Systemic Therapy for Advanced HER2-Positive Breast Cancer Guideline Update

An interview with Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, WA, co-chairs on "Systemic Therapy for Advanced HER2-Positive Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on systemic therapies for advanced HER2-positive breast cancer, focusing on second-line, third-line, and greater treatment. Read the full guideline.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, co-chairs on 'Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: ASCO Guideline Update'. Thank you for being here. Dr. Giordano and Dr. Davidson.

Dr. Sharon Giordano: Thank you.

Dr. Nancy Davidson: Thank you for having us.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Giordano, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Sharon Giordano: No, I do not.

Brittany Harvey: Thank you. And Dr. Davidson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Nancy Davidson: No, I do not.

Brittany Harvey: Thank you. Let's talk about the content of this guideline update. So first, Dr. Giordano, what prompted an update to this guideline on the systemic therapy for advanced HER2-positive breast cancer, and what is the focus of this update?

Dr. Sharon Giordano: So, we were prompted to update the guidelines for HER2-positive metastatic breast cancer because several new studies have been presented and published, which are really changing our standard of care approaches.

We have new therapies and new combinations that have resulted in improvements in progression-free survival and in overall survival for this patient population. Given the clinical importance of these new studies, we felt that an update of the treatment guidelines was clearly needed. Overall, the focus of our update is really in the title, so, it's systemic therapies for advanced HER2-positive breast cancer. And specifically, what we're focusing on is updating the recommendation for second-line therapy, and then adding multiple new options for systemic therapies for third-line and greater treatment.

Brittany Harvey: Great. Thank you for that overview. So, then I'd like to review the updated recommendations of this guideline for our listeners. Starting with, Dr. Davidson, what is recommended for first-line therapy for patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: So, that was the part of this guideline that really did not change. In the previous iteration and in the current iteration, we felt that the evidence suggested that a combination of trastuzumab and a taxane should be the first-line treatment for individuals with metastatic HER2-positive breast cancer unless they have some sort of contraindication to the taxanes.

Now, the evidence supporting that is very strong. The trial that supported this continues to be updated and continues to show benefit. So, that's a very high level of evidence and our recommendation on this was extremely strong.

Brittany Harvey: Great. And then following those first-line recommendations, Dr. Giordano, what is recommended for second-line treatment for these patients?

Dr. Sharon Giordano: So, we did change our recommendation for second-line treatment for HER2-positive patients. The current new recommendation is, and I quote from our guideline, "If a patient's HER2-positive, advanced breast cancer has progressed during or after first-line HER2 targeted therapy, and the patient has not received trastuzumab deruxtecan, clinicians should recommend trastuzumab deruxtecan as a second-line treatment."

So, as I said before, this recommendation is a change from our prior second-line recommendation. Previously, we had recommended T-DM1. So, this change was really, I think, one of the most important changes to the guidelines with this update.

We made the recommendation based on the initial presentation of the results of the Destiny-Breast03 trial, really given the magnitude of the benefit that was seen in the study. And the manuscript I would note was published this month in the New England Journal of Medicine.

Overall, the study showed statistically significant and highly clinically meaningful reduction in progression-free survival. So, just to give you some of these numbers, to kind of give you a sense of how big the impact was, so 76% of patients who were treated with trastuzumab deruxtecan versus 34% of patients treated with trastuzumab emtansine were alive and without disease progression at a year, with a hazard ratio of 0.28.

The response rates are also quite impressive with 80% versus 34% response rates. And the overall survival data are still immature but do favor treatment with trastuzumab deruxtecan and that hazard was 0.55.

So, I will note though, that toxicity was a bit higher with the new drug, with trastuzumab deruxtecan. So, any grade adverse events were 98% versus 87%. And then if you look at grade three and four drug-related adverse events, it was 45% versus 40%.

I think of note, rather than just kind of the overall numbers, though, one thing that clinicians need to be aware of is the risk of interstitial lung disease with this new drug. And this occurred in about 10% of treated patients in this study, although only 1%, or I think it was two patients, who had grade three or higher pulmonary toxicity. So, this is a toxicity that is specific to this drug that clinicians do need to be aware of.

Dr. Nancy Davidson: I think the other thing on that, Sharon, is that the incidence was lower in the Destiny Breast03 trial than it had been in some of the really early studies of this agent, so, that should be reassuring to us. Although, of course, it doesn't mean that the side effect doesn't happen, you have to take note of it.

Dr. Sharon Giordano: That's a great point. It definitely was lower than we'd seen before. So, a little bit of a relief, but still there.

Brittany Harvey: Great, thank you both for reviewing that data. I appreciate the overview. So then, following those recommendations for second-line treatment, Dr. Davidson, what are the recommended options for third-line therapy for patients with HER2-positive advanced breast cancer that has progressed on second-line or greater HER2 targeted therapy?

Dr. Nancy Davidson: Well, of course, this is the area where there has been considerable change as well. And that's because of the wealth of new anti-HER2 agents that Dr. Giordano talked about earlier.

So, we had a variety of recommendations for clinicians and patients to make decisions about how to proceed. I think certainly one of them, is that if the patient did not receive trastuzumab emtansine (T-DM1) in the second line, as we just talked about, our new recommendation would be that they would not, that they would receive trastuzumab deruxtecan, so you put off for T-DM1 in that [third-line] setting. And that's a new recommendation for us. And the strength of the recommendation is quite high.

Another agent that's come along that's very exciting is tucatinib, one of the small molecule inhibitors. And we think that that is also an alternative, that tucatinib in combination with trastuzumab and capecitabine, again, nice activity and pretty strong recommendation based on analyzed critical trials. And then finally, if for some reason the patient didn't receive the trastuzumab deruxtecan in a second-line setting and you're now in the third-line setting, that would be a very reasonable agent for them as well.

Those are all pretty strong recommendations. And I think the choice of which to proceed will depend a little bit on the decision making between the patient and the doctor about the mode of administration, your side effect profile, what seems the most appropriate, and it might be more one of the order of the recommendation. As opposed to saying, 'This one, but not that one', it might be, 'Pick this one next and know that you will be able to return to some of these in the future.'

Now, there are a lot of other possibilities here. We already had available to us neratinib and capecitabine, that continues to be part of the portfolio. And we also had lapatinib and capecitabine, also part of the portfolio. Other combinations of chemotherapy, trastuzumab could be considered, a new agent called margetuximab with chemotherapy, which has also come on to the market.

And of course, there's the possibility of thinking about the anti-HER2 agents in the context of endocrine therapy for those patients who have estrogen receptor-positive breast cancer as well. And new information suggesting that you might, in some cases, even think about one with CDK 4/6 inhibitors in the context of trastuzumab and fulvestrant.

So, lots of possibilities here that patients and doctors can weigh, and again think about order of administration as opposed to selecting for or against the other. I do think that the leading contenders at the beginning are going to be T-DM1 or trastuzumab deruxtecan, if that hasn't been used, or tucatinib in combination, those would be my personal preferences.

Brittany Harvey: Great. Thank you for reviewing those options and describing where a patient might receive these during their treatment.

Dr. Nancy Davidson: I'd like to hear Dr. Giordano's thoughts on that, how would you stack those up?

Dr. Sharon Giordano: Yeah, well, as you said, I think it does depend on what the patient's been treated with previously. I mean, certainly, T-DM1 or trastuzumab deruxtecan, if they haven't had those agents. Otherwise, I think the data from the tucatinib trastuzumab capecitabine regimen is pretty impressive as it did show an overall survival benefit. And as you know, I think that regimen is also really interesting, because it does seem to have some efficacy for patients with brain metastases. That actually has a very nice advantage.

Then the other ones, I think it just sort of depends on what they've seen previously, what side effects they may be experiencing, and kind of other quality of life issues. I don't see that there's a clear way to sequence the other ones since most of them haven't really been directly compared head-to-head against each other.

Brittany Harvey: It seems like it may be an individual discussion between clinicians and patients at that level. So, then, Dr. Giordano following that, how will this guideline impact clinicians and what should they know as they implement these updated recommendations?

Dr. Sharon Giordano: I think the bottom line is really the clinicians are now going to have more options for the treatment of HER2-positive advanced breast cancer which is fantastic news to have all these different choices and options for our patients.

To me, I think probably the most important changes and recommendations, again, are the addition of trastuzumab deruxtecan in the second-line setting just given the very impressive clinical benefit that's seen with that drug, or, as Nancy mentioned in the third-line setting if patients, for some reason haven't received it previously.

And then I also think, as we talked about, the tucatinib combination is really an exciting new combination that does seem to have significant clinical benefit. I think the clinicians will need to be aware that that might be an option for patients with CNS metastases that are progressing. And also, just to be aware, as we mentioned before, about the risk of the interstitial lung disease with trastuzumab deruxtecan but it's really encouraging to me to have such a long list of drugs and combinations that we can use to treat our patients.

Brittany Harvey: Excellent. Those are great points. So, then finally, to wrap us up, Dr. Davidson, in your view, how will these guideline recommendations impact patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: Well, Brittany, I think one thing we hope, of course, is that those patients will cumulatively have a longer survival, and a better survival as a consequence of all of these new insights that we've been able to make.

I can imagine it would be maybe a little confusing to patients that there are so many things that they might potentially be able to choose from, but this is one where I think that the larger the panel of agents that you have available to you, the happier it is.

So, I hope that patients are going to look at this as an opportunity for partnership with their oncologists to try to figure out of all these possibilities, what's the best one for me now, and they're going to have the comfort of knowing that there'll be other things that they can fall back on in the future, and that, hopefully, these things will improve outcomes. And again, without excessive toxicity.

This last thing I'm going to hope that clinicians and physicians will remember is that we've made a lot of headway here, but that our results are not perfect. And so, right now, we're able to change guidelines, these guidelines today because of clinical trials that have been put together in the last several years and successfully implemented. And I hope that we're going to continue to do that because until we get to a point where survival from HER2-positive breast cancer is 100%, we've got work to do. So, they're going to be other new clinical research strategies, and I hope that doctors and patients will take advantage of those whenever possible.

Brittany Harvey: Absolutely, both hoping for longer survival and better quality of life and looking forward to more clinical trials to give clearer answers. I want to thank you both so much for your time today and for all of your work on updating these guideline recommendations, Dr. Davidson and Dr. Giordano.

Dr. Nancy Davidson: Thanks, Brittany.

Dr. Sharon Giordano: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guideline Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines.

There's a companion guideline update on the management of advanced HER2-positive breast cancer and brain metastases also just published in the Journal of Clinical Oncology and on asco.org. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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Guests on this podcast expressed their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.