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Kathy D. Miller: Hi. I'm Dr Kathy Miller. Welcome to the Medscape InDiscussion podcast series on breast cancer and HER2. Today, we'll be discussing sequencing of the antibody-drug conjugates (ADCs) for metastatic HER2-low disease. Whenever we have new agents that enter our list of therapeutic options, it brings a whole host of questions, including when we use them. What's their activity after other therapies that patients have had, and what works in patients who had these new agents and are now progressing, which is even more complicated with the ADCs?
I am delighted to introduce you to my guest. Dr Stephanie Graff. Dr Graff is an associate professor in the division of hematology and oncology at Brown University and the director of breast oncology at Brown University Health in Providence, Rhode Island. Welcome to the Medscape InDiscussion: Breast Cancer and HER2 podcast, Stephanie.
Stephanie L. Graff, MD: Thank you so much for having me. I think today will be a fun discussion.
Miller: So just to make sure everyone is speaking the same language, can you remind us all, what are the ADCs?
Graff: Right now in breast cancer, the ADCs that we have approved are trastuzumab emtansine. It's only approved for HER2-positive breast cancer. I suspect you and I are not going to spend as much time talking about that one today. The other ADCs that we have approved right now are sacituzumab govitecan. Sacituzumab is approved for both HR-positive metastatic breast cancer and triple-negative breast cancer. Trastuzumab deruxtecan — T-DXd is our doctor slang for that — is approved now for HER2-low and HER2-positive metastatic breast cancer. Of course, HER2-low branches across those two cohorts of HR-positive and triple-negative breast cancer. So both groups are folded into that definition. Probably not so far out on the horizon is patritumab deruxtecan. That drug is not yet approved but has advanced down the clinical trial pipeline with good maturity, so I think maybe we'll be seeing it in the not so distant future, which I'm sure will be a part of our talk as well today.
Miller: Life has already gotten complicated here because we have three approved agents with overlapping patient populations. Two agents are approved for classically HER2-positive patients and one agent that was not specifically approved for HER2-low patients, but its approval encompasses patients that would be HER2-low.
We're going to focus on the ones that would be available for patients with HER2-low disease. That's a category that we didn't talk about until a few years ago. Who are the HER2-low patients that we're going to focus on today?
Graff: HER2 has historically been defined by, first, immunohistochemistry (IHC) and then in situ hybridization (ISH). IHC is done first. Patients' tumors score 0, 1, 2, or 3. Scores of 0 and 1 were considered negative. A score of 2 needed that ISH to be the tiebreaker. A score of 3 was positive. Patients that were a score of 2 had ISH, and it was either negative or positive. I realize there's a lot more nuance, but we'll keep it simple. If you were HER2+ and ISH positive, you were HER2 positive; and if you were IHC2+ and ISH negative, you are considered HER2 negative.
Now we use the language of HER2-low to talk about patients that have an IHC of 1 or an IHC of 2 who were then negative by ISH testing. More recently, at ASCO 2024, we saw that even some of the patients that are HER2 0 but still have some degree of membrane staining may also be HER2 ultra-low, because we just love to add new nomenclature to our wheelhouse here in breast oncology. They may also be responders for T-DXd, and so that HER2-low definition is creeping downward.
Miller: We have two agents in that group of patients. T-DXd has been specifically studied, and that group includes patients whose tumors may also be ER positive or ER negative. Sacituzumab, on the other hand, took a different path. It was first studied in the triple-negative patients, then studied in ER-positive HER2-negative patients.
But in both of those studies were patients who would have met the HER2-low definition. So, for HER2-low patients, we have two ADCs available. They have a similar payload, but different targets for specificity and delivery. How do you decide which of these two are you going to reach for first when you have a patient with metastatic HER2-low disease sitting in front of you?
Graff: I think it's a lot of shared decision-making. People are probably tired of getting that answer. But, sacituzumab govitecan and T-DXd have slightly different side-effect profiles. They have different dosing administration schedules. Depending on the time frame that the patient is diagnosed with a metastatic disease progression relative to their prior lines of therapy and their experience with prior lines of therapy in terms of side effects and toxicities that they may have experienced with those, all may fold into your thinking about which agent makes the most sense for that patient, or which agent the patient is willing to accept, based on the side effects, risk benefit discussion.
Right now, at least in the US, we have approval for treatment with HER2-low targeted therapy after progression on one line of systemic chemotherapy, which in the HR-positive space, means that we can use it slightly sooner than sacituzumab govitecan's approval which requires two or more lines of chemotherapy, including potentially adjuvant or neoadjuvant. But because of how HR-positive breast cancer is treated, it may mean that patients are eligible for T-DXd before sacituzumab. Sometimes you're also considering things like payer reimbursement and cost to the patient on your recommendation and how we're sequencing these agents.
Miller: So we try to focus on the medical aspects, because the approvals and insurance willingness to provide coverage and really how strictly they will require us to stay within the boundaries of the FDA approval tend to change over time. I've certainly had requests denied. A year later, I sent the same request to the same company for the same patient when there was no new data, and it was approved. I do think there's some shift and loosening of those approval requirements over time, even when our data might be lacking. Assuming both are equally available, and there are not those approval and financial barriers, who is the sort of patient who you would be preferring or trying to head her to T-DXd?
Graff: T-DXd was studied in this HER2-low population in the DESTINY-Breast04 trial. Obviously our listeners probably know that at this point. The DESTINY-Breast04 trial was mostly a HR-positive trial. I think that the strength of the body of evidence for T-DXd lies in that HR-positive patient population. The historically triple-negative population that was considered HER2-low and enrolled was a much smaller patient population. Now there's additional data from DESTINY-Breast that continues to develop from the DESTINY-Breast portfolio. But right now, I think that the maturity of the data is a little bit stronger for HR-positive patients. Patients were ineligible for the DESTINY-Breast trials if they had significant preexisting lung disease, because there is, of course, a risk for interstitial pneumonitis with T-DXd that has caused concern, particularly in some of the earlier work that was done. And so somebody with a lot of preexisting lung disease would be a red flag for somebody that perhaps I was steering away. It is an every 3-week dosing schedule. In my patient population, we have many patients that aren't excited about travel and are trying to minimize trips to the cancer center.
Sacituzumab govitecan is a day 1, day 8 schedule, so slightly more frequent infusions. That sometimes factors into our thinking on how we're sharing that decision about which is the right agent. The risk of neutropenia and diarrhea is higher with sacituzumab govitecan. For example, if a HR-positive patient had abemaciclib on monarchE as a part of their early stage disease and had diarrhea as a part of that experience — and now as they've progressed and moved into the metastatic space, or maybe they had abemaciclib as their CDK4/6 inhibitor in the first line setting — if they had diarrhea, they may not be willing to consider an agent that increases their risk of diarrhea.
Alternatively with T-DXd, patients have reported fatigue and nausea as more significant side effects that they are experiencing. And so, again, for patients where that is particularly cumbersome or upsetting as a side effect for them, it's a variable.
Risk of alopecia is higher with sacituzumab govitecan, and that's a factor for patients, too, as they're considering which drug they're going to choose in sequence. Often the first line chemotherapeutic that we choose will not necessarily lead to alopecia. So at this point, moving into that sort of second-line chemotherapy in the HR-positive space, patients often still have had maintenance of their hair for a long time through oral therapy and then first-line chemotherapy.
Miller: I want to focus on this difference between ER positive and ER negative for a bit, because you're absolutely right. But I think sometimes when people hear that, it can come across almost as if the DESTINY studies somehow stacked the deck by enrolling all these ER-positive patients. And that's just the reality of the biology.
But we talk about them as HER2-low, as if we've magically found this group that we've never looked at before. A few years ago, we would have said they were HER2 negative. If you just did a study of a chemotherapy in patients who were HER2 negative, who progressed on previous chemotherapy, you would expect 70%-75% or so of the patients to be ER positive, because that's more common.
So it is an interesting conundrum that, that is where the data is more compelling because the numbers are greater. But I think it's almost come across as a negative or people assuming it only works in the ER-positive patients.
Graff: That's an excellent point. I certainly do not think that the evidence suggests that T-DXd is an ineffective therapy in patients that are estrogen receptor negative HER2-low. If you consider that, “triple-negative breast cancer” is a small proportion of the total patient population with metastatic disease or breast cancer in general, if it's 10 to 15 to 20 percent of breast cancer, what was included DESTINY-Breast 04 is a representative sample.
I think the more complicated question is, particularly as you and I dive into talking about sequencing, if triple-negative breast cancer is a more mutagenic cancer, is a more proliferative cancer, how does the differences in things like payload, target, and exposure to prior lines of therapy alter your approach when it comes to a triple-negative breast cancer as opposed to a HR-positive breast cancer and also if there's a higher or lower degree of heterogeneity between a triple-negative breast cancer versus a HR-positive breast cancer.
Ultimately, that may not be true. It may be that many of the HR-positive patients in this space are much more luminal B and they've shifted to this more biologically aggressive phenotype and have many of those more triple-negative like behaviors that I just mentioned. But these are all those translational science questions that remain sort of unanswered while we're waiting out here, making clinical decisions in the trenches every day.
Miller: We did promise our listeners that we would tackle the question of sequencing. These are questions that we deal with every day. We frequently use chemotherapies in sequence. The recommendations are typically not to combine them, but to use them in sequence to get similar efficacy and minimize the cumulative toxicity.
So, with any new agent, we do have these questions of what works after treatment with this new agent. There are certainly patients in the community who've been treated with T-DXd and then switch to sacituzumab or who may have gotten sacituzumab first and then switch to T-DXd. Do we know anything about activity of one after progression on the other?
Graff: We have scant data, which is not the same as great data. We have seen sequencing data from real world evidence studies, notably the Massachusetts General Hospital (MGH) was able to present their experience with sequencing ADCs at one of the major conferences, and they had originally just presented that as progression-free survival (PFS) with ADC 1 as compared to ADC 2, not even necessarily telling us what ADC 1 vs ADC 2 was. What we saw was that PFS with ADC 2 was much lower than PFS with ADC 1, which is what we expect, right?
We think as medical oncologists that each subsequent line of therapy will be a little less good than our first line of therapy. We expect to get the most bang for our buck, for lack of a better description, with the earlier lines of therapy. So as we move through progressive lines of therapy, we're expecting less time on treatment, less response, less clinical benefit. When they broke that down for patients that transitioned from sacituzumab govitecan to T-DXd, or from T-DXd to sacituzumab, we saw what I'll describe as disappointing results regardless. But those were a very small number of patients. Again, real-world, single-institution data, which makes it hard to say, well, this is the clear way to approach that. We do have a handful of early analysis from both a great paper, that was again led by the MGH team, looking at clinical resistance pathways to sacituzumab govitecan in triple-negative breast cancer, as well as the biomarker analysis from DAISY, which start to give us some hints about how these resistance mechanisms may be developing and whether or not sequencing is going to be an effective option.
I think at this time, we're all getting uncomfortable that the primary mechanism of resistance may not be target changing, specifically in DAISY. Although HER2 expression may have slightly decreased, uptake of T-DXd for patients that developed resistance did not seem to be negatively affected. This suggests that the drug was still being delivered for patients that were no longer responding, which makes you suspect that it's more of a payload resistance that we're seeing with T-DXd that would immediately call into concern sequencing sacituzumab govitecan immediately after, because it's the same payload topoisomerase inhibitor. Not necessarily the exact same drug, but the same class.
In the sacituzumab govitecan resistance paper, they saw numerous competing developed strains of resistance in both the mutation of the receptor and alterations in the enzyme pathway that altered the payload. And so I think that there's probably very complicated resistance mechanisms across different diseases, whether that's HER2-low, estrogen receptor positive, or triple-negative breast cancer as they experience exposure to these ADCs.
Miller: So we think that the mechanism of resistance really becomes key here. And while we do have some limited data from these early efforts, that's a bit different because in the clinic, I don't have an easy way that I can say Mrs Jones became resistant because there was major change in the receptor expression. So I'm no longer delivering the target. But Mrs Brown became resistant because she's resistant to the payload.
It's almost as if, even though the ADCs are one drug, I think of it a bit like when we give someone hormone therapy with a CDK inhibitor and their disease is progressing. And we wonder, are they resistant to the hormone therapy or the CDK inhibitor? Do I change one? Do I change both? I think we have sort of the similar conundrum there where, when we've looked, we sometimes see mechanisms of resistance. I would say it's a problem with the hormone therapy. And sometimes we find mechanisms of resistance that it's a problem with the hormone therapy partner. When I think about resistance, I have almost come to think about the ADCs as I have resistance to two components that are at play — until we really have sequencing data, because there are some at least small clinical trial efforts ongoing that are trying to look at the sequence to see we're not surprised that whoever goes second is going to be less effective. But I think the real question we want to know, and our patients want to know, is, does it matter which one you get first? Is the result of 1 plus 2 better than the result of 2 plus 1? There will be at least some small efforts to try to get some data.
In my practice, it means you're probably going to get both of the ADCs, but it's not going to be my first choice to switch you to the other one — simply because it feels more likely, from the limited data I've seen, that resistance to the payload is probably the more common problem. And with payloads that are so similar, I feel better thinking about a drug that has a very different mechanism of action.
Graff: Yeah, I realized when we were shouting out ADCs, I didn't mention datopotamab deruxtecan (Dato-DXd) which is the other one that's very close on the horizon. It's a TROP2 target with the same deruxtecan payload. So, this problem continues to compound.
Miller: It almost feels like that one is not going to help us, because you've got the same antibody as sacituzumab but the same payload as T-DXd. It's different, and yet it's not different.
Graff: Yes. It's maybe a lateral step in terms of trying to figure out how to put them into the pieces of the puzzle or potentially compete with both drugs somehow in a way that just makes choosing more complicated. But the trial that I think has the best steam looking at sequencing is TRADE-DXd, which is actually sequencing the two deruxtecan drugs. For all the investigators and clinical trialists that are listening, time will tell, I guess, how that mechanism or strategy works.
I think one of the reasons it's so key for us to continue to commit to biomarkers and samples on progression is that for patients enrolled in clinical trials, we still just don't have a wealth of data. And that's often that point in a clinical trial where a patient's like, "Ugh, one more thing. I've progressed. Leave me alone." And having that last bit of biomarker tissue that can help us discern what is really happening is ultimately what's going to drive that decision moving forward on how we can best answer this question.
Miller: Today we've talked to Dr Graff about the ADCs for HER2-low disease and particularly sequencing them. Unfortunately, there's no clear answer yet. We will be getting data from some important trials evaluating sequencing and evaluating response after previous exposure. This is yet another area where shared decision-making, thinking carefully about differences in schedule, differences in the number of times the patient comes to the clinic, differences in diarrhea and myelosuppression and nausea and alopecia can allow us to come to a decision that feels the best for the patient in front of us with everything we know and don't know now.
We will be learning more about sequencing. Unfortunately, it feels like just as we might be figuring out sequencing with the two available ADCs for this patient population now, we'll have even more choices with more ADCs — some with similar payloads, some with different payloads, some with different targets. These are exciting drugs that have the real potential to improve efficacy and minimize toxicity for our patients. I suspect we will be talking about sequencing over and over again as new agents come up. Thank you for joining us.
Please take a moment to download the Medscape app to listen and subscribe to this podcast series on breast cancer and HER2. Dr Graff, thank you for being our guest today. This is Dr Miller for the Medscape InDiscussion podcast.
Resources
Antibody-Drug Conjugates in Breast Cancer: Current Status and Future Directions
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer
Sequencing Antibody Drug Conjugates in Breast Cancer: Exploring Future Roles
Decoding TROP2 in Breast Cancer: Significance, Clinical Implications, and Therapeutic Advancements
TReatment of ADC-Refractory Breast CancEr With Dato-DXd or T-DXd: TRADE DXd (TRADE DXd)
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Cite this: Shared Decision-Making in Sequencing ADCs for HER2-Low Breast Cancer - Medscape - Nov 21, 2024.
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