In this expert roundtable series, Ruta Rao, MD, Rush University, Chicago, Illinois, leads a 3-part panel discussion on the management of patients with HER2-low metastatic breast cancer with William Gradishar, MD, Northwestern University, Chicago, Illinois, and Seth Wander, MD, PhD, Massachusetts General Cancer Center, Boston, Massachusetts.

In the first part of this discussion, our experts share how they identify patients as HER2-low, and about their use of trastuzumab deruxtecan in this population, including data presented at the 2024 ASCO Annual Meeting.

Transcript:

Ruta Rao, MD: Welcome to the Oncology Learning Network. My name is Ruta Rao and I'm a professor of medicine in the Department of Hematology and Oncology at Rush University Medical Center. It is my pleasure to moderate today's discussion on HER2-low metastatic breast cancer.

I'm joined by a distinguished panel of experts in this field. Would each of you like to introduce yourselves and tell us a little bit about you? Why don't we start with you, Bill?

William Gradishar, MD: Bill Gradishar, I'm from Northwestern University in Chicago, professor of medicine and focus on breast cancer.

Dr Rao: And Seth?

Seth Wander, MD, PhD: And I'm Seth Wander, I'm a medical oncologist at the Mass General Cancer Center in Boston, also focused on breast cancer and it's a pleasure to be with everybody today.

Dr Rao: Welcome, everyone, and thank you for joining us today. As we start, I think it's useful to remind ourselves of the progress we've made in treating patients with breast cancer. We know that overall mortality is declining, and we can attribute a lot of this to improvements in early detection and screening.

In addition, we have seen improvements in overall survival in metastatic breast cancer, in large part due to the novel therapies we're seeing, including CDK4/6 inhibitors, targeted therapies for ESR1, PIK3CA, the PIK3CA/MTOR/AKT pathway, and the antibody drug conjugates to name a few.

We're going to start today's discussion on [trastuzumab deruxtecan] T-DXd in HER2-low metastatic breast cancer. Can you tell us how you identify a patient as HER2-low? Seth, do you want to start?

Dr Wander: When we think about HER2 expression, traditionally up until a couple of years ago, I would say we viewed it as a dichotomy: positive or negative. But just like with estrogen receptor expression, it exists across a spectrum. And so, a large percentage of the majority of traditionally hormone receptor-positive, HER2-negative tumors actually have low levels of HER2 expression. In our practice, generally we would view that as an IHC of 1 to 2 with negative [fluorescence in situ hybridization] FISH analysis.

Dr Rao: Based on that, can you talk to us about your current use of T-DXd in HER2-low metastatic breast cancer, based on the DESTINY-Breast04 (DB-04) study?

Dr Gradishar: DB-04 really changed how we approach patients with breast cancer broadly and then of course in that entity that we now consider HER2-low. As Seth was saying, the testing we had was basically to tell us “are you high or something else?” Because the test is really to determine whether you're HER2 IHC3+ and you're a candidate for trastuzumab and those kind of therapies. This entity of HER2-low really didn't exist. Now, we appreciate that there's some level of expression in the majority of patients. And probably there's only a small fraction of patients that don't have any expression at all, where they may not be candidates for a targeted therapy like T-DXd.

To your question, DB-04 really changed, I think, how most oncologists treated patients almost overnight. And the magnitude of the benefits seen in that trial, both from the standpoint of [progression-free survival] PFS and overall survival, was not only clinically meaningful and statistically significant, it was a real impact in how we take care of patients and I think it was widely adopted almost immediately.

Dr Rao: Right. And what line of therapy do you use that in, based on this trial?

Dr Wander: Looking at DB-04, traditionally for hormone receptor-positive, HER2-low disease we would wait until the patients are endocrine-refractory. Typically, they've had an aromatase inhibitor with a CDK4/6 inhibitor. Often, they've had fulvestrant or a fulvestrant-based combination if they have a targetable alteration in, for example, PI3-kinase or AKT, and at least one line of chemotherapy, based upon the DB-04 inclusion criteria. In our practice, most clinicians will probably use capecitabine, just given ease of administration, but I think you have multiple choices there that you could use. And then if the patient is HER2-low based upon the criteria we just discussed, we would think about trastuzumab deruxtecan in that context.

Dr Gradishar: And I would agree with that. And I think what we've probably all seen is a creeping phenomenon — although we try to stick with the criteria of the trial, we have seen patients and perhaps we've done it ourselves on occasion, but beyond what the criteria were to enter the trial, some patients get it earlier.

Dr Rao: Right, so that's a great lead-in actually to our next question. We heard some really exciting data this morning from the DESTINY-Breast06 (DB-06) trial. Seth, do you want to talk about the design of that trial?

Dr Wander: Yes, to follow up on Bill's analogy, we're moving backwards along the treatment algorithm for the DB-06 study, very similar to DB-04, over 700 patients, prospective phase 3 hormone receptor-positive patients with either HER2-low or what we're now going to call HER2-ultralow. Ultralow would be somebody who has an IHC score of 0, but has some membranous expressions — not completely 0 in terms of the eyes of the pathologist, but wouldn't traditionally meet criteria for 1 or 2. DB-06, very similar to DB-04, looked at these patients who had become endocrine refractory, but unlike DB-04, had no prior cytotoxic chemotherapy. They were randomized to trastuzumab deruxtecan, or chemotherapy of clinicians choice.

Similar to what we saw for DB-04, we saw a very significant magnitude of progression free survival benefit on the order of approximately 8 to 13 months. When we look across that study population, if you look at the entire population, or if you look at just the HER2-low traditionally, or if you look at the HER2-ultralow, the magnitude of benefit appeared to be very similar, again approximately 8 to 13 month progression free survival.

The HER2-ultralow population here was relatively small, about 70 to 75 plus patients in each arm compared to an overall study population of over 700. So, I do think we need to interpret that data with some caution and I'm curious to hear what both of you think about these traditionally HER2-0 patients where we really haven't had a good chance to look at this in a large prospective context yet.

Dr Gradishar: One of the trials that came up as the discussion went on was the previous DAISY trial that looked at different levels of expression of HER2 and there was a gradient sort of effect, that as the level of expression declined the response rate declined. I don't think it's necessarily surprising. And then I know that in the panel discussion this morning, there was a point brought up about, is there any reason to think if you were totally absent any expression you might benefit? And they referred to cell line data that failed to demonstrate any effect. But if you get beyond [HER2] 0-0, there's probably some benefit from this drug, if you have some level of expression.

Dr Wander: I think this also brings up the interesting philosophic point about targeted therapy.

We think of these [antibody drug conjugates] ADCs as targeted therapy, but when we talk about sacituzumab [govitecan], we talk about trastuzumab deruxtecan, we're really in a situation, at least that we're moving toward, where you don't really need to test for the theoretical target. And so how specific, how targeted are these agents, in comparison to example, for a PI3-kinase inhibitor or a next-generation oral selective estrogen receptor degrader? I think we're entering the realm of kind of philosophic discussion, but it's an important concept because we have to talk to our patients about this. We have to describe these drugs. In some cases it's targeted therapy, in some cases more like conventional chemotherapy. I usually describe them as something in between. They're probably more toxic than some of your traditional oral, obviously anti-estrogen agents or even targeted agents, and they're probably less toxic than some of your combination IV cytotoxic chemotherapies.

Dr Gradishar: And based on the data we're getting now, it's becoming a diminishing fraction of all patients who might not be a candidate, because if you look at the numbers with [HER2-]ultralow, it was starting to get into the 80% plus range.

Dr Rao: In the hormone receptor positive, traditionally HER2-negative subgroup.

Dr Gradishar: Right.

Dr Rao: When you go back to clinic next week, how are you going to identify your HER2-ultralow patients?

Dr Gradishar: Part of this is going to be incumbent on pathologists having an appreciation of these data. It was a little bit of an ask for them to be looking at HER2-low, because it was sort of a reflex: “you're not HER2 IHC3+, so what does it matter?” Now we're asking even more of them, to look in a more refined granular way and at first we're going to have to be educated in our community that this will potentially be a drug, I assume it'll be approved for this indication broadly, that we have to make sure the pathologists understand this and start reporting it out. The ASCO guidelines don't really capture this. I suspect that that'll change.

Dr Rao: Now we have the option, based on this trial, to consider this in our first line. How will that change your practice, your treatment algorithm for these ER-positive patients?

Dr Wander: I think this is a really important question and the data of course is quite compelling, and it's great to have these options for our patients. I think tomorrow in clinic, and I will be in clinic tomorrow, we have to practically think about this and make some decisions.

Of course, for hormone receptor-positive patients, we want to try to exhaust all of our endocrine-directed therapies and easily tolerated oral agents. Then the question becomes, you have a patient who's failed aromatase inhibitor, fulvestrant, CDK4/6 inhibitor, or maybe PI3K pathway inhibitor. Based on this data, it would seem quite compelling to think about reaching for trastuzumab deruxtecan. I think the counterargument, of course, has always been, we have drugs like capecitabine that are oral, they don't cause alopecia, patients don't need to come in all that frequently, although I guess it would be a similar cadence every 3 weeks or so. And I think there'll be some debate about which patients might be better suited for this oral agent, which patient might need to go quicker to an IV.

We're moving forward into a world where we're really trying to focus on precision oncology. And we need to develop better, not just qualitative, but quantitative genomic molecular assessments to make good decisions about which patients are likely to need some of these more aggressive IV therapies sooner.

When you think about, for example, the EMERALD study, the CAPItello-291 study, you see this quick drop-off in the curves of anywhere from 20% to 40 % of the patients, truly endocrine refractory regardless of kind of which arm you're using on the study. You would imagine those types of patients are good candidates for perhaps earlier use of a drug like trastuzumab deruxtecan, and having better tools to identify these patients is a key priority for our work in the translational research space.

Dr Gradishar: One of the comments that was made in the presentation when they looked at the data for what happens to people after CDK4/6 inhibitor therapy, whichever path you take, is the PFS and whatever comes next isn't that robust or long. That said, I still think that many people people are probably going to stick to endocrine therapy for a while, but as Seth was saying, the data from this is pretty compelling. It’s going to jump over in terms of duration, anything that we see with any of these other options. What we've typically learned, whether we were talking about ADCs in sequence, or endocrine therapy in sequence, the more you give them, the PFS starts to diminish.This one is sort of long. There could be a compelling argument for specific patients.

The other piece though of course is you have to talk to patients about the difference between an oral, an IV and the side effect profiles.

Dr Rao: Let’s actually round out this discussion by discussing the side effect profile of T-DXd. What do you find is the hardest thing for patients to tolerate?

Dr Wander: It's generally a well -tolerated drug in clinic. Alopecia can be quite variable. I'm curious if you've all had experience with cold caps in this situation, it's something we've been looking into a little bit. Patients can have some GI toxicity. Patients can have some cytopenia, again, depending on the degree of prior therapy. As we move these drugs earlier, we're going to, I think, run into less toxicity in some of these areas that we've been experiencing when we were using it more fourth, fifth, sixth line of therapy. Because it has Herceptin (trastuzumab), we have all the things we need to watch for in terms of Herceptin: cardiac toxicity, echocardiograms, things like that.

Dr Gradishar: And then of course the thing we always think about in the back of our mind is [interstitial lung disease] ILD, or pneumonitis, that could develop. Fortunately, it hasn't been common, but it can be devastating when it does happen, it can be lethal. But that's always in the back of every clinician's mind. I would agree that the most common things are generally things we can manage pretty well.

Dr Wander: And I think the ILD story is interesting. When the drug was first developed, we saw what appeared to be higher rates of more severe ILD toxicity. And I think as a community, as we become more aware of it, we know to watch for it on the scans. We know to react quickly. We know patients who might need steroids or pulmonary intervention, dose reductions, things like that. As time has gone on, we've had more experience, we're looking at this drug in larger phase 3 studies. The rate of high-grade pneumonitis has actually been significantly lower than what we saw in the initial phase 2 estimates. And I think that's a testament to imaging and sort of being more cognizant of this potential risk.

Dr Rao: Well, thank you both so much for that really robust discussion of T-DXd in the HER2-low and now -ultralow categories of patients. We really appreciate you sharing your insights and thank you to the audience for watching.

Please join us now for part 2 of this discussion, where we will explore sequencing of ADCs in metastatic breast cancer and a newer ADC, [datopotamab deruxtecan] Dato-DXd.

Sources:

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously-treated HER2-low metastatic breast cancer. N Engl J Med. Published on June 5, 2022; 387:9-20. doi:10.1056/NEJMoa22036

Curigliano G, Hu X, Dent R, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Presented at the 2024 ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract LBA#1000.

Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: The phase 2 DAISY trial. Nat Med. 2023;29:2110-2120. doi:10.1038/s41591-023-02478-2