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What is New for HER2 MBC?

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: Tuesday, Jul 26, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
So, speaking of HER2, let’s turn to HER2-positive breast cancer. I think that’s a great segue. I think that this really—as we all know—has been a success story in the treatment, especially metastatic disease and early stage therapy. We have tremendous therapies now, and in the CLEOPATRA data that was announced about a year-and-a-half ago, it showed an almost 5-year disease-free survival for THP (docetaxel, trastuzumab and pertuzumab). Here’s the first question I want to throw out to people before we get into a little bit more specifics. Does the taxane matter in THP when you give it?

Kimberly L. Blackwell, MD: In the metastatic setting?

Adam M. Brufsky, MD, PhD: Yes, in the metastatic setting.

Kimberly L. Blackwell, MD: I personally don’t think it matters. If they had a taxane in the adjuvant setting, I’ll switch them to the different taxane. Certainly it matters in terms of tolerability. In part of the NCCN guidelines, weekly paclitaxel is included as an appropriate chemotherapy backbone or pertuzumab-/trastuzumab-based regimens. So, I find myself going to that probably more frequently than I do with the every 3-week docetaxel.

Adam M. Brufsky, MD, PhD: Joyce?

Joyce A. O’Shaughnessy, MD: I tend to use the docetaxel just because it keeps down the number of visits to the clinic, and I know I’m going to stop it, give six or eight cycles and stop. But I agree, I don’t think it makes any difference. I think nab-paclitaxel is also reasonable, although I don’t think it’s on the guidelines—but I think it’s quite, quite reasonable. I wish we had a little bit more data on vinorelbine. What we have looks promising, but it would be nice not to lose hair. That would be a nice option for patients. But, no, I don’t think it matters.

Adam M. Brufsky, MD, PhD: Okay. The other thing I want to get comments on before we get into a little bit more specifics from ASCO: what do we all think of MARIANNE? This is from last year’s data. T-DM1 (trastuzumab emtansine), an antibody drug conjugate (ADC), is spectacular—as we know, Kim and Sunil—just spectacular data. Then we try to use it with pertuzumab up front and it’s just as good as TH.

Sunil Verma, MD, MSEd, FRCPC: It was a negative trial in the sense that there was no additional benefit of T-DM1/pertuzumab, or THP, or TH. But, furthermore, there was no real synergy between pertuzumab and T-DM1, and I think there has been a lot of discussions as to why that is. And potentially you need enough trastuzumab to be present for the synergy to take place. And T-DM1, it’s 3.6 mg/kg if you take a look at the proportion of the stable link or the DM1; it’s probably about 3 mg/kg of trastuzumab that actually exists in that compound and not the 8 mg and the 6 mg Q3 weekly dose that we use. So, it’s probably not sufficient trastuzumab that’s there for the synergy to take place, and I think that’s exactly what transpired there. It did show some interesting findings in the sense that there is some suggestion that in those patients who have had prior adjuvant trastuzumab, that T-DM1 is still more effective. I think it’s going to be really adjuvant trastuzumab. It’s going to be really interesting to see as we take a look at the follow-up of that data, is there a role of T-DM1 in those patients who have adjuvant trastuzumab? Because most of the patients in CLEOPATRA did not have adjuvant trastuzumab. If you compare, do a cross-trial comparison; that’s, I think, still an option on the table for those patients we talked about taxanes before with, who don’t want to go through hair loss, who don’t want to go through chemotherapy, and who don’t want to have those therapies. I think there is a role for consideration of T-DM1 in the first-line setting for such patients. The challenge that we have then is, what do they get afterwards? Because we don’t have any data for pertuzumab post–T-DM1. So, that’s where we tend to continue to use pertuzumab in the first-line, and then we consider T-DM1 in the second-line. I think that’s really what’s holding us with that same algorithm in place.

Kimberly L. Blackwell, MD: I think I tend to agree with you on everything, except I didn’t view MARIANNE as a negative study. It was an equivalent study, and it showed equivalence between T-DM1 and traditional taxane/trastuzumab. And I think everyone’s impression was that was a negative study, when, in fact, what it showed me was that an ADC in the first-line metastatic setting offers equivalence to hair losing, myelotoxic taxane plus trastuzumab. So, I think that everyone is disappointed that pertuzumab wasn’t additive or even synergistic with the T-DM1. But it practically boils down to how do you sequence these so you can get them covered, and where’s the data? And I think it showed us that T-DM1 is a very active agent; that’s my perspective. It just didn’t find its place in the first-line setting.

Sunil Verma, MD, MSEd, FRCPC: I think you’re right, Kim. It was negative in the sense that there was no additional benefit of pertuzumab to T-DM1. But, otherwise, the fact that you could get ADC in there is just as effective.

Kimberly L. Blackwell, MD: And I think the other important point is if you look at the tails of the curve, if you respond to trastuzumab and taxane, you cannot maintain that for years and years and years. When you look at that, the patient stayed on T-DM1 longer, and at least the tails of the curves, for what it’s worth, the patients appear to do better if they were long-term receivers of T-DM1. Because, obviously, the taxane was dropped out. So, I think there are still some questions there. I want to convey this message that I don’t perceive MARIANNE as a negative.

Adam M. Brufsky, MD, PhD: Oh no, I don’t think it’s negative either.

Kimberly L. Blackwell, MD: It actually showed that T-DM1 is as good as chemotherapy plus trastuzumab.

Adam L. Brufsky, MD, PhD: Oh, I agree with you. I think it’s more of an equivalence trial, but not a superiority trial.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
So, speaking of HER2, let’s turn to HER2-positive breast cancer. I think that’s a great segue. I think that this really—as we all know—has been a success story in the treatment, especially metastatic disease and early stage therapy. We have tremendous therapies now, and in the CLEOPATRA data that was announced about a year-and-a-half ago, it showed an almost 5-year disease-free survival for THP (docetaxel, trastuzumab and pertuzumab). Here’s the first question I want to throw out to people before we get into a little bit more specifics. Does the taxane matter in THP when you give it?

Kimberly L. Blackwell, MD: In the metastatic setting?

Adam M. Brufsky, MD, PhD: Yes, in the metastatic setting.

Kimberly L. Blackwell, MD: I personally don’t think it matters. If they had a taxane in the adjuvant setting, I’ll switch them to the different taxane. Certainly it matters in terms of tolerability. In part of the NCCN guidelines, weekly paclitaxel is included as an appropriate chemotherapy backbone or pertuzumab-/trastuzumab-based regimens. So, I find myself going to that probably more frequently than I do with the every 3-week docetaxel.

Adam M. Brufsky, MD, PhD: Joyce?

Joyce A. O’Shaughnessy, MD: I tend to use the docetaxel just because it keeps down the number of visits to the clinic, and I know I’m going to stop it, give six or eight cycles and stop. But I agree, I don’t think it makes any difference. I think nab-paclitaxel is also reasonable, although I don’t think it’s on the guidelines—but I think it’s quite, quite reasonable. I wish we had a little bit more data on vinorelbine. What we have looks promising, but it would be nice not to lose hair. That would be a nice option for patients. But, no, I don’t think it matters.

Adam M. Brufsky, MD, PhD: Okay. The other thing I want to get comments on before we get into a little bit more specifics from ASCO: what do we all think of MARIANNE? This is from last year’s data. T-DM1 (trastuzumab emtansine), an antibody drug conjugate (ADC), is spectacular—as we know, Kim and Sunil—just spectacular data. Then we try to use it with pertuzumab up front and it’s just as good as TH.

Sunil Verma, MD, MSEd, FRCPC: It was a negative trial in the sense that there was no additional benefit of T-DM1/pertuzumab, or THP, or TH. But, furthermore, there was no real synergy between pertuzumab and T-DM1, and I think there has been a lot of discussions as to why that is. And potentially you need enough trastuzumab to be present for the synergy to take place. And T-DM1, it’s 3.6 mg/kg if you take a look at the proportion of the stable link or the DM1; it’s probably about 3 mg/kg of trastuzumab that actually exists in that compound and not the 8 mg and the 6 mg Q3 weekly dose that we use. So, it’s probably not sufficient trastuzumab that’s there for the synergy to take place, and I think that’s exactly what transpired there. It did show some interesting findings in the sense that there is some suggestion that in those patients who have had prior adjuvant trastuzumab, that T-DM1 is still more effective. I think it’s going to be really adjuvant trastuzumab. It’s going to be really interesting to see as we take a look at the follow-up of that data, is there a role of T-DM1 in those patients who have adjuvant trastuzumab? Because most of the patients in CLEOPATRA did not have adjuvant trastuzumab. If you compare, do a cross-trial comparison; that’s, I think, still an option on the table for those patients we talked about taxanes before with, who don’t want to go through hair loss, who don’t want to go through chemotherapy, and who don’t want to have those therapies. I think there is a role for consideration of T-DM1 in the first-line setting for such patients. The challenge that we have then is, what do they get afterwards? Because we don’t have any data for pertuzumab post–T-DM1. So, that’s where we tend to continue to use pertuzumab in the first-line, and then we consider T-DM1 in the second-line. I think that’s really what’s holding us with that same algorithm in place.

Kimberly L. Blackwell, MD: I think I tend to agree with you on everything, except I didn’t view MARIANNE as a negative study. It was an equivalent study, and it showed equivalence between T-DM1 and traditional taxane/trastuzumab. And I think everyone’s impression was that was a negative study, when, in fact, what it showed me was that an ADC in the first-line metastatic setting offers equivalence to hair losing, myelotoxic taxane plus trastuzumab. So, I think that everyone is disappointed that pertuzumab wasn’t additive or even synergistic with the T-DM1. But it practically boils down to how do you sequence these so you can get them covered, and where’s the data? And I think it showed us that T-DM1 is a very active agent; that’s my perspective. It just didn’t find its place in the first-line setting.

Sunil Verma, MD, MSEd, FRCPC: I think you’re right, Kim. It was negative in the sense that there was no additional benefit of pertuzumab to T-DM1. But, otherwise, the fact that you could get ADC in there is just as effective.

Kimberly L. Blackwell, MD: And I think the other important point is if you look at the tails of the curve, if you respond to trastuzumab and taxane, you cannot maintain that for years and years and years. When you look at that, the patient stayed on T-DM1 longer, and at least the tails of the curves, for what it’s worth, the patients appear to do better if they were long-term receivers of T-DM1. Because, obviously, the taxane was dropped out. So, I think there are still some questions there. I want to convey this message that I don’t perceive MARIANNE as a negative.

Adam M. Brufsky, MD, PhD: Oh no, I don’t think it’s negative either.

Kimberly L. Blackwell, MD: It actually showed that T-DM1 is as good as chemotherapy plus trastuzumab.

Adam L. Brufsky, MD, PhD: Oh, I agree with you. I think it’s more of an equivalence trial, but not a superiority trial.

Transcript Edited for Clarity
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