwell, MD: Yes. There is a fairly vigorous drug replacement program. I’ve not done it, but for these women that are facing fourth- and fifth-line triple-negative breast cancer—where honestly, unless I’m going to give them CMF (cyclophosphamide, methotrexate and fluorouracil) or something, there isn’t a lot—if they don’t match in the MATCH study, which many of them don’t, triple-negative, that’s for me something that I’ve been contemplating. I haven’t done it yet, but I wish there were more trials in those fourth- and fifth-line settings. What we’re really limited to, at least in breast cancer right now, is the first- and the second-line. I sit through molecular tumor boards with my GI colleagues who get this high mutational burden even on the Foundation Medicine assay, which we haven’t talked about, and then they give it and the disease melts away. And I’m thinking, if I could figure out which of my breast cancer patients have that, it would be interesting. But I was just curious if anyone else had broken the law of off-label use and done it.

Transcript Edited for Clarity
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