This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Experts Discuss Novel Approaches to First-line Therapy for HER2-Positive Metastatic Breast Cancer

Hello and welcome to the Decera Clinical Education Oncology Podcast. I’m your host, Ryan Topping. Today’s episode features Dr. Erika Hamilton from the Sarah Cannon Research Institute in Nashville, Tennessee; and Dr. Ian Krop from the Yale Cancer Center in New Haven, Connecticut, as they discuss recent developments in the field of first-line therapy and maintenance treatment for patients with HER2-positive metastatic breast cancer.

This episode is part of a larger educational program titled, “The Evolving and Transformative Role of Maintenance Therapy in the First Line Setting of HER2+ Metastatic Breast Cancer.” For more information, along with a link to the larger education program, please visit the show notes for this episode.

Now let’s get started and hear what our experts have to say about this important topic.

Dr. Ian Krop (Yale Cancer Center): Hello. My name is Ian Krop. I'm a Breast Medical Oncologist at the Yale Cancer Center. And I am very honored to be joined by my colleague, Dr. Erika Hamilton.

Dr. Erika Hamilton (Sarah Cannon Research Institute): Hi, Ian. Happy to join you. Erika Hamilton, I'm a Breast Medical Oncologist, Chief Development Officer and Director of the Breast Cancer Research Program at Sarah Cannon here in Nashville, Tennessee.

Dr. Krop: And thanks. And we are going to be talking about management of metastatic hormone - hormone receptor-positive and hormone receptor-negative HER2-positive breast cancer. This is a field that's changing very rapidly. And I think it's going to be a great time to be discussing how we should best manage these patients.

And I’ll - I'll start out with kind of the historical background for our management of these patients, which is based on a trial that was done some time ago, the CLEOPATRA trial. This is a trial that led to the approval, in 2012, of a regimen of a taxane with trastuzumab and pertuzumab. And that regimen was - has been our standard for some time since then. And the trial was very straightforward trial. It was patients with newly diagnosed HER2-positive metastatic breast cancer and patients were randomized to docetaxel with trastuzumab with or without pertuzumab.

So the question of whether using two different HER2-targeted monoclonal antibodies was beneficial. And the trial was - was clearly positive. It demonstrated that patients who were on the dual-antibody regimen had a median progression-free survival of almost 19 months, about six-month improvement in - in PFS, and even more impressive, the overall survival was improved by almost 17 months with the dual targeting HER2 regimen. And so that, you know, became the standard of care in 2012. And, you know, I think most of us are still using this regimen. We'll talk about how that's changed in a minute.

But I think one of the more interesting things about the CLEOPATRA trial in the regimen that was tested is not only was it more effective, but it really highlighted the ability of using a induction regimen of - of a cytotoxic drug, in this case, docetaxel. For a limited amount of time in the trial, patients were on the chemotherapy for, you know, in the six to eight cycle range.

And then the chemotherapy was stopped and patients continued on their trastuzumab and pertuzumab, you know, for the rest of the time that their disease was controlled. So it really highlighted the ability of - of allowing a maintenance type approach. Obviously, the toxicity of - of the regimen is - is much more manageable when you're not giving chemotherapy, just giving the antibodies. And, you know, I think that's really has been appealing for patients.

What we've seen in the interim and more recently has been looking at approaches to try to improve upon that maintenance strategy. Can we prolong that maintenance strategy with adding additional targeted agents? And I'll tell you about one that was reported last year called the PATINA trial, which was asking whether adding a CDK4/6 inhibitor to patients who had hormone receptor-positive HER2-positive breast cancer would provide further benefit in that maintenance setting.

And so this trial looked at patients who had triple-positive breast cancer that had already started their induction chemotherapy with trastuzumab and pertuzumab. It wasn't actually mandated that you have the pertuzumab, but 97% of the patients had - were on the dual antibody regimen in the trial.

And so patients who had started that induction regimen and had disease control either stable disease or a partial or complete response after six to eight cycles of chemotherapy were then registered to the trial. They stopped the chemotherapy. And they were then randomized to endocrine therapy with trastuzumab and pertuzumab with and without the CDK4/6 inhibitor, palbociclib.

The idea - the rationale for this approach was that we had known for - for many years that the CDK4/6 pathway was important in HER2-positive breast cancer, just like it is in - in hormone receptor-positive HER2-negative cancers. But also there were some really interesting data suggesting synergy between HER2-targeted therapy and CDK4/6 inhibition. And so that was a rationale for the trial. And the results of the trial clearly supported this hypothesis.

The patients who were on endocrine therapy, HP plus palbociclib, had a median progression-free survival of a very impressive 44 months, about 15 months longer than the patients who were on the endocrine therapy, HER2 therapy arm alone.

The regimen was fairly well tolerated. There was some increase in diarrhea, about 11% grade 3 diarrhea rates. And of course, there was significant neutropenia with the addition of palbociclib, as you would expect, but the rate of discontinuation due to toxicities was only about 7%. So this overall was fairly manageable. And again, I think the - the substantial improvement in median progression-free survival was, at least in my mind, fairly compelling. And the absolute number of 44 months really also, I think is fairly impressive.

Erika, do you want to talk about yet another strategy for improving maintenance?

Dr. Hamilton: Yeah, I think that was a fantastic summary of the PATINA data. And I completely agree with you. I think we were all really probably quite surprised at how impressive the magnitude of benefit for PATINA was.

I'm going to present the HER2CLIMB-05 data. This was a similar idea in the idea that it was a maintenance strategy for those patients that had had, you know, four to eight cycles of the taxane in combination with trastuzumab and pertuzumab, is kind of an induction strategy per CLEOPATRA, hadn't had progression and they were going to drop that taxane out.

What was different about HER2CLIMB-05 is it included patients that were both ER-positive as well as ER-negative. And the drug that we were looking at adding was tucatinib. This is a HER2 specific tyrosine kinase inhibitor. It was FDA approved as part of the original HERCLIMB trial in combination with capecitabine and trastuzumab. And so we were really looking at whether, you know, adding this additional HER2 specific tyrosine kinase inhibitor was beneficial.

The results of this trial was positive. It provided an 8.6-month improvement in progression-free survival. I think one of the concerns was that we would see more diarrhea. We know that we can see diarrhea with tucatinib. We also know that pertuzumab causes diarrhea.

And I think actually, quite surprisingly, we really didn't see a ton more diarrhea. In terms of grade 3 or more severe diarrhea, we only saw a 2% increase over the control arm of the pertuzumab alone. So this really was not a common reason for reductions or discontinuations. In fact, a more common reason for discontinuation was actually LFT elevation, which is we know we have to monitor that while on tucatinib as well.

We did break down this data for patients that were ER-positive as well as those patients that were ER-negative. And there was a larger magnitude of benefit for those patients that had ER-negative disease a little over 12 months. Whereas the magnitude of benefit for patients that had ER-positive disease was just shy of about seven months. But this was statistically significant in both groups.

So you know, the PATINA study came first. This was presented, I believe, at San Antonio Breast in 2024. This is now in NCCN guidelines pretty recently, in fact. HER2CLIMB-05 was a little bit later to the party. It was presented at San Antonio Breast in 2025, kind of more recently really. And so, you know, this is not FDA approved yet, but we're going to have kind of two regimens probably for maintenance. And so a lot of people are saying, you know, that perhaps the hormone receptor status is going to kind of influence which one that they may pick.

But I - and what do you - what do you think about maintenance? I mean, I think most people think that this is a pretty attractive strategy for patients to be able to kind of get rid of the cytotoxic. But from an oncologist standpoint, you know, how do you think about maintenance here?

Dr. Krop: Yeah. No, I think that's exactly right. I - I - you know, I think it's - well, clearly there is a, you know, role for cytotoxics in HER2-positive breast cancer. You know, what these studies - you know, first with CLEOPATRA and then these subsequent add-on strategy trials have - have clearly shown is that you can get a lot of mileage out of maintenance therapy here. You know, we're talking, you know, you know, 40 - you know, over 40 months with the - the PATINA regimen. So, you know, I have to think back, you throw around months of it, you know, that's - that's over, you know, 3.5 years of - of treatment on - on, you know, without progression on a regimen that - that's fairly well tolerated.

And, you know, the - the fact that we now have HER2CLIMB-05 which gives regimen - gives an option both, you know, for the hormone receptor-positive and hormone receptor-negative patients is - you know, is even more, you know, kind of comprehensive in terms of – of - of options for these patients.

So, you know, I think we've - you know, based on CLEOPATRA alone, we've been giving maintenance therapy for these patients as our standard, you know, for - for well over a decade. And I think having these additional options is just with even better efficacy, you know, really is - is you know - I think is a great set of results for our patients.

Dr. Hamilton: Yeah. I completely agree with you. I guess one additional question. You know, besides the hormone receptor positive or negative, is there anything else about a patient's disease status that may influence you in one direction or another?

Dr. Krop: Yeah. So that's a good question. And I was going to ask you about the similar question, which is, you know, one of the things that that, you know, we were excited about since - you know, since the development of tucatinib has been its ability to, you know, cross the blood brain barrier and have, you know, demonstrable benefit in - in patients who have CNS metastases, which is unfortunately is - you know, is a relatively common occurrence in patients with HER2-positive disease.

We don't have a lot of data from PATINA in - in patients with brain metastases or patients who then went on to develop brain metastases. But I think there was - in HER2CLIMB-05, there was some data there that - that showed, you know, some benefit in patients who had pre-existing brain metastases and also looking at development of brain metastases. So that might be one thing that I think you might factor in if somebody had brain metastases at baseline might favor using - using the tucatinib regimen, if it gets approved. I don't know what your thoughts are about that.

Dr. Hamilton: Yeah, I agree with you. You know, we - we didn't have a ton of brain mets. You know, luckily brain mets are pretty rare in that first-line patient population. We did look at patients that had brain mets at baseline. It was a pretty small sample size. There was about 81 patients. But the CNS, PFS did look to be about double for those patients that received tucatinib. So there was a signal that those patients receiving tucatinib looked like they were doing better. So I think that is a factor that would influence me.

Dr. Krop: Yeah. No. And, you know, I think, you know, certainly the HER2CLIMB is kind of right off the presses and the PATINA data are - are - are not completely mature either. So we'll get more, you know, kind of subgroup data as - as we have more mature data from these trials. And - and hopefully as you are kind of alluding to, it'll - it'll start to be clear whether there are particular subsets who benefit particularly from one of these approaches versus the other that we can start using to personalize treatment management for this - for this situation.

Dr. Hamilton: Yeah, absolutely. So, you know, just when we think we kind of start to have things figured out often happens in breast cancer literature, we throw a wrench in things. And that wrench is really the DESTINY-Breast09 data. So DESTINY-Breast09 was the study looking at moving trastuzumab deruxtecan up into the first-line setting.

So this trial was a three-arm trial. It looked at trastuzumab deruxtecan alone. And we actually don't have the data from that arm. But we do have the data from the trastuzumab deruxtecan plus pertuzumab arm versus the standard THP arm.

Now, what this trial did not take into account was any sort of maintenance regimen. This was a very straightforward trial that was just treat until progression. And so we did have results of DESTINY-Breast09 presented at ASCO 2025 by Dr. Tolaney. I think, you know, not a whole lot of surprises and demographics here. We saw a little over 50% of patients having de novo disease. We saw a little over 50% of patients also having hormone receptor-positive disease.

I don't think any of this was surprising, but we saw a really trastuzumab deruxtecan in combination with pertuzumab clearly beating THP with PFS of 40.7 months, compared to 26.9 months with THP. So really kind of, you know, DB09 really the newcomer here in the first-line setting.

And so, you know, I think as we think about moving this up into the first-line, a lot of things that we're thinking about. We did see the CR rate really about double, 8.5% of patients getting a CR on THP and about 15.1% getting a CR in T-DXd plus P. And CRs for me in HER2-positive carry with it a little bit of weight. You know, we all have these kind of exceptional responders that have CR. And then at least on CLEOPATRA, you know, went on to HP maintenance and maybe five, six years out and really still have no evidence of disease. And we start to flirt with this idea of, are they cured?

And so seeing that, you know, doubling of a CR rate, I think was very intriguing for me of, you know, are we potentially converting some patients to cure? But I think really exciting data. We always have to be vigilant for ILD with trastuzumab deruxtecan. I think we are getting better at treating the nausea. We do have this classified as a highly emetogenic drug now. And so with that is coming at least a three-drug antiemetic prophylactic regimen. And I think patients are doing much better in controlling nausea now that we recognize that and are supporting them up front and not in a reactionary nature.

But I think it really brings forward some tough questions for us because right as we kind of have some of these maintenance regimens, we now have a study that is challenging the first-line regimen and doesn't account for maintenance regimens. So I guess maybe I'll ask you the tough question. Do you think we can think about any of these maintenance regimens in light of the DB09 data? Or do we have to be clinical trial purists and think it's THP with maintenance regimens or it's DB09 and treat to progression?

Dr. Krop: Yeah, no, I appreciate the - that question. It is a hard one. You know, we are in - in - in the breast cancer field, I think spoilt that we have feel like we have good data to support almost all the things we do. And this one is, is one where we're - we're - we're lacking to some extent.

I would point out to - to the listeners that, even though there was not prospectively built in maintenance phase in DESTINY-Breast09, you know, there were patients who - who stopped their - their T-DXd because of toxicity or for - for other reasons. And, you know, the - the - while the median PFS was over 40 months in that trial, the median number of months of T-DXd that was given was more like 20 months. So - so there - there were patients who - who, de facto developed - you know, were received a maintenance type approach.

And in the - in the T-DXd/pertuzumab arm, if you stop the T-DXd, you were able to continue the pertuzumab and add trastuzumab. So there was a - it ended up being some maintenance, but it - it wasn't, you know, officially built into the trial in a way that we can, you know - you know, measure so well.

But you know, I think as - as Erika, you – you - you kind of brought up, in practice, should we be doing that. And, you know, I think without good data, I'm not going to - and I haven't yet told patients, “Oh, we're going to treat you for - you know, the plan will be, we're going to treat you for 20 months and then we're going to move on to X or Y treatment.” But you know, I think we - you know, we are obviously needing to - to pay attention to when patients are having toxicities. They're - you know - you know, every patient is different and how they tolerate drugs like T-DXd.

And so I think in practice - certainly in my practice, if patients are having toxicities, they're starting to affect their quality of life. Then, you know, stopping the T-DXd and continuing them on - on antibodies alone, it makes sense. And - and that's what I will be doing. You know, obviously, we - we just had these DB09 data relatively recently, so we're just starting to use T-DXd. So I haven't had a patient who's had - who's had to or wanted to come off their T-DXd yet. But I certainly won't have any hesitation in doing that if - if that seems like the right thing to do from a toxicity standpoint.

Dr. Hamilton: Yeah. I - I agree with you. And I think the way you presented that was very - very smart. You know, I mean, I - I do think it's unlikely that we're going to have patients that realistically can remain on T-DXd for three, four years, etc.. Right? I mean, even just the cumulative fatigue, etc., I think is going to is add up.

I think what probably would not be wise is to adapt the CLEOPATRA six to eight cycles and stop to T-DXd. You know, we are getting data. And I - I do think that, you know, if we stop patients prematurely before they've gotten their maximal response, we're probably not doing our patients a service.

And so if I - if I am going to stop patients, I would at least want to treat those patients until their maximal response. So I do think that at least that would be very important. But I - I agree with you that I think in the real world, we are going to be probably looking towards maintenance. But I don't think that it's going to be as soon as we were kind of looking to maintenance for a CLEOPATRA type regimen. So I guess we'll stay tuned.

Dr. Krop: Yeah, no good point. And you know, there is a trial that's - that's ongoing called the DEMETHER study that - that is looking at, I think six cycles of - of T-DXd and then prospectively with a maintenance phase. But I agree. I mean - and just to be clear, you know, the - the reason why, in CLEOPATRA, patients were on six to eight cycles of - of THP in - in that trial the key was - was docetaxel. And that's, you know, kind of - you know, that's been what - what these other trials have done as well.

It's just because, you know, we know patients can't tolerate docetaxel more than six to eight cycles. So it wasn't done because of some, you know, incredibly insightful science that tells us that's the maximum number, that's the optimal number of cycles. It was just, you know, from a practical standpoint. So you're right. I think in going forward, this idea of looking for maximal benefit, you know, kind of plateaued benefit at least in the absence of some other data would probably seems like it makes the most sense to - to - to be targeting at this point, if we are planning on doing a maintenance approach going forward.

Dr. Hamilton: Absolutely. Well, I - I think we've conquered what we know and the many remaining questions of first-line HER2-positive metastatic breast cancer. And thanks to our listeners for joining us.

Dr. Krop: Yes, it was a good discussion. It's always a pleasure talking with you.

Thank you, Dr. Hamilton and Dr. Krop, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “The Evolving and Transformative Role of Maintenance Therapy in the First Line Setting of HER2+ Metastatic Breast Cancer,” please click the link in the show notes. Be sure to check back regularly for more episodes on important Decera Clinical Education Oncology Podcast topics.