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Neoadjuvant Combinations in HER2+ Breast Cancer

Panelists: Adam M. Brufsky, MD, University of Pittsburgh Cancer Institute; Ahmad Awada, MD, PhD, Jules Bordet Institute; Wolfgang J. Janni, MD, PhD, University of Ulm; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published Online: Monday, Nov 28, 2016



Transcript:

Adam M. Brufsky, MD, PhD:
Let’s talk about that for a minute. The first real dual inhibition that got approved on this basis, Hope, really was pertuzumab. So, we have NeoSphere, we have TRYPHAENA, we have trials that really now have improved the pathologic complete response rate. What’s your feeling? Now, we even have data that, at least minimally—and we’ll talk about this in a minute—support the idea that pathologic CR did result in an improved 5-year disease-free survival. You want to talk a little bit about the long-term data from NeoSphere?

Hope S. Rugo, MD: Well, I think that, first of all, the FDA approving drugs based on pathologic complete response rate is a very unique situation. We have one drug that has accelerated approval and no others. That drug happened to have already been approved based on very favorable toxicity and not only improved progression-free survival, but improved survival. It was quite dramatic in the metastatic setting in the CLEOPATRA trial. So, I think that it’s a unique situation where you couldn’t really lose from giving it, and it’s such a limited exposure. You only give it in that time course, and certainly, we give it in that time course in the adjuvant setting, as well, based on that information.

Looking at long-term results from neoadjuvant therapy is complicated. A lot of these trials, including NeoSphere, gave anthracycline post surgery. I think that there’s certainly the ability in HER2-positive and triple-negative disease to overcome resistance to taxane-based therapy and maybe even to some degree in HER2-positive disease to HER2-targeted therapy by giving an anthracycline. So, you do change the disease-free survival assessment if you give chemotherapy post surgery, and that’s been an issue, as well as the fact that neoadjuvant trials by design are not powered as a primary endpoint to look at disease-free survival. I think that we definitely saw that giving trastuzumab versus not in the early trials, like NOAH, improved outcome. That wasn’t a question.

Once we’ve gotten into already improved outcome and adding more drugs, it’s been more complicated. And I think NeoSphere is an example of that. It certainly didn’t show no benefit, but the benefit was modest. I think it’s affected by what you give patients after surgery and by a number of other factors. So, it doesn’t really bother me that we don’t see the huge differences, but I think it has taught us a lesson about what we should expect in terms of the long-term outcome from these neoadjuvant trials.

Adam M. Brufsky, MD, PhD: Right. One question, really, that has brought this into perspective, and I’d like to ask my European colleagues about this, is NeoALTTO. Lapatinib doubled the pathologic complete response rate when added to trastuzumab-based therapy, but really did not have a significant 5-year disease-free survival benefit. Michael, can you comment on that?

Michael Untch, MD: Absolutely, yes. I have the impression that we, in the neoadjuvant area—and Hope was focusing exactly on this, she put the fingers a little bit in the wound—do some kind of two steps forward and one step back. So, NeoALTTO, number 1, was underpowered to see a survival benefit because this trial was designed to see a path CR difference between the study arm—so, either the trastuzumab arm, or the lapatinib arm, or the combination of trastuzumab and lapatinib. And number 2, one of the major design flaws of the study, which might explain the outcome, is that the anthracycline portion of the chemotherapy was given after surgery, which means that these patient have not received the optimal neoadjuvant chemotherapy portion. And just giving a taxane with an anti-HER2 therapy or a double combination is a very nice hypothesis-generating trial. But to use the results of this trial to extrapolate for disease-free and overall survival is not the proper way.

The proper way is to do the optimal chemotherapy as a neoadjuvant backbone treatment, with the addition of anti-HER2 therapy. If the double combination is giving us better results for pCR, especially for HER2-positive disease with a delta that is quite high, in the region of 10% to 20% between the study arm and the standard, it makes me still feel positive that we are going to see positive results in disease-free and overall survival. Let’s say for the AFFINITY trial next year in the adjuvant setting, the double combination, trastuzumab/pertuzumab, was done. Then we will see, is it going to be positive or is it going to be positive maybe just in a patient with high-risk, like node-positive? Because that study learned from ALTTO that we should stop enrolling node-negative patients in which the 5-year overall survival with anthracycline, taxane, and trastuzumab is in the range of 95%. So, how can you increase 95% to 100%-plus? That study, AFFINITY, was enriched in the patient population with node-positive disease. Let’s wait for that one, but I think it was a clever, very intelligent, and very good step for the patients to give a provisional approval for the double combinations, trastuzumab/pertuzumab, in the neoadjuvant setting. And, by the way, that was followed by the EMEA. In Germany, because I’m the speaker of all German breast cancer centers, I did a survey 2 months ago. I would say 90% of us are using, if we treat patients with neoadjuvant therapy in HER2-positive disease, double combination at the moment.

Adam M. Brufsky, MD, PhD: With pertuzumab?

Michael Untch, MD: With pertuzumab.

Adam M. Brufsky, MD, PhD: Okay. Ahmad, is it the same thing in Brussels?

Ahmad Awada, MD, PhD: It probably is not reimbursed in Belgium. But if we did exactly the same survey among our breast specialists, the majority, meaning 95%, of medical oncologists want to give the combination, dual inhibition.

Adam M. Brufsky, MD, PhD: But they can’t because of reimbursement.

Ahmad Awada, MD, PhD: Exactly, and I think this is a problem in other countries.

Michael Untch, MD: I ask this question also to the breast cancer centers. It makes me very happy, but we have no reimbursement problem at the moment for the last 12 months. So, it’s covered completely by the health insurance companies.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
Let’s talk about that for a minute. The first real dual inhibition that got approved on this basis, Hope, really was pertuzumab. So, we have NeoSphere, we have TRYPHAENA, we have trials that really now have improved the pathologic complete response rate. What’s your feeling? Now, we even have data that, at least minimally—and we’ll talk about this in a minute—support the idea that pathologic CR did result in an improved 5-year disease-free survival. You want to talk a little bit about the long-term data from NeoSphere?

Hope S. Rugo, MD: Well, I think that, first of all, the FDA approving drugs based on pathologic complete response rate is a very unique situation. We have one drug that has accelerated approval and no others. That drug happened to have already been approved based on very favorable toxicity and not only improved progression-free survival, but improved survival. It was quite dramatic in the metastatic setting in the CLEOPATRA trial. So, I think that it’s a unique situation where you couldn’t really lose from giving it, and it’s such a limited exposure. You only give it in that time course, and certainly, we give it in that time course in the adjuvant setting, as well, based on that information.

Looking at long-term results from neoadjuvant therapy is complicated. A lot of these trials, including NeoSphere, gave anthracycline post surgery. I think that there’s certainly the ability in HER2-positive and triple-negative disease to overcome resistance to taxane-based therapy and maybe even to some degree in HER2-positive disease to HER2-targeted therapy by giving an anthracycline. So, you do change the disease-free survival assessment if you give chemotherapy post surgery, and that’s been an issue, as well as the fact that neoadjuvant trials by design are not powered as a primary endpoint to look at disease-free survival. I think that we definitely saw that giving trastuzumab versus not in the early trials, like NOAH, improved outcome. That wasn’t a question.

Once we’ve gotten into already improved outcome and adding more drugs, it’s been more complicated. And I think NeoSphere is an example of that. It certainly didn’t show no benefit, but the benefit was modest. I think it’s affected by what you give patients after surgery and by a number of other factors. So, it doesn’t really bother me that we don’t see the huge differences, but I think it has taught us a lesson about what we should expect in terms of the long-term outcome from these neoadjuvant trials.

Adam M. Brufsky, MD, PhD: Right. One question, really, that has brought this into perspective, and I’d like to ask my European colleagues about this, is NeoALTTO. Lapatinib doubled the pathologic complete response rate when added to trastuzumab-based therapy, but really did not have a significant 5-year disease-free survival benefit. Michael, can you comment on that?

Michael Untch, MD: Absolutely, yes. I have the impression that we, in the neoadjuvant area—and Hope was focusing exactly on this, she put the fingers a little bit in the wound—do some kind of two steps forward and one step back. So, NeoALTTO, number 1, was underpowered to see a survival benefit because this trial was designed to see a path CR difference between the study arm—so, either the trastuzumab arm, or the lapatinib arm, or the combination of trastuzumab and lapatinib. And number 2, one of the major design flaws of the study, which might explain the outcome, is that the anthracycline portion of the chemotherapy was given after surgery, which means that these patient have not received the optimal neoadjuvant chemotherapy portion. And just giving a taxane with an anti-HER2 therapy or a double combination is a very nice hypothesis-generating trial. But to use the results of this trial to extrapolate for disease-free and overall survival is not the proper way.

The proper way is to do the optimal chemotherapy as a neoadjuvant backbone treatment, with the addition of anti-HER2 therapy. If the double combination is giving us better results for pCR, especially for HER2-positive disease with a delta that is quite high, in the region of 10% to 20% between the study arm and the standard, it makes me still feel positive that we are going to see positive results in disease-free and overall survival. Let’s say for the AFFINITY trial next year in the adjuvant setting, the double combination, trastuzumab/pertuzumab, was done. Then we will see, is it going to be positive or is it going to be positive maybe just in a patient with high-risk, like node-positive? Because that study learned from ALTTO that we should stop enrolling node-negative patients in which the 5-year overall survival with anthracycline, taxane, and trastuzumab is in the range of 95%. So, how can you increase 95% to 100%-plus? That study, AFFINITY, was enriched in the patient population with node-positive disease. Let’s wait for that one, but I think it was a clever, very intelligent, and very good step for the patients to give a provisional approval for the double combinations, trastuzumab/pertuzumab, in the neoadjuvant setting. And, by the way, that was followed by the EMEA. In Germany, because I’m the speaker of all German breast cancer centers, I did a survey 2 months ago. I would say 90% of us are using, if we treat patients with neoadjuvant therapy in HER2-positive disease, double combination at the moment.

Adam M. Brufsky, MD, PhD: With pertuzumab?

Michael Untch, MD: With pertuzumab.

Adam M. Brufsky, MD, PhD: Okay. Ahmad, is it the same thing in Brussels?

Ahmad Awada, MD, PhD: It probably is not reimbursed in Belgium. But if we did exactly the same survey among our breast specialists, the majority, meaning 95%, of medical oncologists want to give the combination, dual inhibition.

Adam M. Brufsky, MD, PhD: But they can’t because of reimbursement.

Ahmad Awada, MD, PhD: Exactly, and I think this is a problem in other countries.

Michael Untch, MD: I ask this question also to the breast cancer centers. It makes me very happy, but we have no reimbursement problem at the moment for the last 12 months. So, it’s covered completely by the health insurance companies.

Transcript Edited for Clarity
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