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Novel Therapies in TNBC: Real-World Experience

Panelists: Joyce OShaughnessy, MD, Baylor University Medical Center; Kevin Kalinsky, MD, MS New York-Presbyterian Hospital; Elizabeth Mittendorf Dana-Farber; Ruth ORegan, MD, University of Wisconsin Carbone Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Tuesday, May 07, 2019



Transcript: 

Joyce O’Shaughnessy, MD: We have 2 PARP [poly (ADP-ribose) polymerase] inhibitors now, and the data are impressive, certainly, in the later line with substantial improvements in progression-free survival, a survival advantage up front with the olaparib but not in the overall trials. But there are sort of impressive response rates with these agents and also some intriguing data—small but with preoperative use of the talazoparib as well. Very, very interesting. Any experience with these agents, Kevin?

Kevin Kalinsky, MD, MS: I think our population is somewhat limited in terms of those who have BRCA mutations that we’re clinically seeing. So my experience has been similar to what we saw in the trials. We see some nice responses. Those responses can be quick. They’re not terribly durable, but we can see some initial nice responses. The main adverse effect [AE] that I’ve seen has been hematologic toxicity, but certainly I’ve utilized those drugs in patients with triple-negative disease who have BRCA mutations early on. In those patients who have hormone receptor–positive disease, who have BRCA mutations, I tend to start out with endocrine therapy–based agents and then use a PARP inhibitor a little bit later on.

Joyce O’Shaughnessy, MD: Yeah, very similar. Beth, have you been involved in any of the preoperative PARP inhibitor trials?

Elizabeth A. Mittendorf, MD, PhD: Yeah. When I was still in Houston at [The University of Texas] MD Anderson [Cancer Center], I was 1 of the primary surgical partners for Dr Jennifer Litton, who ran a clinical trial that was presented [last spring] at ASCO [the American Society of Clinical Oncology Annual Meeting], where she gave talazoparib as a single agent. It was a small trial of 22 or so patients in which she had a pretty impressive pCR [pathologic complete response] rate. That has now prompted a phase II trial that, I believe, has initiated looking at the potential. And so the way I always thought of it was, in fact, if you have a tumor that has an Achilles’ heel and you hit it, that’s what you need to do. So I think that data are really encouraging. From a surgical standpoint, those tumors shrunk down. They did. So even if they didn’t have a pCR, we still saw responses. I had a couple of patients, in fact, who had pCR in that trial, who then didn’t want to get their chemotherapy, but of course there are no data to support that.

Hope S. Rugo, MD: It’s interesting. Those responses were so quick, and we saw that in the phase III trials, too, which we participated in with BRCA with talazoparib. It’s interesting because you mention the endocrine therapy. Again, to be in the off-label world, giving PARP inhibitors to a patient who has a BRCA mutation in the first-line endocrine setting, particularly if that patient already saw a CDK4/6 inhibitor, is very appealing to me to look at. The combination is reasonably well tolerated. Again, anemia and a little nausea are major issues.

Joyce O’Shaughnessy, MD: You were telling us earlier about some patients who you’ve had in the metastatic setting with checkpoint inhibitors, which was kind of inspiring. Tell us about your patient.

Kevin Kalinsky, MD, MS: I was asking if anybody has seen any long-term responses in the metastatic setting. I have 1 patient who’s on the eribulin-pembrolizumab study who now is about 2½ years out. She had bone, lymph node, and breast disease and essentially has no disease on her scans now 2½ years later, except for some scarring in the bones. This patient experienced some pneumonitis. We had to stop the checkpoint inhibitor, and now she’s been on single-agent eribulin for some time. As I said, probably the eribulin by itself has been for about a year and a half. So 1 of the questions I was asking earlier was what you thought about stopping the eribulin. Is it really adding much? It’s something that I’ve been discussing with the patient, but certainly she’s had a really nice, sustained response.

Joyce O’Shaughnessy, MD: Wow.

Hope S. Rugo, MD: Impressive that she could tolerate the eribulin for so long.

Kevin Kalinsky, MD, MS: Well, we have had to dose reduce because of neuropathy.

Ruth O’Regan, MD: I find people on that study get kind of this wasting thing, which appears to be from the eribulin. We dose reduce, they get better. I have 2 patients. The first patient’s case is particularly interesting. She had an axillary lymph node and a pulmonary nodule, and the skin metastases was measurable. We put her on the eribulin-pembrolizumab study. She initially had some response to the chemotherapy, then had a little bit of progression in the lymph node, but not by RECIST, so we kept her on. And then it started basically decreasing in size. She had a deep response. She was on it for maybe 12 months or so and got autoimmune arthritis, so we had to take her off. So we took her off everything. She has not had chemotherapy, a year and a half later. All her scans have been pretty stable. That was that 1 lady.

And then another lady had no luck with chemotherapy at all. Every time she came in to see me, she’d be like, “It’s always bad news.” I put her on the study. She’s had a complete response. She came in this week. Her creatinine had gone from 0.8 2 weeks ago to 4.2. She’s got autoimmune nephritis now.

Joyce O’Shaughnessy, MD: Still on the pembrolizumab?

Ruth O’Regan, MD: Well, she was on the pembrolizumab, but obviously we’ve taken her off for now. We’ll see what we do with her.

Hope S. Rugo, MD: How long was she on?

Ruth O’Regan, MD: I’d say about 9 months. And again, it took a while to actually get the complete response.

Joyce O’Shaughnessy, MD: Wow.

Hope S. Rugo, MD: What I’ve seen in looking—just to put together a talk on immune-related adverse events—is that those renal effects, cardiac issues, etc, can be quite late, which is interesting. I had a patient recently who had grade 3 skin rash with 1 dose of pembrolizumab. It took 12 weeks to go away with steroids. And then we rechallenged her because she has really bad triple-negative disease eroding through her chest wall. She didn’t get a rash. We still need to learn a lot more about this. I had 1 patient who was on the single-agent pembrolizumab trial, and in the second line and greater, where the response rate was 4.8% or something, she had no decrease in her tumor but no progression on capecitabine. So she went on the single-agent pembrolizumab study 3 years ago. She had lung-only disease, so the trial made you stop at 2 years. I really worked hard on them about not stopping. They’re like, “No, we’re stopping at 2 years. You can always re-treat.” And I’m like, “Right.” They said, “But we’ll give you compassionate-use drug.” So we put her on compassionate-use drug. Now she’s at 3 years. Would you stop? Diarrhea.

It’s interesting. She went on a trip to Mexico with her family about 6 months into it. She got a great response, and she got diarrhea. Everybody got sick. They all ate on the beach and got sick. So she took her antibiotics, and then, 10 days later, the diarrhea came back again. So I’m like, “OK, this could be immune related.” So we scoped her, and she did have colitis on biopsy. So they suggested, because it was grade 2, that she go on budesonide, which I put her on and got approval from Merck to keep her on the study. She stayed on budesonide, decreasing doses for about 6 months, and then went off. Here she is now, at 3 years. She gets occasional diarrhea, but it’s fascinating that there’s some adaptability with the curves that we don’t understand.

Joyce O’Shaughnessy, MD: I love it.

Elizabeth A. Mittendorf, MD, PhD: I’ve seen some interesting data recently that suggests that something as simple as vitamin D could actually be associated. We know vitamin D is associated with ulcerative colitis that flares.

Joyce O’Shaughnessy, MD: You mean if you’re low?

Elizabeth A. Mittendorf, MD, PhD: Yeah.

Joyce O’Shaughnessy, MD: Vitamin D, if you had your levels up, might help ameliorate some of these immune-related AEs?

Elizabeth A. Mittendorf, MD, PhD: Correct. This is just so preliminary, but I think I’m speaking to Hope’s point. Again, just [as] biomarkers have now become our problem, [so will] toxicity and figuring out these toxicities. And I think what’s going to be really important too—again, this is just putting on an immunologist’s hat—is that a lot of these toxicities right now, because of trial design, we’ve been treating with steroids. I don’t know if that’s always going to be the answer. Not only is it not going to be the answer to necessarily reverse the toxicity, but it also could influence the immune response that you’re trying to generate.

Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD: We have 2 PARP [poly (ADP-ribose) polymerase] inhibitors now, and the data are impressive, certainly, in the later line with substantial improvements in progression-free survival, a survival advantage up front with the olaparib but not in the overall trials. But there are sort of impressive response rates with these agents and also some intriguing data—small but with preoperative use of the talazoparib as well. Very, very interesting. Any experience with these agents, Kevin?

Kevin Kalinsky, MD, MS: I think our population is somewhat limited in terms of those who have BRCA mutations that we’re clinically seeing. So my experience has been similar to what we saw in the trials. We see some nice responses. Those responses can be quick. They’re not terribly durable, but we can see some initial nice responses. The main adverse effect [AE] that I’ve seen has been hematologic toxicity, but certainly I’ve utilized those drugs in patients with triple-negative disease who have BRCA mutations early on. In those patients who have hormone receptor–positive disease, who have BRCA mutations, I tend to start out with endocrine therapy–based agents and then use a PARP inhibitor a little bit later on.

Joyce O’Shaughnessy, MD: Yeah, very similar. Beth, have you been involved in any of the preoperative PARP inhibitor trials?

Elizabeth A. Mittendorf, MD, PhD: Yeah. When I was still in Houston at [The University of Texas] MD Anderson [Cancer Center], I was 1 of the primary surgical partners for Dr Jennifer Litton, who ran a clinical trial that was presented [last spring] at ASCO [the American Society of Clinical Oncology Annual Meeting], where she gave talazoparib as a single agent. It was a small trial of 22 or so patients in which she had a pretty impressive pCR [pathologic complete response] rate. That has now prompted a phase II trial that, I believe, has initiated looking at the potential. And so the way I always thought of it was, in fact, if you have a tumor that has an Achilles’ heel and you hit it, that’s what you need to do. So I think that data are really encouraging. From a surgical standpoint, those tumors shrunk down. They did. So even if they didn’t have a pCR, we still saw responses. I had a couple of patients, in fact, who had pCR in that trial, who then didn’t want to get their chemotherapy, but of course there are no data to support that.

Hope S. Rugo, MD: It’s interesting. Those responses were so quick, and we saw that in the phase III trials, too, which we participated in with BRCA with talazoparib. It’s interesting because you mention the endocrine therapy. Again, to be in the off-label world, giving PARP inhibitors to a patient who has a BRCA mutation in the first-line endocrine setting, particularly if that patient already saw a CDK4/6 inhibitor, is very appealing to me to look at. The combination is reasonably well tolerated. Again, anemia and a little nausea are major issues.

Joyce O’Shaughnessy, MD: You were telling us earlier about some patients who you’ve had in the metastatic setting with checkpoint inhibitors, which was kind of inspiring. Tell us about your patient.

Kevin Kalinsky, MD, MS: I was asking if anybody has seen any long-term responses in the metastatic setting. I have 1 patient who’s on the eribulin-pembrolizumab study who now is about 2½ years out. She had bone, lymph node, and breast disease and essentially has no disease on her scans now 2½ years later, except for some scarring in the bones. This patient experienced some pneumonitis. We had to stop the checkpoint inhibitor, and now she’s been on single-agent eribulin for some time. As I said, probably the eribulin by itself has been for about a year and a half. So 1 of the questions I was asking earlier was what you thought about stopping the eribulin. Is it really adding much? It’s something that I’ve been discussing with the patient, but certainly she’s had a really nice, sustained response.

Joyce O’Shaughnessy, MD: Wow.

Hope S. Rugo, MD: Impressive that she could tolerate the eribulin for so long.

Kevin Kalinsky, MD, MS: Well, we have had to dose reduce because of neuropathy.

Ruth O’Regan, MD: I find people on that study get kind of this wasting thing, which appears to be from the eribulin. We dose reduce, they get better. I have 2 patients. The first patient’s case is particularly interesting. She had an axillary lymph node and a pulmonary nodule, and the skin metastases was measurable. We put her on the eribulin-pembrolizumab study. She initially had some response to the chemotherapy, then had a little bit of progression in the lymph node, but not by RECIST, so we kept her on. And then it started basically decreasing in size. She had a deep response. She was on it for maybe 12 months or so and got autoimmune arthritis, so we had to take her off. So we took her off everything. She has not had chemotherapy, a year and a half later. All her scans have been pretty stable. That was that 1 lady.

And then another lady had no luck with chemotherapy at all. Every time she came in to see me, she’d be like, “It’s always bad news.” I put her on the study. She’s had a complete response. She came in this week. Her creatinine had gone from 0.8 2 weeks ago to 4.2. She’s got autoimmune nephritis now.

Joyce O’Shaughnessy, MD: Still on the pembrolizumab?

Ruth O’Regan, MD: Well, she was on the pembrolizumab, but obviously we’ve taken her off for now. We’ll see what we do with her.

Hope S. Rugo, MD: How long was she on?

Ruth O’Regan, MD: I’d say about 9 months. And again, it took a while to actually get the complete response.

Joyce O’Shaughnessy, MD: Wow.

Hope S. Rugo, MD: What I’ve seen in looking—just to put together a talk on immune-related adverse events—is that those renal effects, cardiac issues, etc, can be quite late, which is interesting. I had a patient recently who had grade 3 skin rash with 1 dose of pembrolizumab. It took 12 weeks to go away with steroids. And then we rechallenged her because she has really bad triple-negative disease eroding through her chest wall. She didn’t get a rash. We still need to learn a lot more about this. I had 1 patient who was on the single-agent pembrolizumab trial, and in the second line and greater, where the response rate was 4.8% or something, she had no decrease in her tumor but no progression on capecitabine. So she went on the single-agent pembrolizumab study 3 years ago. She had lung-only disease, so the trial made you stop at 2 years. I really worked hard on them about not stopping. They’re like, “No, we’re stopping at 2 years. You can always re-treat.” And I’m like, “Right.” They said, “But we’ll give you compassionate-use drug.” So we put her on compassionate-use drug. Now she’s at 3 years. Would you stop? Diarrhea.

It’s interesting. She went on a trip to Mexico with her family about 6 months into it. She got a great response, and she got diarrhea. Everybody got sick. They all ate on the beach and got sick. So she took her antibiotics, and then, 10 days later, the diarrhea came back again. So I’m like, “OK, this could be immune related.” So we scoped her, and she did have colitis on biopsy. So they suggested, because it was grade 2, that she go on budesonide, which I put her on and got approval from Merck to keep her on the study. She stayed on budesonide, decreasing doses for about 6 months, and then went off. Here she is now, at 3 years. She gets occasional diarrhea, but it’s fascinating that there’s some adaptability with the curves that we don’t understand.

Joyce O’Shaughnessy, MD: I love it.

Elizabeth A. Mittendorf, MD, PhD: I’ve seen some interesting data recently that suggests that something as simple as vitamin D could actually be associated. We know vitamin D is associated with ulcerative colitis that flares.

Joyce O’Shaughnessy, MD: You mean if you’re low?

Elizabeth A. Mittendorf, MD, PhD: Yeah.

Joyce O’Shaughnessy, MD: Vitamin D, if you had your levels up, might help ameliorate some of these immune-related AEs?

Elizabeth A. Mittendorf, MD, PhD: Correct. This is just so preliminary, but I think I’m speaking to Hope’s point. Again, just [as] biomarkers have now become our problem, [so will] toxicity and figuring out these toxicities. And I think what’s going to be really important too—again, this is just putting on an immunologist’s hat—is that a lot of these toxicities right now, because of trial design, we’ve been treating with steroids. I don’t know if that’s always going to be the answer. Not only is it not going to be the answer to necessarily reverse the toxicity, but it also could influence the immune response that you’re trying to generate.

Transcript Edited for Clarity
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