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Adjuvant Therapy for HER2+ Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, FACP, University of Pittsburgh School of Medicine; Francisco Esteva, MD, PhD, Langone Medical Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Lee Schwartzberg, MD, FACP, The University of Texas Health Science Center
Published: Monday, Mar 19, 2018



Transcript: 

Adam M. Brufsky, MD, PhD, FACP: Let’s get to de-escalation for a minute and talk a little bit about the SOLD trial. Are we sold on SOLD? That’s the question. Could someone describe SOLD? Do you want to describe SOLD, Hope?

Hope S. Rugo, MD: The SOLD trial looked at, similar to 2 other trials that have been reported already, whether or not you could treat with a FinHer-like approach: 9 weeks of trastuzumab versus the standard 12 months. I think it’s a really important question for a number of reasons. One is that we’ve never really asked the question of how long the optimal duration of trastuzumab was in the original trials, and second is that most people in the world can’t afford trastuzumab. Now, with the advent of biosimilars, we hope that will change, but we have yet to see what the cost differentials will be and what the impact will be. So, these are important trials, but 9 weeks is a funny choice.

I was looking at this trial being presented and I thought, how did you choose 9 weeks? Couldn’t you give them 12 weeks? That was from FinHer, so that’s the only way to do it. What they showed was that these trials were noninferior, otherwise they’d need huge numbers of patients. So, is 9 weeks just as good as 12 months? Just like in the other 2 trials, they showed that 9 weeks did not meet that noninferiority. It didn’t meet the criteria for being noninferior. But when they looked at subsets—you could either get 75 mg/m2 of docetaxel or 100 mg/m2—they did show that patients who got 100 mg/m², albeit a toxic dose of docetaxel, seemed to do just as well with 9 weeks versus 12 months. We’ve seen previously that the patients who have lower-risk disease may do just as well with a shorter course versus a longer course. I think we’re a little encouraged by the fact that shorter courses may be enough for some patients and that some trastuzumab is better than none. But our gold standard is still 12 months. Now, how long should you get pertuzumab for? We don’t know.

Adam M. Brufsky, MD, PhD, FACP: That’s a whole other issue. We could bring it up. You want to bring it up now? How long should you give pertuzumab?

Hope S. Rugo, MD: Who knows.

Adam M. Brufsky, MD, PhD, FACP: Most pertuzumab use in this country really is in the neoadjuvant setting. Would most people agree with that? It’s the uncommon patient.

Hope S. Rugo, MD: Now it’s approved.
 
Adam M. Brufsky, MD, PhD, FACP: It’s basically how many; it’s 6 pertuzumabs versus 17.

Lee Schwartzberg, MD, FACP: Or 4.

Adam M. Brufsky, MD, PhD, FACP: Or 4 versus 17.

Lee Schwartzberg, MD, FACP: Right.

Adam M. Brufsky, MD, PhD, FACP: So, the issue is does that extra 11 to 13 pertuzumabs really make a difference? We’re talking about the APHINITY trial, obviously.

Lee Schwartzberg, MD, FACP: I think it really all comes down to—and I would go back to SOLD, the same thing—the absolute benefit versus the proportional benefit. Yes, SOLD said that for all patients, you can’t prove noninferiority. When you get down to very small absolute risk difference, the practical benefit, even if it was 10% or 20%, will be less than the toxicity. Remember, there was a doubling of cardiac toxicity in that study. It was 2% to 4%, which is high. But even if it’s 1% to 2%, you’re buying 1% of clinical heart problems for maybe less than 1% of absolute benefit. So, I always do the risk-benefit ratio.

Hope S. Rugo, MD: But that’s trastuzumab. Pertuzumab is funny. In the last week, I saw 2 patients who were on trastuzumab and got neoadjuvant therapy. They had great responses, pCR. And I said, “Well, pertuzumab is now approved, so we can add pertuzumab to your trastuzumab and you can finish the year.” They said, “No!” Really, I was surprised because they said, “But our GI tract is only just now better.”

Lee Schwartzberg, MD, FACP: So, they got pertuzumab in the neoadjuvant setting?

Hope S. Rugo, MD: Yes.

Lee Schwartzberg, MD, FACP: OK.

Adam M. Brufsky, MD, PhD, FACP: Pushing that a little bit forward, say you have somebody who has a pCR, gets THP, TCHP, or whatever you want to give. In my practice, it would be TCHP for 6 cycles and probably dropping the carboplatin because it’s too toxic. But say they get TCHP for 6 cycles, and they have a pCR. Would you give them extra pertuzumab at that point or no?

Hope S. Rugo, MD: It’s a huge question, because they had a great response to that. We do continue the trastuzumab for a year.

Adam M. Brufsky, MD, PhD, FACP: We do. Should we add the pertuzumab as well? They have grade 2 diarrhea. Let’s add that to it.

Hope S. Rugo, MD: I wouldn’t, then.

Lee Schwartzberg, MD, FACP: I typically don’t. If they have a pCR to neoadjuvant dual–anti-HER2 therapy, I stop there.

Adam M. Brufsky, MD, PhD, FACP: Because it’s the concept of, if you had a pCR, what do you add?

Lee Schwartzberg, MD, FACP: Right.

Komal Jhaveri, MD, FACP: You do that for all patients who are high-risk young women?

Lee Schwartzberg, MD, FACP: No, not necessarily.

Komal Jhaveri, MD, FACP: For node-positive patients with pCRs? I’ve been nervous about doing that. If it was for women where I started off something, got a pCR, and I want to grab on to that pCR and that outcome that she’s going to have and I don’t know if…

Lee Schwartzberg, MD, FACP: It’s patient dependent.

Adam M. Brufsky, MD, PhD, FACP: But you have something that tells you it’s probably OK to stop, even everything.

Komal Jhaveri, MD, FACP: Right.

Lee Schwartzberg, MD, FACP Yes, but there are still some relapses if you have a stage III ER-negative and HER2-positive cancer.

Komal Jhaveri, MD, FACP: For a young woman, I’m not sure I feel very comfortable making that decision not knowing exactly what’s going to happen for that individual patient.

Hope S. Rugo, MD: I wish that we looked at duration in APHINITY.

Komal Jhaveri, MD, FACP: I know, I know.

Adam M. Brufsky, MD, PhD, FACP: Unfortunately, but that’s the point. Basically, someone comes in now with triple-positive disease and gets whatever regimen—I’m going to use TCHP as an example—has a 50% reduction in tumor, and maybe has 1 or 2 lymph nodes involved, which you find during surgery. What will you do for her? Will you give her the extra pertuzumab or not?

Francisco Esteva, MD, PhD: I would.

Lee Schwartzberg, MD, FACP I wouldn’t.

Francisco Esteva, MD, PhD: I would. But in patients with pCR, it’s a more difficult question. But if we have residual disease and positive lymph nodes, I think it’s more justifiable.

Hope S. Rugo, MD: It’s ER-positive disease, so at the end of the year are you going to give neratinib?

Adam M. Brufsky, MD, PhD, FACP: That’s the nest question, will you give neratinib?

Hope S. Rugo, MD: If you gave pertuzumab for a whole year and you have all that GI distress, then you’re going to give neratinib. It’s hard for me to know how to parse that out.

Adam M. Brufsky, MD, PhD, FACP: Well, there you go. The neratinib data was also presented, the extended data at least, at ESMO.

Hope S. Rugo, MD: ExteNET.

Adam M. Brufsky, MD, PhD, FACP: ExteNET showed a 4% benefit, especially in ER-positive patients at 5 years. You can criticize the trial design, but nonetheless, it shows a benefit and it’s approved for that indication now.

Hope S. Rugo, MD: We can control diarrhea with colestipol.

Adam M. Brufsky, MD, PhD, FACP: We can, and we’ll talk about that. We can control it with budesonide and colestipol. So, what do we do? Do we give them both, neither?

Lee Schwartzberg, MD, FACP: I would give neratinib to that patient.

Adam M. Brufsky, MD, PhD, FACP: Would you give pertuzumab also?

Lee Schwartzberg, MD, FACP: After the year, following ExteNET.

Adam M. Brufsky, MD, PhD, FACP: Would you give pertuzumab also?

Lee Schwartzberg, MD, FACP: Probably not, because in APHINITY there wasn’t much benefit, and I worry about cumulative GI toxicity.

Francisco Esteva, MD, PhD: I generally don’t like to use subgroup analysis to treat my patients prospectively, but this is the only exception.

Hope S. Rugo, MD: For all of us.

Adam M. Brufsky, MD, PhD, FACP: It was prospectively defined, so why not?

Lee Schwartzberg, MD, FACP: It was prospectively defined.

Adam M. Brufsky, MD, PhD, FACP: Although the trial itself was not quite preplanned, the preplanning was planned.

Komal Jhaveri, MD, FACP: But unlike APHINITY, I think this was more…

Adam M. Brufsky, MD, PhD, FACP: It was a bigger factor.

Komal Jhaveri, MD, FACP: Right.

Francisco Esteva, MD, PhD: Thinking about APHINITY and ExteNET, unless you want to give everything to everybody, which I think is not reasonable, it makes sense to give neratinib to the ER-positive population and pertuzumab to the ER-negative population, especially if they have positive nodes.

Hope S. Rugo, MD: I wonder if we’re going to maybe give neratinib earlier in those patients, if they have disease that doesn’t get a pCR.

Adam M. Brufsky, MD, PhD, FACP: We have those data from San Antonio.

Hope S. Rugo, MD: Well, that’s earlier, after a year. But you do wonder, and my colleague, Jo Chien, is opening a study this year looking at giving neratinib earlier during that year.

Adam M. Brufsky, MD, PhD, FACP: With the trastuzumab together?

Hope S. Rugo, MD: With the trastuzumab, and I think it’s a really interesting idea because we know that there are some patients who have disease resistant to the antibodies that will respond to the TKIs, although we can’t identify them. So, maybe that’s a way to go if somebody has resistant disease. It’s hard to know.

Transcript Edited for Clarity 

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Transcript: 

Adam M. Brufsky, MD, PhD, FACP: Let’s get to de-escalation for a minute and talk a little bit about the SOLD trial. Are we sold on SOLD? That’s the question. Could someone describe SOLD? Do you want to describe SOLD, Hope?

Hope S. Rugo, MD: The SOLD trial looked at, similar to 2 other trials that have been reported already, whether or not you could treat with a FinHer-like approach: 9 weeks of trastuzumab versus the standard 12 months. I think it’s a really important question for a number of reasons. One is that we’ve never really asked the question of how long the optimal duration of trastuzumab was in the original trials, and second is that most people in the world can’t afford trastuzumab. Now, with the advent of biosimilars, we hope that will change, but we have yet to see what the cost differentials will be and what the impact will be. So, these are important trials, but 9 weeks is a funny choice.

I was looking at this trial being presented and I thought, how did you choose 9 weeks? Couldn’t you give them 12 weeks? That was from FinHer, so that’s the only way to do it. What they showed was that these trials were noninferior, otherwise they’d need huge numbers of patients. So, is 9 weeks just as good as 12 months? Just like in the other 2 trials, they showed that 9 weeks did not meet that noninferiority. It didn’t meet the criteria for being noninferior. But when they looked at subsets—you could either get 75 mg/m2 of docetaxel or 100 mg/m2—they did show that patients who got 100 mg/m², albeit a toxic dose of docetaxel, seemed to do just as well with 9 weeks versus 12 months. We’ve seen previously that the patients who have lower-risk disease may do just as well with a shorter course versus a longer course. I think we’re a little encouraged by the fact that shorter courses may be enough for some patients and that some trastuzumab is better than none. But our gold standard is still 12 months. Now, how long should you get pertuzumab for? We don’t know.

Adam M. Brufsky, MD, PhD, FACP: That’s a whole other issue. We could bring it up. You want to bring it up now? How long should you give pertuzumab?

Hope S. Rugo, MD: Who knows.

Adam M. Brufsky, MD, PhD, FACP: Most pertuzumab use in this country really is in the neoadjuvant setting. Would most people agree with that? It’s the uncommon patient.

Hope S. Rugo, MD: Now it’s approved.
 
Adam M. Brufsky, MD, PhD, FACP: It’s basically how many; it’s 6 pertuzumabs versus 17.

Lee Schwartzberg, MD, FACP: Or 4.

Adam M. Brufsky, MD, PhD, FACP: Or 4 versus 17.

Lee Schwartzberg, MD, FACP: Right.

Adam M. Brufsky, MD, PhD, FACP: So, the issue is does that extra 11 to 13 pertuzumabs really make a difference? We’re talking about the APHINITY trial, obviously.

Lee Schwartzberg, MD, FACP: I think it really all comes down to—and I would go back to SOLD, the same thing—the absolute benefit versus the proportional benefit. Yes, SOLD said that for all patients, you can’t prove noninferiority. When you get down to very small absolute risk difference, the practical benefit, even if it was 10% or 20%, will be less than the toxicity. Remember, there was a doubling of cardiac toxicity in that study. It was 2% to 4%, which is high. But even if it’s 1% to 2%, you’re buying 1% of clinical heart problems for maybe less than 1% of absolute benefit. So, I always do the risk-benefit ratio.

Hope S. Rugo, MD: But that’s trastuzumab. Pertuzumab is funny. In the last week, I saw 2 patients who were on trastuzumab and got neoadjuvant therapy. They had great responses, pCR. And I said, “Well, pertuzumab is now approved, so we can add pertuzumab to your trastuzumab and you can finish the year.” They said, “No!” Really, I was surprised because they said, “But our GI tract is only just now better.”

Lee Schwartzberg, MD, FACP: So, they got pertuzumab in the neoadjuvant setting?

Hope S. Rugo, MD: Yes.

Lee Schwartzberg, MD, FACP: OK.

Adam M. Brufsky, MD, PhD, FACP: Pushing that a little bit forward, say you have somebody who has a pCR, gets THP, TCHP, or whatever you want to give. In my practice, it would be TCHP for 6 cycles and probably dropping the carboplatin because it’s too toxic. But say they get TCHP for 6 cycles, and they have a pCR. Would you give them extra pertuzumab at that point or no?

Hope S. Rugo, MD: It’s a huge question, because they had a great response to that. We do continue the trastuzumab for a year.

Adam M. Brufsky, MD, PhD, FACP: We do. Should we add the pertuzumab as well? They have grade 2 diarrhea. Let’s add that to it.

Hope S. Rugo, MD: I wouldn’t, then.

Lee Schwartzberg, MD, FACP: I typically don’t. If they have a pCR to neoadjuvant dual–anti-HER2 therapy, I stop there.

Adam M. Brufsky, MD, PhD, FACP: Because it’s the concept of, if you had a pCR, what do you add?

Lee Schwartzberg, MD, FACP: Right.

Komal Jhaveri, MD, FACP: You do that for all patients who are high-risk young women?

Lee Schwartzberg, MD, FACP: No, not necessarily.

Komal Jhaveri, MD, FACP: For node-positive patients with pCRs? I’ve been nervous about doing that. If it was for women where I started off something, got a pCR, and I want to grab on to that pCR and that outcome that she’s going to have and I don’t know if…

Lee Schwartzberg, MD, FACP: It’s patient dependent.

Adam M. Brufsky, MD, PhD, FACP: But you have something that tells you it’s probably OK to stop, even everything.

Komal Jhaveri, MD, FACP: Right.

Lee Schwartzberg, MD, FACP Yes, but there are still some relapses if you have a stage III ER-negative and HER2-positive cancer.

Komal Jhaveri, MD, FACP: For a young woman, I’m not sure I feel very comfortable making that decision not knowing exactly what’s going to happen for that individual patient.

Hope S. Rugo, MD: I wish that we looked at duration in APHINITY.

Komal Jhaveri, MD, FACP: I know, I know.

Adam M. Brufsky, MD, PhD, FACP: Unfortunately, but that’s the point. Basically, someone comes in now with triple-positive disease and gets whatever regimen—I’m going to use TCHP as an example—has a 50% reduction in tumor, and maybe has 1 or 2 lymph nodes involved, which you find during surgery. What will you do for her? Will you give her the extra pertuzumab or not?

Francisco Esteva, MD, PhD: I would.

Lee Schwartzberg, MD, FACP I wouldn’t.

Francisco Esteva, MD, PhD: I would. But in patients with pCR, it’s a more difficult question. But if we have residual disease and positive lymph nodes, I think it’s more justifiable.

Hope S. Rugo, MD: It’s ER-positive disease, so at the end of the year are you going to give neratinib?

Adam M. Brufsky, MD, PhD, FACP: That’s the nest question, will you give neratinib?

Hope S. Rugo, MD: If you gave pertuzumab for a whole year and you have all that GI distress, then you’re going to give neratinib. It’s hard for me to know how to parse that out.

Adam M. Brufsky, MD, PhD, FACP: Well, there you go. The neratinib data was also presented, the extended data at least, at ESMO.

Hope S. Rugo, MD: ExteNET.

Adam M. Brufsky, MD, PhD, FACP: ExteNET showed a 4% benefit, especially in ER-positive patients at 5 years. You can criticize the trial design, but nonetheless, it shows a benefit and it’s approved for that indication now.

Hope S. Rugo, MD: We can control diarrhea with colestipol.

Adam M. Brufsky, MD, PhD, FACP: We can, and we’ll talk about that. We can control it with budesonide and colestipol. So, what do we do? Do we give them both, neither?

Lee Schwartzberg, MD, FACP: I would give neratinib to that patient.

Adam M. Brufsky, MD, PhD, FACP: Would you give pertuzumab also?

Lee Schwartzberg, MD, FACP: After the year, following ExteNET.

Adam M. Brufsky, MD, PhD, FACP: Would you give pertuzumab also?

Lee Schwartzberg, MD, FACP: Probably not, because in APHINITY there wasn’t much benefit, and I worry about cumulative GI toxicity.

Francisco Esteva, MD, PhD: I generally don’t like to use subgroup analysis to treat my patients prospectively, but this is the only exception.

Hope S. Rugo, MD: For all of us.

Adam M. Brufsky, MD, PhD, FACP: It was prospectively defined, so why not?

Lee Schwartzberg, MD, FACP: It was prospectively defined.

Adam M. Brufsky, MD, PhD, FACP: Although the trial itself was not quite preplanned, the preplanning was planned.

Komal Jhaveri, MD, FACP: But unlike APHINITY, I think this was more…

Adam M. Brufsky, MD, PhD, FACP: It was a bigger factor.

Komal Jhaveri, MD, FACP: Right.

Francisco Esteva, MD, PhD: Thinking about APHINITY and ExteNET, unless you want to give everything to everybody, which I think is not reasonable, it makes sense to give neratinib to the ER-positive population and pertuzumab to the ER-negative population, especially if they have positive nodes.

Hope S. Rugo, MD: I wonder if we’re going to maybe give neratinib earlier in those patients, if they have disease that doesn’t get a pCR.

Adam M. Brufsky, MD, PhD, FACP: We have those data from San Antonio.

Hope S. Rugo, MD: Well, that’s earlier, after a year. But you do wonder, and my colleague, Jo Chien, is opening a study this year looking at giving neratinib earlier during that year.

Adam M. Brufsky, MD, PhD, FACP: With the trastuzumab together?

Hope S. Rugo, MD: With the trastuzumab, and I think it’s a really interesting idea because we know that there are some patients who have disease resistant to the antibodies that will respond to the TKIs, although we can’t identify them. So, maybe that’s a way to go if somebody has resistant disease. It’s hard to know.

Transcript Edited for Clarity 
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