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First-Line Treatment of HER2-Positive MBC

Panelists:Adam M. Brufsky, MD, University of Pittsburgh; Sara A. Hurvitz, MD, David Geffen School of Medicine; Joyce A. O'Shaugnessy, MD, Baylor Charles A. Sammons Cancer Center; Hope S. Rugo, MD, University of CaliforniaChristy A. Russell, MD, University of Southern California
Published: Thursday, Mar 17, 2016


Transcript:

Adam M. Brufsky, MD:
Let’s turn our topic away from HER2-positive disease which is actually an area that’s been quite successful. So the treatment of HER2-positive metastatic breast cancer has become a success story in the landscape of therapies and it continues to expand, owing to the advent of novel anti-HER2– targeted agents and multi-targeted HER2 receptor blockade. Let’s look at some of the important data that have recently come out. Before we do that though, Sara, UCLA has really been at the forefront of a lot of this HER2. Dennis Slamon was there. He discovered HER2, and a lot of the really cool studies really have originated from there. And so could you kind of talk a little bit about where we are at least in the first-line therapy in the management of HER2-positive metastatic breast cancer?

Sara A. Hurvitz, MD: Yeah. So it’s, I think we would all agree, kind of a fun type of disease to treat. We all kind of smile when we see we’ve been referred a patient with HER2-positive first or second-line metastatic breast cancer because it’s fairly simple. And the one thing that is so striking is the prognosis now for somebody diagnosed with first-line disease is very good in terms of median survivals approaching five years now. So it’s just not the depressing, horrible story that it was a decade or more ago.

The first study that really changed things in recent years is the CLEOPATRA trial which evaluated dual HER2 targeting with trastuzumab and pertuzumab, combined with docetaxel in the frontline setting compared to docetaxel and trastuzumab. Patients receive the chemotherapy portion for four to six cycles and then were allowed to come off of the chemo and just continue the HER2 targeted agent or agents. And, in that study, the progression-free survival was 18 months in the patients who received pertuzumab and trastuzumab together which was six months longer than the patients who only received the trastuzumab. And the overall survival was about 16 months improved in the patients who received, so 56 1/2 months if I’ve got that right.

Adam M. Brufsky, MD: That’s right, it was four-and-a-half years, five years almost.

Sara A. Hurvitz, MD: Yeah. What’s exciting is a) that women treated with this frontline regimen do have a median survival that’s very good, b) that the therapy is really well tolerated. The addition of pertuzumab to trastuzumab doesn’t appear to increase cardiac toxicity. What I think clinicians need to be aware of is the fact that it increases the rates of diarrhea and skin toxicity. So you have to forewarn patients, especially when receiving the chemotherapy portion. And I’m seeing a lot of community oncologists drop off the pertuzumab somewhere around eight or nine cycles.

Adam M. Brufsky, MD: Why?

Sara A. Hurvitz, MD: Because they don’t feel there’s enough data. The message I try and get out to referring oncologists is follow the way the study was done. The one exception to that is estrogen receptor (ER)-positive/HER2-positive. In the CLEOPATRA study, they didn’t begin endocrine therapy with the dual HER2-targeted therapies in that study for ER-positive disease. In my practice I do because I think dual blockade is probably beneficial, although I don’t have data. So I think that has set the way now. All the guidelines support us for using for first-line HER2-positive, the THP regimen.

Adam M. Brufsky, MD: Does it matter whether you use docetaxel or paclitaxel?

Sara A. Hurvitz, MD: Probably not. We now have data that paclitaxel is probably just as good, so it’s really a preference based on patient, and timing, and your perceived side effects, and the known side effects of each of the therapies.

Hope S. Rugo, MD: And the coordination of timing of the infusions is more complicated.

Sara A. Hurvitz, MD: Exactly, much more complicated.

Hope S. Rugo, MD: Because of the every-three-week pertuzumab. But it is interesting in CLEOPATRA that almost everybody was in the first-line setting, first-line but not treatment naive.

Sara A. Hurvitz, MD: de novo, yeah, 90%.

Hope S. Rugo, MD: I think that we treat people really heavily and if we’re going to give them even more therapy in the adjuvant setting, we may not be seeing that same benefit in some of those patients. But hopefully those patients are not going to recur.

Sara A. Hurvitz, MD: Right. A lot of our registry data, some that you’ve presented, show that de novo metastatic HER2-positive breast cancer is much higher than we previously thought.

Adam M. Brufsky, MD: Which is the same thing with ER-positive. And I never would have thought that, especially in the US, it was that much. So we have that. So I think we all agree that pertuzumab in that setting is good. But the other major drug that you’ve been very involved in as well is TDM-1.

Sara A. Hurvitz, MD: Right. So TDM-1 is trastuzumab stably linked to mertansine which is a microtubule toxin, very potent. But it’s not released until the trastuzumab, which is linked to it, is internalized in the HER2 overexpressing cancer cell. When within the cell, it’s released. So it’s truly targeted delivery of the chemotherapy to the HER2 overexpressing cancer cell. And the end result is a much less toxic delivery of chemotherapy. Some people call it a non-chemotherapy regimen. I disagree entirely with that. This is real chemo and there are side effects that we need to watch for including thrombocytopenia and liver enzyme elevation.

The EMILIA study is the study that established this drug as the standard of care for second and third-line breast cancer comparing TDM-1 to lapatinib plus capecitabine, and again, not only an improved progression-free survival but a much better overall survival in patients treated with TDM-1 as well as much less toxicity. And then the TH3RESA data which were presented at San Antonio showed, again, in the beyond second-line setting, an improved overall survival for patients treated with TDM-1 compared to treatment of physician’s choice.

Adam M. Brufsky, MD: I’m curious of the panel, would you then use TDM-1 at any line as long as someone’s never had it based on that data? TH3RESA is physician’s choice, right? It was second to fifth-line or something like that.

Joyce A. O’Shaughnessy, MD: One thing that’s interesting about TH3RESA where there was a very nice survival advantage, which was great to see, patients were required to have prior trastuzumab and prior lapatinib.

Sara A. Hurvitz, MD: Exactly.

Adam M. Brufsky, MD: Really?

Joyce A. O’Shaughnessy, MD: Yeah. So I think that’s an important point because you get this big survival advantage with the TDM-1 after lapatinib. Now, we don’t have any data on the TDM-1 after pertuzumab.

Sara A. Hurvitz, MD: Correct.

Joyce A. O’Shaughnessy, MD: So I actually utilize that particular fact in my practice based on my experience that I see the beautiful TDM-1, multi-year responses, not necessarily right after pertuzumab.

Adam M. Brufsky, MD: So you’ll interrupt it and give like some other regimen in between?

Joyce A. O’Shaughnessy, MD: Like lapatinib.

Adam M. Brufsky, MD: Oh, lapatinib, okay.

Joyce A. O’Shaughnessy, MD: I do it like in the TH3RESA study. So, anyway, I just want to make that point. I think we need some data. I’d like to see some data because that’s a very important agent and these ladies can sit on that drug for years, you know what I mean? And it’s got a nice survival advantage, but we need some data basically.

Christy A. Russell, MD: But, how are you using the lapatinib, are you using it with capecitabine?

Joyce A. O’Shaughnessy, MD: Yes, either with capecitabine or trastuzumab.

Adam M. Brufsky, MD: Trastuzumab.

Christy A. Russell, MD: I mean, you have the trial that is capecitabine/lapatinib versus TDM-1 with a significant advantage of TDM-1.

Adam M. Brufsky, MD: Correct.

Christy A. Russell, MD: So why would you put …

Sara A. Hurvitz, MD: But these were not pertuzumab pretreated patients.

Joyce A. O’Shaughnessy, MD: That’s a good point, Joyce. I never thought of it that way.

Hope S. Rugo, MD: I do wonder if the resistance to pertuzumab does change disease, having had one patient just have this massive progression after two doses of TDM-1 who’s been alive with her HER2-positive metastatic disease for 15 years. So you do wonder. There are those patients, even when we were doing the phase II trials, who just didn’t respond at all. I have another patient who’s been on for five years on TDM-1.

Adam M. Brufsky, MD: Well, who knows what mutations in the targets there are now that cause that or whatever.

Hope S. Rugo, MD: Yes, that’s right.

Sara A. Hurvitz, MD: And it has some EGFR activity so it is somewhat similar to…

Christy A. Russell, MD: The other thing I’ve noticed is if I’ve used trastuzumab and Navelbine, I’m not getting responses to TDM-1 and I wonder if it’s the same vinca alkaloid kind of chemotherapy interaction that they’re just not as responsive.

Adam M. Brufsky, MD: So after TDM-1 or after pertuzumab?

Hope S. Rugo, MD: Vinorelbine.

Christy A. Russell, MD: If I use vinorelbine.

Adam M. Brufsky, MD: So vinorelbine/trastuzumab.

Christy A. Russell, MD: Yes. And then go to a TDM-1, I’m not getting responses.

Hope S. Rugo, MD: Also, if I see people who are truly taxane-refractory, they don’t get as much of a response either, so very refractory, really got two years of a taxane, really grew on everything. So maybe that’s part of it.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD:
Let’s turn our topic away from HER2-positive disease which is actually an area that’s been quite successful. So the treatment of HER2-positive metastatic breast cancer has become a success story in the landscape of therapies and it continues to expand, owing to the advent of novel anti-HER2– targeted agents and multi-targeted HER2 receptor blockade. Let’s look at some of the important data that have recently come out. Before we do that though, Sara, UCLA has really been at the forefront of a lot of this HER2. Dennis Slamon was there. He discovered HER2, and a lot of the really cool studies really have originated from there. And so could you kind of talk a little bit about where we are at least in the first-line therapy in the management of HER2-positive metastatic breast cancer?

Sara A. Hurvitz, MD: Yeah. So it’s, I think we would all agree, kind of a fun type of disease to treat. We all kind of smile when we see we’ve been referred a patient with HER2-positive first or second-line metastatic breast cancer because it’s fairly simple. And the one thing that is so striking is the prognosis now for somebody diagnosed with first-line disease is very good in terms of median survivals approaching five years now. So it’s just not the depressing, horrible story that it was a decade or more ago.

The first study that really changed things in recent years is the CLEOPATRA trial which evaluated dual HER2 targeting with trastuzumab and pertuzumab, combined with docetaxel in the frontline setting compared to docetaxel and trastuzumab. Patients receive the chemotherapy portion for four to six cycles and then were allowed to come off of the chemo and just continue the HER2 targeted agent or agents. And, in that study, the progression-free survival was 18 months in the patients who received pertuzumab and trastuzumab together which was six months longer than the patients who only received the trastuzumab. And the overall survival was about 16 months improved in the patients who received, so 56 1/2 months if I’ve got that right.

Adam M. Brufsky, MD: That’s right, it was four-and-a-half years, five years almost.

Sara A. Hurvitz, MD: Yeah. What’s exciting is a) that women treated with this frontline regimen do have a median survival that’s very good, b) that the therapy is really well tolerated. The addition of pertuzumab to trastuzumab doesn’t appear to increase cardiac toxicity. What I think clinicians need to be aware of is the fact that it increases the rates of diarrhea and skin toxicity. So you have to forewarn patients, especially when receiving the chemotherapy portion. And I’m seeing a lot of community oncologists drop off the pertuzumab somewhere around eight or nine cycles.

Adam M. Brufsky, MD: Why?

Sara A. Hurvitz, MD: Because they don’t feel there’s enough data. The message I try and get out to referring oncologists is follow the way the study was done. The one exception to that is estrogen receptor (ER)-positive/HER2-positive. In the CLEOPATRA study, they didn’t begin endocrine therapy with the dual HER2-targeted therapies in that study for ER-positive disease. In my practice I do because I think dual blockade is probably beneficial, although I don’t have data. So I think that has set the way now. All the guidelines support us for using for first-line HER2-positive, the THP regimen.

Adam M. Brufsky, MD: Does it matter whether you use docetaxel or paclitaxel?

Sara A. Hurvitz, MD: Probably not. We now have data that paclitaxel is probably just as good, so it’s really a preference based on patient, and timing, and your perceived side effects, and the known side effects of each of the therapies.

Hope S. Rugo, MD: And the coordination of timing of the infusions is more complicated.

Sara A. Hurvitz, MD: Exactly, much more complicated.

Hope S. Rugo, MD: Because of the every-three-week pertuzumab. But it is interesting in CLEOPATRA that almost everybody was in the first-line setting, first-line but not treatment naive.

Sara A. Hurvitz, MD: de novo, yeah, 90%.

Hope S. Rugo, MD: I think that we treat people really heavily and if we’re going to give them even more therapy in the adjuvant setting, we may not be seeing that same benefit in some of those patients. But hopefully those patients are not going to recur.

Sara A. Hurvitz, MD: Right. A lot of our registry data, some that you’ve presented, show that de novo metastatic HER2-positive breast cancer is much higher than we previously thought.

Adam M. Brufsky, MD: Which is the same thing with ER-positive. And I never would have thought that, especially in the US, it was that much. So we have that. So I think we all agree that pertuzumab in that setting is good. But the other major drug that you’ve been very involved in as well is TDM-1.

Sara A. Hurvitz, MD: Right. So TDM-1 is trastuzumab stably linked to mertansine which is a microtubule toxin, very potent. But it’s not released until the trastuzumab, which is linked to it, is internalized in the HER2 overexpressing cancer cell. When within the cell, it’s released. So it’s truly targeted delivery of the chemotherapy to the HER2 overexpressing cancer cell. And the end result is a much less toxic delivery of chemotherapy. Some people call it a non-chemotherapy regimen. I disagree entirely with that. This is real chemo and there are side effects that we need to watch for including thrombocytopenia and liver enzyme elevation.

The EMILIA study is the study that established this drug as the standard of care for second and third-line breast cancer comparing TDM-1 to lapatinib plus capecitabine, and again, not only an improved progression-free survival but a much better overall survival in patients treated with TDM-1 as well as much less toxicity. And then the TH3RESA data which were presented at San Antonio showed, again, in the beyond second-line setting, an improved overall survival for patients treated with TDM-1 compared to treatment of physician’s choice.

Adam M. Brufsky, MD: I’m curious of the panel, would you then use TDM-1 at any line as long as someone’s never had it based on that data? TH3RESA is physician’s choice, right? It was second to fifth-line or something like that.

Joyce A. O’Shaughnessy, MD: One thing that’s interesting about TH3RESA where there was a very nice survival advantage, which was great to see, patients were required to have prior trastuzumab and prior lapatinib.

Sara A. Hurvitz, MD: Exactly.

Adam M. Brufsky, MD: Really?

Joyce A. O’Shaughnessy, MD: Yeah. So I think that’s an important point because you get this big survival advantage with the TDM-1 after lapatinib. Now, we don’t have any data on the TDM-1 after pertuzumab.

Sara A. Hurvitz, MD: Correct.

Joyce A. O’Shaughnessy, MD: So I actually utilize that particular fact in my practice based on my experience that I see the beautiful TDM-1, multi-year responses, not necessarily right after pertuzumab.

Adam M. Brufsky, MD: So you’ll interrupt it and give like some other regimen in between?

Joyce A. O’Shaughnessy, MD: Like lapatinib.

Adam M. Brufsky, MD: Oh, lapatinib, okay.

Joyce A. O’Shaughnessy, MD: I do it like in the TH3RESA study. So, anyway, I just want to make that point. I think we need some data. I’d like to see some data because that’s a very important agent and these ladies can sit on that drug for years, you know what I mean? And it’s got a nice survival advantage, but we need some data basically.

Christy A. Russell, MD: But, how are you using the lapatinib, are you using it with capecitabine?

Joyce A. O’Shaughnessy, MD: Yes, either with capecitabine or trastuzumab.

Adam M. Brufsky, MD: Trastuzumab.

Christy A. Russell, MD: I mean, you have the trial that is capecitabine/lapatinib versus TDM-1 with a significant advantage of TDM-1.

Adam M. Brufsky, MD: Correct.

Christy A. Russell, MD: So why would you put …

Sara A. Hurvitz, MD: But these were not pertuzumab pretreated patients.

Joyce A. O’Shaughnessy, MD: That’s a good point, Joyce. I never thought of it that way.

Hope S. Rugo, MD: I do wonder if the resistance to pertuzumab does change disease, having had one patient just have this massive progression after two doses of TDM-1 who’s been alive with her HER2-positive metastatic disease for 15 years. So you do wonder. There are those patients, even when we were doing the phase II trials, who just didn’t respond at all. I have another patient who’s been on for five years on TDM-1.

Adam M. Brufsky, MD: Well, who knows what mutations in the targets there are now that cause that or whatever.

Hope S. Rugo, MD: Yes, that’s right.

Sara A. Hurvitz, MD: And it has some EGFR activity so it is somewhat similar to…

Christy A. Russell, MD: The other thing I’ve noticed is if I’ve used trastuzumab and Navelbine, I’m not getting responses to TDM-1 and I wonder if it’s the same vinca alkaloid kind of chemotherapy interaction that they’re just not as responsive.

Adam M. Brufsky, MD: So after TDM-1 or after pertuzumab?

Hope S. Rugo, MD: Vinorelbine.

Christy A. Russell, MD: If I use vinorelbine.

Adam M. Brufsky, MD: So vinorelbine/trastuzumab.

Christy A. Russell, MD: Yes. And then go to a TDM-1, I’m not getting responses.

Hope S. Rugo, MD: Also, if I see people who are truly taxane-refractory, they don’t get as much of a response either, so very refractory, really got two years of a taxane, really grew on everything. So maybe that’s part of it.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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