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Experts Discuss ADCs for HER2-Negative/Ultralow/Low MBC

[00:00:00] Hello, and welcome to the Dera Clinical Education Oncology Podcast. I'm your host, Ryan Topping. Today's episode features Dr. A Baria from the Geffen School of Medicine at the University of California in Los Angeles, California, and Dr. Ruta Rao from the Rush University Medical Center in Chicago, Illinois, as they discuss antibody drug conjugates for HER two negative ultra low and low metastatic breast cancer, including contemporary HER two expression classifications, optimal use of ADCs and best practices in patient communication.

This episode is part of a larger educational program titled Integrating ADCs into Patient-Centered Management of HER Two Negative Ultra Low and Low Metastatic Breast Cancer, enhancing the Patient Provider Therapeutic Connection For more information, along with a link to the larger educational program, please visit the show notes [00:01:00] for this episode.

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

Hello everyone. I'm Aade Yia medical oncologist at UCLA, and look forward to the discussion today. And I'm Ruta Rao, a breast medical oncologist at Rush University Medical Center in Chicago, and I'm pleased to be here with you all today. Excellent. Uh, thanks Dr. Rao. Um, let me set the stage.

Why don't we talk about her two low, HER two ultra low, and what does her two expression essentially mean in metastatic breast cancer in 2026? Yeah, it's a great question and I think this is a, uh. A definition that has really evolved over the last few years. Um, previously we used to think of her two classification in a very binary, um, way.

It was either her two positive or a patient was her two negative. But today we have these classifications of her two ultra-low and her two [00:02:00] low. Um, I apologize, I let me, my phone went off, but I had put it on do not disturb. Let me say that again. Um, but today we have, um. Newer classifications. We know that our patients who are traditionally thought to be her two negative can be reclassified as her two low, HER two ultra low, or HER two null, which is truly zero.

And this is really important for us to know about a patient's tumor because. It can make them eligible for treatments. Um, specifically for Trastuzumab Deruxtecan, which is now approved in the setting of her two low and HER two ultra-low, um, ER-positive metastatic breast cancer. Absolutely, it's been a game changer because previously we were looking at HER two positive and negative for uh, trastuzumab, but her two negative does not necessarily mean that there is no expression of her two.

So if we go back [00:03:00] and look at our classification for her two, her two positive was defined as immunohistochemistry three plus, or. Two plus along with fish amplification, but one plus, uh, which means that there is her two expression, uh, was classified as her two negative. But now we have this new category of her two low and even her two zero.

Technically was tumor cells that have either no expression or zero to 10% of tumor cells having some. HER two expression was classified as HER two I to zero, but zero is not necessarily 0%, and that's this new classification of HER two ultra low, where one to 10% of tumor cells have some HER two expression.

So it's really been a game changer. Um, Dr. Rao, have you had pushback from oncologists or pathologists in terms of if there's a tumor that's, say her two IC zero or HER two IC one plus trying to reclassify that as ultra low or HER two low. [00:04:00] We really in clinical practice have not had that pushback. Um, we did have to make an effort to discuss and educate our pathologists about trying to define especially the category of her two ultra low.

Um, you know, the patients who are zero but have this, as you mentioned, um. One to, to less than 10% expression of HER two because otherwise, these were patients who were, um, classified as her two zero. And so to ask them to go back or now in our pathology specimens that they report out, now we're asking them to report zero or zero plus.

And once we kind of had this discussion with them, it was, um, it was pretty straightforward, but I think it was a matter of educating them. They're always trying to help us out in terms of. Finding new treatments for patients. So, um, they were more than willing to do it, but it was, it was just letting them know why it makes a difference to us clinically.

That's a great point. Um, and that's, you know, education so that, uh, the team is [00:05:00] aware that this is a new category and it's important because that's actionable. So that's a message for, uh, practitioners, providers, oncologists, the. That if there's a patient who has her two negative disease or you see a prior specimen, that's her two IHC zero zero does not mean 0%.

Then it's important to evaluate and see if that could be ultra low, um, because that's potentially actionable with newer therapies, particularly Trastuzumab, dutan. Uh, any final thoughts, uh, related to this topic, Dr. Rao, before we move on? Yeah, I think, you know, one other thing I think about when I'm seeing these patients with metastatic breast cancer is that we do have some heterogeneity in their different tumor samples.

So oftentimes you might have a patient who had a biopsy that has some her two, uh, defined on it, uh, a mastectomy or lumpectomy specimen, and then a specimen from their, um, metastatic disease diagnosis. So. I would like to identify any patient [00:06:00] who's eligible for this. So in my practice, I'll look at any of these specimens to see if there's any HER two low or HER two ultra low expression in any of them, and then consider the patient eligible.

Great point. Great point.

Great. So let's move on. Um, Dr. Baria, and I'd love to get your thoughts about, um, antibody drug conjugates. Uh, we've seen these really take over, um, in terms of treatment of our metastatic breast cancer patients. So maybe we can start by talking about an antibody drug conjugates in the, uh, ER-positive metastatic breast cancer space.

Um. Absolutely these are slowly replacing chemotherapy. So if you look at management of ER-positive metastatic breast cancer, usually we use endocrine based therapy, CDK four six inhibitors, uh, oral ERDs. If a patient has ESR one mutant disease. P three kinase, a KT inhibitors for patients who have [00:07:00] alterations in the P three kinase, uh, pathway in the tumor.

But then after a patient has disease progression on endocrine based therapy, we usually go to chemotherapy, and that's where antibody drug conjugates come in. The current ADCs we have are essentially targeted chemotherapy. They have an antibody that binds to an antigen that's, uh, over expression tumor, and then deliver the payload, which is a chemotherapy agent.

There are three that are f FDA approved at this time. Trastuzumab Dutan, sacituzumab, go vCAN and Umab Oxetane. In terms of these different agents, um, it's important to know about HER two Low and ultralow because that's actionable with Trastuzumab. Oxetane in Know Pivotal Studies, destiny Breast oh four and Destiny Breast oh six essentially showed that, uh, trastuzumab Oxetane or T dx t is superior to standard chemotherapy, be it irritable in naval being, or even oral capecitabine.

The progression-free [00:08:00] survival was much higher with TD XT as opposed to, uh, these, uh, standard chemo agents. So essentially that has replaced standard chemotherapy and in this, in these trials, patients with her two low and ultra-low disease were included. And that's why it's important to, uh, look at this.

And in these trials, any prior specimen that had her two lower ultra low. Was considered eligible for the trial. So it may not be the last biopsy, it could be the primary breast cancer specimen or a prior archival specimen. The other agents, uh, target trop two. So both sacituzumab, GOVI, Tecan, and Umab Cean target TR two.

So the HER two expression in a way does not matter because the drug targets trope two. So these are. Drugs that are approved both for her two low ultra low disease, as well as the small category of HER two IHC null, uh, or completely, uh, zero in terms of, uh, how to use these agents. I think these are all options to consider [00:09:00] generally given the significant results we've seen with TD xt.

Significant magnitude of, uh, overall survival improvement. Generally, TD XT is prioritized first, and then after that one is an option of using DA DXT or sg. But I'm curious to hear from you as well, Dr. Rao, you know, given that we have these three agents, how do you use them? How do you sequence these drugs for patients with ER-positive metastatic breast cancer?

Yeah, I think, you know, having them available has really been, like you said, a game changer for our patients with metastatic breast cancer. Um, and. The issue we face in clinic is that we don't really have any data on how to sequence them. Um, I would agree with what you said, that in general, if a patient has her two ultralow or her two low expression, then Trastuzumab Deruxtecan is my first choice of a DC.

Um, if a patient is truly HER two null, then I think we really have our [00:10:00] choice between Datto DXD and sg. Um. In subsequent lines of therapy, I think what we've seen from some real world analyses is that sometimes there is some efficacy with a second a DC after a first one. But in general, we kind of get the biggest bang from our buck from the first A, d, C that a patient receives.

Yeah, makes sense. And partly speaks to potential cross resistance between these drugs because all the three FD approved ADCs in this space, da Dxt, SG, and T Dxt have similar payloads. It's identical with Da Dxt and tdx T, which is oxetane and even sacituzumab gov. Tecan the gov. Tecan and cean both are.

Top one inhibitors. So there's definitely some cross resistance because of similar payloads, and it's an open question at this time in terms of how to sequence these drugs. And I think one of the things is when a patient progresses on one, we're not quite sure if [00:11:00] they've become resistant to the antibody or to D target.

And so we know that, um, trastuzumab, uh, deruxtecan and dto DxD have the, have the same payload and dto, DxD and SG have the same antibody, the anti trope two. So I think that's yet another thing to think about when we're sequencing these. That's a great point. Absolutely. And I think we need more research in terms of trying to understand resistance related to these ADCs and how to sequence them, I guess, at this time.

Then the question becomes how do we select, say a patient receives TD XD and then has disease progression, how do we select between, uh, SG and DxD? I can talk about my practice. Often it boils down to the, uh, adverse effect profile. Um, these drugs have different AEs, so both SG and DA dxt are TR two ADCs with similar payloads, but the side effect profile is quite different.

Uh, SG or sacituzumab gov tecan, [00:12:00] the three most common AEs are neutropenia. Including grade three, grade four neutropenia rate of, uh, more than 50%. So one in two patients will have an A NC that's, uh, significant, that would need some intervention. The second is, uh, diarrhea. And the third is, uh, alopecia and nausea.

Vomiting is also seen, but often can be managed with, uh, three drug antiemetic regimen. In contrast with DA ODXD, it's mucositis. That's the number one side effect. Usually you need, uh, steroid mouthwash for primary as well as secondary prophylaxis can also cause keratitis and very rarely, um. 1% or less can cause uh, significant pneumonitis as well.

Uh, the schedule is also different. Sacituzumab, govi, Tecan is day one, day eight, every 21 days, and ro dxt is every three weeks. So if have to choose between SG and ro dxt, given that efficacy looks similar, it's often the [00:13:00] schedule as well as side effect profile. That helps me, uh, discuss this with the patient and then, you know, select one option.

How about your practice, Dr. Rao? I would agree with you a hundred percent. I think, you know, one of the things to think about with Datto, DXD, like you mentioned, it's really nice to have something that patients are only coming in once every three weeks for, but to prevent, um, the stomatitis, we do recommend using a steroid mouthwash four times a day.

And sometimes that can be really burdensome for patients. Um, and if they develop stomatitis, we know that that can be a, a severe side effect. Um, similarly. There's the ophthalmic side effects with, uh, Datto DXD, for which, uh, it's recommended to use eyedrops multiple times a day. And again, we have to make sure we have patients who will comply with these, uh, preventative measures so that they don't get severe side effects from this.

Dr. Baria, can you talk to us about, uh, using these antibody drug conjugates in first line triple [00:14:00] negative breast cancer? I think we've seen some recent data presentations in these settings. Yeah, absolutely.

Um, so Sacituzumab Govi, Tecan based on the ascent study previously was approved for second line and beyond metastatic TNBC. But Ascent O three and oh four evaluated sg with without immunotherapy in the first line setting. Then Trion Breast two two evaluated DA dxt in the first line setting for patients with metastatic TNBC.

And all of these trials are positive and essentially have moved these Trop two ADCs in the first line setting SG with without immunotherapy for patients with metastatic t, nbc, and then DA dxt as first line for patients with metastatic TNBC as well. And the question is how to choose between SG versus DA DxD.

Uh, and as we were saying, for ER-positive Disease, it's similar, um, based on side effects as well as the schedule. Day one, day eight, with the SG versus every [00:15:00] three weeks with data DXT.

Continuing on this theme in terms of patient counseling, uh, and Dr. Ra, you know, the team did a survey where they asked in terms of, you know, unmet need and what patients and patient advocates would like to hear about. And a common theme was, uh, how do we as oncologists, as providers discuss treatment options with patients and how do we counsel them on side effects?

So what's your, um. In your opinion in terms of or your own clinical practice in terms of discussing side effects with patients and counseling patients? So I think it's really important to be upfront with them because, uh, sorry. I think it's really important to be upfront with them about the side effects that they may experience.

Um, I try to go through it with the patients, but I think this is also a team effort. So I involve my clinical pharmacists. Um, as well as our nurses, uh, to talk to the patients about the side effects that they can expect. [00:16:00] Um, what supportive care measures to use, what preventative measures to use? Um, I think it's, it's the more education that we can give them and I, um, the more that we can encourage them to be in contact with us when these side effects.

Develop so that the side effects don't get very severe and we can step in and help them with management of the side effects. I think it's really just important to, um, to provide that education before they start the treatment. Yeah, no, that's a great point. And often, if you spend a lot of time in the first visit, it saves time, uh, during subsequent visits.

And it's also, you know, a good, uh, clinical practice to let patients know about potential AEs and potential mitigation strategies. So, for example, we were talking about neutropenia. When we talk about neutropenia, mentioning that there is a medication, GCSF. Pal Filgrastim or filgrastim one could use.

Similarly, when we talk about diarrhea, mentioning that there's loperamide one can [00:17:00] use, uh, talk about mucositis, talking about steroid mouthwash. So just whenever we're talking about AEs, also talking about the potential mitigating strategy, uh, is in general, uh, quite helpful. And the other point to make is that.

This is not just one time. The key is follow up. Uh, and often when you start a new medication, it's good to have a date follow up just to check in. And that could be with, um, uh, the nurse practitioner or the pharmacist, someone from the healthcare team. Uh, so just check in, uh, how the patient is doing. It could be a virtual visit as well.

It could be a phone call. But just, you know, when you start a new medication, having a short term follow up often can then help on, uh, maintaining compliance and adherence to these therapies. Uh, because if you're able to manage the AEs, uh, often patients would remain on the drug, but if they have significant AEs, that's where you have to discontinue.

And compliance could be an issue. Um, your thoughts, Dr. [00:18:00] Rao, in terms of compliance and adherence with these drugs? I think you're absolutely right. I think, um, you know, the main way we can get our patients to continue to be compliant and, and take these drugs again every three weeks or two weeks on, one week off, is to help them, uh, manage and mitigate the side effects.

Just like you mentioned. Fantastic. Fantastic. Well, this was a great discussion. We talked about the new HER two classification. We talked about newer therapies, ADCs, we talked about their side effects, how to select different ADCs and how to consult patients and, uh, help with adherence. Uh, really enjoyed the discussion.

Dr. Rao, thanks for joining. Yes, thank you. Me too. Thank you so much.

Thank you, Dr. Baria and Dr. Rao, and many thanks to you, our listeners, for joining us. As a reminder to view the full program integrating ADCs into patient-centered management of HER two negative ultra low and low metastatic breast cancer, enhancing the patient provider therapeutic connection. [00:19:00] Please click the link in the show notes and be sure to check back regularly for more episodes on Important to Sarah Clinical Education Oncology Podcast topics.