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The antibody-drug conjugate trastuzumab deruxtecan (T-DXd; Enhertu) significantly improved progression-free survival (PFS) versus chemotherapy in previously treated metastatic hormone receptor (HR)-positive/HER2-low/ultralow breast cancer, according to a randomized trial presented at the American Society of Clinical Oncology (ASCO) annual meeting.

番茄社区app brought together three expert leaders in the field: Moderator Hope S. Rugo, MD, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, is joined by Joyce O'Shaughnessy, MD, of Baylor University Medical Center, Texas Oncology, in Dallas, and Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in Boston, for a virtual roundtable discussion. This first of four exclusive episodes focuses on the DESTINY-Breast06 (DB06) results.

Following is a transcript of their remarks:

Rugo: Hello, I'm Hope Rugo, breast medical oncologist from the University of California San Francisco. And I'm here in Chicago, Illinois, at ASCO 2024 for a roundtable to talk about some of the most exciting data that came out in breast cancer, both early- and late-stage disease, on behalf of 番茄社区app. I'm here with my two colleagues and friends, Joyce O'Shaughnessy and Sara Tolaney. Tell us about yourselves.

O'Shaughnessy: Hi, Hope and Sara, good to be here. I'm a breast medical oncologist at Baylor University Medical Center, Texas Oncology, and the Sarah Cannon Research Institute in Dallas, Texas.

Tolaney: Very nice to be here with both of you guys. I'm Sara Tolaney, I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston.

Rugo: Thanks so much for joining me. We've had a lot of discussions here about some exciting but controversial data. I think some of the data this year that's most practice changing also has some controversies associated with it. So let's start with DESTINY-Breast06, which I think was the most hotly awaited topic, looking at trastuzumab deruxtecan in both a large first-line chemotherapy trial in hormone receptor-positive, HER2-negative breast cancer in both HER2-low as well as this new group called ultralow. Sara, tell us about DB06. What did you take home from that presentation?

Tolaney: It was a really very anticipated study. We've had DB04 telling us we can use T-DXd in metastatic hormone receptor-positive patients that are HER2-low. So 1 plus 2 plus not amplified, but there are patients who've had one or two prior lines of chemotherapy. And so here now, DB06 was trying to move things earlier. So it's taking patients who've progressed on endocrine therapy and are receiving treatment for the first-line setting with their first chemo and they're randomized to T-DXd or choice of chemotherapy where chemo was either capecitabine or taxane.

And I think the results were very impressive. It showed that it improved progression-free survival from about 8 to 13 months. So I think getting over a year of PFS in the T-DXd arm was pretty remarkable. And then they had this really interesting subgroup of about 150 patients that were ultralow, meaning that they're not a HER2-0, meaning they don't have absolutely no staining. They're not 1+, but they've got a little bit of faint staining that's somewhere between null and 1+, so somewhere between 0 and 1. And that cohort showed very similar data. So if you look at the PFS numbers, the response numbers, they're identical in essence to the HER2-low group.

I think the caveat there is that the numbers are small, so the precision around those estimates is not as tight, but definitely shows that the direction of benefit seems to be very much like the HER2-low.

So I think the question's going to come back as to what do we do with this? Are we all going to give T-DXd as the first-line treatment? And I don't know what you think, Joyce and Hope, but I think it's very remarkable and I think practice changing and offers this as a new standard approach for most and many of our patients.

But I think it doesn't address maybe every single patient because in the trial there are only 3% of patients who are bone only. I think this is great for someone who maybe had rapid progression on endocrine treatment and has a lot of visceral disease where you want to get a rapid response, T-DXd is perfect, but it does have some toxicities. And so I think balancing that is always important. So nice to have another choice, but for some, maybe capecitabine is also a reasonable alternative.

Rugo: Joyce, did you take the same take-home message from DB06?

O'Shaughnessy: Yes. I'm thinking about those patients that had the heavy tumor burden or just very symptomatic, the ascites, the recurrent pleural effusions, the severe lytic bone disease, and okay, what are you going to give those ladies when you need that fast response? And the response rate was 60%, clinical benefit rate was around 80%. It usually is even higher, so 80+ percent of patients really getting a rapid response.

I think it's really, really a nice option because right now, before this, we would go on to some other single-agent chemotherapy, or if they were really in trouble, a doublet. But this really is superior and it works very, very quickly. And we also know once women get used to it after a couple of cycles, generally speaking, it's a good quality-of-life drug. Sometimes they need a little prolonged olaparib (Lynparza) in the evening or something like that, but most don't.

But it's not going to be for absolutely everybody. There are some of our older patients with very, very indolent disease. You don't want to give them an IV therapy. You want to keep them on pill therapy for as long as you possibly can because they're going to respond to whatever you give them basically. So it's not for everybody, but it is a really good addition. We have a lot of symptoms and we see after CDK4/6 progression, we see some symptoms on these ladies and some are very difficult to get any kind of durable benefit for them.

Rugo: And it is interesting, there's so little bone marrow suppression in those patients. I was worried that people would be so excited about T-DXd that they would just go right after CDK4/6 inhibitor, but actually patients had two median lines of endocrine therapy. So, that was kind of encouraging. I think it is really mostly, except for the lack of bone-only soft tissue disease, a patient population we do see. Also, I think it was a little sobering to see that three patients died of ILD [interstitial lung disease], but it was helpful to find out that those were older patients, really considerably older. One got a dose after she had diagnosed ILD because they didn't see the scan. And then two patients were treated with less than the recommended dose of steroids.

So I think that there were real explanations, so that was kind of encouraging. Really a big advance, I think, in trying to improve outcome for our patients. It'll be interesting to see about the sequencing question and what happens when we sequence other drugs. So that will be data to follow as we go forward.

O'Shaughnessy: The ultralow issue kind of on Monday morning is an interesting one because there's no guidance from ASCO-CAP [College of American Pathologists] on this. And so docs are going to be seeing a lot of 0's and really wondering, I think rightly so, if they have any wherewithal, they have the ability to get an accurate read on this ultralow. And so I think docs will probably end up giving the T-DXd to patients that are 0's because they're not going to really have the ability to get that precision on it. And think about it, it goes down to 1% of cells, 1+ positive.

Rugo: But I think our pathologists can tell us 0 to 1+, that there's a range. They do it with ER [estrogen receptor]. I think there just was so much of a bias against HER2 because of the need to define HER2 positivity that meant you responded to trastuzumab. So there's a bias against reporting sort of a little range. I mean, ER, they reported 3%. So it seems to me that they have to sort of get around the definitions that have been created.

O'Shaughnessy: I mean, plasma membrane staining is not circumferential because the nuclei being brown. But anyway, it's...

Rugo: You're right that it looks different.

O'Shaughnessy: It's a new thing. You know what I mean? It's new and it's just docs don't want their patients deprived of it if they're really symptomatic and they really have to have a go-to. My only point was if you've got 1% of cells, 1+ positive, that's HER2-ultralow. It's not 0 -- well, of course it's 0. That's no different than 0. So it's splitting, really slicing the salami very, very thin, trying to separate these categories.

Rugo: It is indeed slicing the salami thin. We'll talk about that more later, but I think a lot of people are going to bug their pathologist to say, can you see a little staining there?

O'Shaughnessy: Please, please, yes.

Rugo: That will help.

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