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At the San Antonio Breast Cancer Symposium, researchers presented updates from two phase III trials -- PHOEBE and -- that could change the treatment landscape for patients with metastatic HER2-positive breast cancer.

In an updated analysis of the PHOEBE trial, two-thirds of patients treated with pyrotinib plus capecitabine were alive after 2 years compared with 58.8% of those on lapatinib (Tykerb) plus capecitabine, while an exploratory analysis of the DESTINY-Breast03 trial showed that trastuzumab deruxtecan (T-DXd; Enhertu) led to prolonged progression-free survival (PFS) and higher responses compared with trastuzumab emtansine (T-DM1; Kadcyla) as second-line therapy in patients with and without baseline brain metastases.

口袋女优 brought together three expert leaders in their field -- moderator , of UT Health San Antonio, , of the University of Rochester Medical Center in New York, and , of Northwestern University Feinberg School of Medicine in Chicago -- for a virtual roundtable discussion on these two studies and other practice-changing data from the meeting. This is the final of four exclusive episodes.

Following is a transcript of their remarks:

Kaklamani: Hello. My name is Virginia Kaklamani, professor of medicine at UT Health San Antonio, MD Anderson Cancer Center, and leader of the breast cancer program. Today I have with me two esteemed colleagues: Dr. Ruth O'Regan, who is chair of medicine at the University of Rochester; and Dr. William Gradishar, who is the chief of the division of medical oncology at Northwestern University. We're going to be talking about the San Antonio Breast Cancer Symposium 2021 highlights and themes.

So our last topic today is going to cover HER2-positive metastatic breast cancer. And obviously, the past few years we've seen an explosion of new drugs that we have now to use for our patients. And there were three presentations that I wanted to highlight.

The first one was the results from the PHOEBE trial looking at pyrotinib in combination with capecitabine. And then the other two trials looked at brain metastasis and the data from the DESTINY-Breast03 trial focusing on brain metastasis as well as some updated data with the tucatinib [Tukysa] again with brain metastasis.

So Dr. Gradishar, can you walk us through these trials, but mostly walk us through how you approach a patient in the metastatic HER2-positive setting. Let's say they've finished their first-line therapy with the of a taxane, trastuzumab, and pertuzumab (Perjeta).

Gradishar: So I think we now have data based on DESTINY-03 showing that T-DM1 has sort of -- I wouldn't say been kicked to the curb -- but it's been moved downstream a little bit. And T-DXd appears to be a very active drug, and the big discussion, maybe 6 or 9 months ago, is it all hinges on whether patients have brain mets or not. Because the data with T-DXd in the setting of somebody with brain mets, there was sort of a paucity of available data, although there were some hints that there would be activity.

So the updated data that Sara A. Hurvitz, MD showed from the DESTINY-03 trial, showed that for inpatients that did have brain mets, there was an equal likelihood of benefiting overall. So if you look at that subset of patients that develop brain mets or had brain mets, they seem to reap the same degree of benefit as patients without brain mets. But equally important is if you look at the fraction of patients with brain mets and sort of drill down, did they respond intracranially? It also appears that there is an effect there as well.

So this is somewhat contrary to what we've always thought, that big molecules don't get into the brain. You know, trastuzumab shouldn't work, T-DM1 shouldn't work. None of these antibody drug conjugates should work. But nonetheless, we have a fair bit of data now that does demonstrate that whether you're looking at the , or whether you're looking at DESTINY 03 for T-DXd, there is a rationale for considering these drugs, even in patients with brain mets.

And the trial was clearly something that was very important, because it made an overt effort to recruit patients with brain mets. And that really demonstrated clearly not only for the overall population, but specifically in those with brain mets, that there clearly was a benefit with the addition of tucatinib. And that was reaffirmed with the updated data.

Do you want me to comment on PHOEBE?

Kaklamani: Yes, please.

Gradishar: So PHOEBE -- again, the investigator should be commended. It's a small molecule, pyrotinib, small HER2-targeted agent. I guess what the question that's raised by looking at the trial is it's capecitabine lapatinib versus pyrotinib plus capecitabine. So it's a battle of two regimens that we don't use a lot of anymore. So I think the issue becomes, at least in the U.S., are those results going to be relevant?

Now, what the results did show is that the investigational drug pyrotinib clearly was superior. There was a big separation between the lines, response rate was better, PFS was better, everything was better. But when we have drugs like tucatinib as an alternative small molecule with more mature data, including in the brain, we have T-DXd and we have other drugs coming. The question would be, where would we place it even if it magically was FDA approved tomorrow?

Kaklamani: And you know, Dr. O'Regan, you and I have visited China to help educate some of the physicians, and it's interesting when they go down the treatment pathway to realize that some of these drugs are just not available there. They have pertuzumab, they just received T-DM1. They had lapatinib, but T-DXd they don't have, tucatinib they don't have. And so pyrotinib for them, I think, is a big deal, right?

O'Regan: Yeah, I think so. And you know, it is tyrosine kinase inhibitors. So again, for patients with brain mets, you would imagine it would have some activity for sure. So yeah, I would assume that they put it after T-DM1, but again, if a patient has brain mets, maybe they would use it earlier than that. But yeah, it's kind of where we were a few years ago -- actually, was it a year ago? Right. All these agents were approved so recently. So lots of choices, which is just awesome.

Kaklamani: And so the two trials that we discussed, the DB03 [DESTINY-Breast03] and the HER2CLIMB, the difference in brain mets was that HER2CLIMB included also active brain mets, whereas the DB03 only included stable brain mets.

So if the two of you have a patient with newly diagnosed, let's say multiple brain metastases, that you either have the opportunity to do whole brain radiation or give systemic therapy, how would you decide on what to do?

Gradishar: Well, I guess it's like it's in the eye of the beholder. So I mean, if their most impending catastrophic thing that's gonna happen is related to their brain, I'd probably give them radiation. Just for what would I hope would be a more immediate effect. If they've gotten prior radiation or they're more stable with respect to the pace of their disease and the CNS [central nervous system], then as good as the T-DXd data is in somebody with active brain mets, if I was choosing a systemic therapy, I would choose a tucatinib-based regimen based on what we know today.

O'Regan: Yeah. I agree with that. It was the only study that had active brain mets, so I would choose tucatinib as well in that scenario. But I do think the data with the T-DXd is definitely very encouraging in the brain. So it was nice to see that.

Kaklamani: Now when you do cross trial comparisons, which we always hate doing, but we always end up doing, the PFS in those stable brain mets were actually pretty similar between the two trials, which again is encouraging for T-DXd. And the only other last abstract, I just wanted to point out for our audience that they should look at, is an abstract on -- again, not a large number of patients, but really the first data that we have looking at leptomeningeal disease.

So I want to thank both of you for today's conversation. I appreciate you being here, and thank you. Thanks to the audience for listening.

Watch episode 1: Latest on Immunotherapy in Triple-Negative Breast Cancer

Watch episode 2: Study Shows Promise for Oral SERD in Breast Cancer

Watch episode 3: Using Genomic Profiling to Select the Right Therapy for Metastatic Breast Cancer

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