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HER2+ Breast Cancer: The KATHERINE Trial

Panelists: Joyce O Shaughnessy, MD, Baylor-Sammons Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital; Adan M. Brufsky, MD, PhD, Comprehensive Breast Cancer Center; Heather L. McArthur, MD, MPH, Cedars-Sinai Medical Center; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Jan 14, 2019



Transcript: 

Joyce O’Shaughnessy, MD:
Let’s talk a little bit about the KATHERINE trial that you’ll hear about at the 2018 San Antonio Breast Cancer Symposium. So who wants to talk about the KATHERINE trial?

Tiffany A. Traina, MD: I’d be happy to.

Joyce O’Shaughnessy, MD: Thank you.

Tiffany A. Traina, MD: So I think this is really some of the hot news that came out of the meeting this week. So the KATHERINE trial was a large randomized study of about 1500 women with early-stage HER2-positive breast cancer receiving neoadjuvant therapy, largely anthracycline and taxane-based. About 76% or so received anthracycline in addition to taxane. Patients receive preoperative trastuzumab. And a small portion of those patients, about 19%, also received pertuzumab in the neoadjuvant setting. Patients went on to surgery and if they failed to achieve a pathologic complete response they were then randomized in one-to-one fashion to either continuing out their year of trastuzumab-based adjuvant therapy, or switching over to T-DM1 for 14 cycles. And so the primary endpoint of this study was to look at invasive-free survival.

In terms of the characteristics, as I mentioned, about a quarter of those patients had inoperable disease. At the start a large portion were ER-positive, about 72% or so. And we talked about most of these patients receiving an anthracycline and taxane-based regimen in the preoperative setting. So I think what was really exciting to see is the group of women that received T-DM1 had a significant improvement in basic disease-free survival, a hazard ratio of 0.5 and an absolute difference of about 11%, favoring switching over to T-DM1 if you fail to achieve a pathologic CR [complete response (PCR)].

Heather L. McArthur, MD, MPH: What was so interesting was that it was consistent regardless of hormone receptor status, which is very different than what we’re seeing.

Adam M. Brufsky, MD, PhD: Obviously. I mean are you guys as surprised as me by these data? If you think about it for a minute, a lot of us participated in a trial. Aditya from Dana-Farber, you guys sponsored it, and a bunch of us did this trial where half of the women got TH [paclitaxel and trastuzumab] and half got the T-DM1 every three weeks. That was a tough regimen to do. It’s hard to get T-DM1 into somebody every 3 weeks for a year. That’s tough.

Tiffany A. Traina, MD: Right, but the study actually showed 71% of patients were able to complete the full 14 cycles of T-DM1, and about 80% or so completed the full trastuzumab-based regimen. But those who stopped T-DM1 early switched over to trastuzumab and finished out their time. So they were receiving effective anti-HER2 therapy, and even despite that you’re seeing this impressive difference. I think that’s one of the key differences. This reminds me of the triple negative space where you are enriching for a population that’s at higher risk or failed to achieve a pathologic CR and switching therapy there is a benefit.

Ruth O'Regan, MD: Yes, I think you need to keep in mind that these were trastuzumab-resistant cancers and you gave them trastuzumab. So I think it’s not surprising T-DM1 was better, but I think the magnitude was quite remarkable.

Tiffany A. Traina, MD: Yes.

Adam M. Brufsky, MD, PhD: Yes, that’s was a surprise. But that changes everything now, doesn’t it? Instead just talking about adjuvant pertuzumab for the last 10 minutes, what are we going to do?

Tiffany A. Traina, MD: Consider that only about 20% of the patient population of those 1500 received pertuzumab. But in the forest plot, that subgroup had also a hazard ratio of 0.54, and that’s still about 300 patients.

Joyce O’Shaughnessy, MD: It was Herceptin- and pertuzumab-resistant disease. So, then it must be the payload, the maytansine payload is non–cross-resistant with those other cytotoxic agents, which is a totally different mechanism of action. Now in order to get on the study, you could not have had T1a or T1b disease, right? You had to either be clinically node-positive or at least be a T1 to get on.

Aditya Bardia, MD, MPH: How many of us treat T1A? Do you treat T1A?

Joyce O’Shaughnessy, MD: If it’s bad biology in the adjuvant setting, but not preoperatively.

Ruth O'Regan, MD: I tend not to but I would discuss paclitaxel, trastuzumab with some patients, but I would tend not to treat T1.

Joyce O’Shaughnessy, MD: Yes, but in terms of the neoadjuvant approach, when we go home Monday morning, if somebody has T1C, it’s increasingly important to know if they’re going to be a pathologic CR or not, right? And if we start with T1C, that doesn’t meet the criteria for preoperative pertuzumab, because that’s T2. You have to have T2 disease to get on label, so we could start with a TCH [docetaxel,  carboplatin, trastuzumab], for example, and then go to surgery. That would be in keeping with the KATHERINE trial. If they’re not a pathologic CR, they could finish out with a T-DM1.

Adam M. Brufsky, MD, PhD: So I was skeptical, and I realize why now. Wasn’t there a neoadjuvant study with T-DM1?

Joyce O’Shaughnessy, MD: Yes. It’s a 44% pathologic CR rate.

Adam M. Brufsky, MD, PhD: But it wasn’t that great.

Joyce O’Shaughnessy, MD: No, no, it was 44% with just the T-DM1 and pertuzumab, it just wasn’t quite as good as TCHP [docetaxel, carboplatin, and trastuzumab plus pertuzumab]. It wasn’t quite as good but, still, 44% is not nothing.

Adam M. Brufsky, MD, PhD: My point though is, if you expect this to work, wouldn’t you have expected a higher PCR for T-DM1 alone?

Joyce O’Shaughnessy, MD: No, I think we’d see it as non–cross-resistant.

Ruth O'Regan, MD: You’re not dealing with trastuzumab-resistant disease in that setting.

Adam M. Brufsky, MD, PhD: True.

Ruth O'Regan, MD: I think that probably makes sense.

Joyce O’Shaughnessy, MD: Right. Now regardless, there’s the question about radiation. So you had to get randomized within 12 weeks of your surgery. But they didn’t say that you had to have a certain amount of disease in the breast or lymph node. There weren’t size cutoffs that I could see in the paper that came out in the New England Journal of Medicine the same day, thank goodness. Everybody can read that themselves you know? So if you just have even 5 mm left, and they didn’t use the residual cancer burden system.

Aditya Bardia, MD, MPH: Should they? Should we be using RCB [residual cancer burden] to make the decisions now? One of us should probably explain RCB to our audience, but the bottom line is, if you are RCB01, would you do that? Would you only reserve this for RCB 2 and 3? I’m asking the question for you guys.

Ruth O'Regan, MD: The data supports using it for RCB1 because they actually had a group with very low volume residual disease that did benefit, although I will note that in that group it did cross unity. So I think that’s a discussion you’d have to have.

Joyce O’Shaughnessy, MD: Yes, because they didn’t measure how much was left.

Adam M. Brufsky, MD, PhD: There is a history of RCB1 versus 0. You know the paper from Fraser Symmans, MD, from a year ago, in the HER2-positive subgroup that they looked at, there was no difference in DFS [disease-free survival] as far as I know. People were RCB0 versus 1. So you’ve got to drive that with these data. You’ve got to put those two trials together now and try to figure out what to do.

Ruth O'Regan, MD: Joyce, the only thing I would say is I do think we still are thinking about de-escalating as well. So I think the T1c is a little tricky because I feel like if I could get away with paclitaxel-trastuzumab for some patients, I might do that.

Joyce O’Shaughnessy, MD: Would you give it preoperatively?

Ruth O'Regan, MD: Probably not. I haven’t done that. But I do think these data are very convincing, and I think they’re going to have be discussed with patients with T1c disease.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD:
Let’s talk a little bit about the KATHERINE trial that you’ll hear about at the 2018 San Antonio Breast Cancer Symposium. So who wants to talk about the KATHERINE trial?

Tiffany A. Traina, MD: I’d be happy to.

Joyce O’Shaughnessy, MD: Thank you.

Tiffany A. Traina, MD: So I think this is really some of the hot news that came out of the meeting this week. So the KATHERINE trial was a large randomized study of about 1500 women with early-stage HER2-positive breast cancer receiving neoadjuvant therapy, largely anthracycline and taxane-based. About 76% or so received anthracycline in addition to taxane. Patients receive preoperative trastuzumab. And a small portion of those patients, about 19%, also received pertuzumab in the neoadjuvant setting. Patients went on to surgery and if they failed to achieve a pathologic complete response they were then randomized in one-to-one fashion to either continuing out their year of trastuzumab-based adjuvant therapy, or switching over to T-DM1 for 14 cycles. And so the primary endpoint of this study was to look at invasive-free survival.

In terms of the characteristics, as I mentioned, about a quarter of those patients had inoperable disease. At the start a large portion were ER-positive, about 72% or so. And we talked about most of these patients receiving an anthracycline and taxane-based regimen in the preoperative setting. So I think what was really exciting to see is the group of women that received T-DM1 had a significant improvement in basic disease-free survival, a hazard ratio of 0.5 and an absolute difference of about 11%, favoring switching over to T-DM1 if you fail to achieve a pathologic CR [complete response (PCR)].

Heather L. McArthur, MD, MPH: What was so interesting was that it was consistent regardless of hormone receptor status, which is very different than what we’re seeing.

Adam M. Brufsky, MD, PhD: Obviously. I mean are you guys as surprised as me by these data? If you think about it for a minute, a lot of us participated in a trial. Aditya from Dana-Farber, you guys sponsored it, and a bunch of us did this trial where half of the women got TH [paclitaxel and trastuzumab] and half got the T-DM1 every three weeks. That was a tough regimen to do. It’s hard to get T-DM1 into somebody every 3 weeks for a year. That’s tough.

Tiffany A. Traina, MD: Right, but the study actually showed 71% of patients were able to complete the full 14 cycles of T-DM1, and about 80% or so completed the full trastuzumab-based regimen. But those who stopped T-DM1 early switched over to trastuzumab and finished out their time. So they were receiving effective anti-HER2 therapy, and even despite that you’re seeing this impressive difference. I think that’s one of the key differences. This reminds me of the triple negative space where you are enriching for a population that’s at higher risk or failed to achieve a pathologic CR and switching therapy there is a benefit.

Ruth O'Regan, MD: Yes, I think you need to keep in mind that these were trastuzumab-resistant cancers and you gave them trastuzumab. So I think it’s not surprising T-DM1 was better, but I think the magnitude was quite remarkable.

Tiffany A. Traina, MD: Yes.

Adam M. Brufsky, MD, PhD: Yes, that’s was a surprise. But that changes everything now, doesn’t it? Instead just talking about adjuvant pertuzumab for the last 10 minutes, what are we going to do?

Tiffany A. Traina, MD: Consider that only about 20% of the patient population of those 1500 received pertuzumab. But in the forest plot, that subgroup had also a hazard ratio of 0.54, and that’s still about 300 patients.

Joyce O’Shaughnessy, MD: It was Herceptin- and pertuzumab-resistant disease. So, then it must be the payload, the maytansine payload is non–cross-resistant with those other cytotoxic agents, which is a totally different mechanism of action. Now in order to get on the study, you could not have had T1a or T1b disease, right? You had to either be clinically node-positive or at least be a T1 to get on.

Aditya Bardia, MD, MPH: How many of us treat T1A? Do you treat T1A?

Joyce O’Shaughnessy, MD: If it’s bad biology in the adjuvant setting, but not preoperatively.

Ruth O'Regan, MD: I tend not to but I would discuss paclitaxel, trastuzumab with some patients, but I would tend not to treat T1.

Joyce O’Shaughnessy, MD: Yes, but in terms of the neoadjuvant approach, when we go home Monday morning, if somebody has T1C, it’s increasingly important to know if they’re going to be a pathologic CR or not, right? And if we start with T1C, that doesn’t meet the criteria for preoperative pertuzumab, because that’s T2. You have to have T2 disease to get on label, so we could start with a TCH [docetaxel,  carboplatin, trastuzumab], for example, and then go to surgery. That would be in keeping with the KATHERINE trial. If they’re not a pathologic CR, they could finish out with a T-DM1.

Adam M. Brufsky, MD, PhD: So I was skeptical, and I realize why now. Wasn’t there a neoadjuvant study with T-DM1?

Joyce O’Shaughnessy, MD: Yes. It’s a 44% pathologic CR rate.

Adam M. Brufsky, MD, PhD: But it wasn’t that great.

Joyce O’Shaughnessy, MD: No, no, it was 44% with just the T-DM1 and pertuzumab, it just wasn’t quite as good as TCHP [docetaxel, carboplatin, and trastuzumab plus pertuzumab]. It wasn’t quite as good but, still, 44% is not nothing.

Adam M. Brufsky, MD, PhD: My point though is, if you expect this to work, wouldn’t you have expected a higher PCR for T-DM1 alone?

Joyce O’Shaughnessy, MD: No, I think we’d see it as non–cross-resistant.

Ruth O'Regan, MD: You’re not dealing with trastuzumab-resistant disease in that setting.

Adam M. Brufsky, MD, PhD: True.

Ruth O'Regan, MD: I think that probably makes sense.

Joyce O’Shaughnessy, MD: Right. Now regardless, there’s the question about radiation. So you had to get randomized within 12 weeks of your surgery. But they didn’t say that you had to have a certain amount of disease in the breast or lymph node. There weren’t size cutoffs that I could see in the paper that came out in the New England Journal of Medicine the same day, thank goodness. Everybody can read that themselves you know? So if you just have even 5 mm left, and they didn’t use the residual cancer burden system.

Aditya Bardia, MD, MPH: Should they? Should we be using RCB [residual cancer burden] to make the decisions now? One of us should probably explain RCB to our audience, but the bottom line is, if you are RCB01, would you do that? Would you only reserve this for RCB 2 and 3? I’m asking the question for you guys.

Ruth O'Regan, MD: The data supports using it for RCB1 because they actually had a group with very low volume residual disease that did benefit, although I will note that in that group it did cross unity. So I think that’s a discussion you’d have to have.

Joyce O’Shaughnessy, MD: Yes, because they didn’t measure how much was left.

Adam M. Brufsky, MD, PhD: There is a history of RCB1 versus 0. You know the paper from Fraser Symmans, MD, from a year ago, in the HER2-positive subgroup that they looked at, there was no difference in DFS [disease-free survival] as far as I know. People were RCB0 versus 1. So you’ve got to drive that with these data. You’ve got to put those two trials together now and try to figure out what to do.

Ruth O'Regan, MD: Joyce, the only thing I would say is I do think we still are thinking about de-escalating as well. So I think the T1c is a little tricky because I feel like if I could get away with paclitaxel-trastuzumab for some patients, I might do that.

Joyce O’Shaughnessy, MD: Would you give it preoperatively?

Ruth O'Regan, MD: Probably not. I haven’t done that. But I do think these data are very convincing, and I think they’re going to have be discussed with patients with T1c disease.


Transcript Edited for Clarity
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