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 second part of this discussion, our experts evaluate the sequencing of available antibody drug conjugates (ADCs) for HER2-low metastatic breast cancer, trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan, and explore use of datopotamab deruxtecan (Dato-DXd).

Transcript:

Ruta Rao, MD: Welcome back to Oncology Learning Network. My name is Ruta Rao and I'm a professor of medicine in the division of oncology at Rush University Medical Center. I'm joined by Dr William Gradishar from Northwestern Feinberg School of Medicine and Dr Seth Wander from Massachusetts General Cancer Center. In this segment, we will focus on sequencing of ADCs in metastatic breast cancer and a newer ADC, Dato-DXd.

Let's jump right in. How do you generally sequence the 2 currently available ADCs we have, trastuzumab deruxtecan and sacituzumab govitecan? And what has been your experience in doing so? Let's start off with the ER-positive patients.

Seth Wander, MD, PhD: I think this is, of course, a key question right now in clinic. We have lots of new data coming in for both of these agents outside of HER2-positive and triple negative disease. We just reviewed the DB-04 and DB-06 data for trastuzumab deruxtecan. We also have to place that into the context of the TROPiCS-02 data for sacituzumab govitecan.

It's important to remember the inclusion criteria for these studies differed a little bit. In both of the DB-04 and obviously DB-06 studies, patients were allowed to have had less prior cytotoxic chemotherapy, whereas in TROPiCS-02 the patient typically had several lines of prior chemotherapy as well as being anti-estrogen–resistant. In terms of following the inclusion criteria for the study, we typically would deploy trastuzumab deruxtecan first.

Also, in considering the 2 of them, you have one that is targeted in the sense that you have a HER2 level that you're considering, whereas sacituzumab [govitecan] is given regardless of the TROP2 level. For the most part, if we're sequencing them, we tend to start with T-DXd a little bit earlier and then go to sacituzumab [govitecan]. I think the key question becomes what's the best way to do this? Are there particular patients where one might be better in the first position? Does it matter if there's an intervening therapy? How does resistance develop to these 2 agents? Is it to the antibody? Is it to the payload? Could it be to either? These are a lot of really important unanswered questions.

I have a colleague in Boston, Dr [Rachel] Abelman [MD, Dana-Farber Cancer Institute/Massachusetts General Cancer Center] who has begun to publish some work on this and shared some data at San Antonio [Breast Cancer Symposium] last year. And as Bill had alluded to earlier, it's a little bit the law of diminishing returns. It tends to be that with the second ADC, the estimated PFS in the real-world setting is less than what you would see on the first one. But we need to learn more. We need bigger data sets. We need better controls in that situation, and a much deeper understanding of the mechanisms that are driving resistance.

The final thing I would say is as we develop new ADCs, sometimes with overlapping antibodies, overlapping payloads, this is going to become even more complex because you're going to have an exponential increase in the number of drugs in this class with all kinds of different patterns of resistance emerging. The more we can personalize this and the way that we personalize targeted therapy for hormone-directed agents and for oncogenic pathways, I think we'll pay dividends for patients.

William Gradishar, MD: I don't know that I have a whole lot to add, but we've seen parallels in the ER-positive world with CDK4/6 inhibitors, this notion that you may not benefit if you're getting another drug in the same class. Well, the antibody drug conjugates, although structurally, you know, look the same, mechanistically, they may act different for all the reasons that Seth outlined: different payload, different target. One shouldn't presume that in sequence they might not have activity. But understanding which patient should get which drug first is still pretty opaque to me. And furthermore, we're going to have more of these drugs as already outlined. They're going to get them all, and the question is, in a given patient, is there one sequence that makes more sense than another? I don't have the answer to that now.

Dr Rao: What is your practice in the triple-negative HER2-Low setting?

Dr Gradishar: In that group, we tend to start with sacituzumab govitecan based on the data, which is more compelling in the ER-negative patient population. And then we would follow that with trastuzumab deruxtecan.

Dr Rao: What data would you like to see about sequencing?

Dr Wander: These are difficult studies to design. We have, as I mentioned, different inclusion criteria from the original trials. It would be nice in a more controlled, prospective fashion, or even in a more rigorous, multi-institutional retrospective way, to take a look at very large data sets and to ask very specific questions about starting with T-DXd versus going to sacituzumab [govitecan] with one intervening therapy, with no intervening therapies. Reversing that, looking at the same question as we were just alluding to in triple-negative disease.

And also thinking about compound toxicity. There's some overlapping toxicities between these drugs. What happens with the second agent in terms of cytopenias and other issues.

These are very practical questions that really do need to be answered as quickly as possible to help clinicians all across the country and the world make the best and the safest decisions they can.

Dr Gradishar: I agree with that. The challenge, of course, is which company is going to spend the money to do such a study, and that may be a challenge, but there may be work around. Many entities that practice oncology have big pathways that collect all the information on everything. McKesson does that, US Oncology, et cetera. There may be a way of getting at that question and the answer to it ,short of doing a formalized clinical trial.

Dr Wander: The last thing I would just say, this really highlights the value of real-world data analysis. I mean, we all appreciate the limitations in some of these data sets, but there are simply questions that are not practical or tractable to answer in prospective homogeneous clinical trials.

As long as we appreciate the limitations of real-world data, leveraging resources like the ones that Bill's alluding to, in terms of big electronic medical records, you can even tie that in sometimes with clinical genomic databases, thinking about tying the clinical outcomes to available next-generation sequencing. If we can appreciate the limitations of that data, but work as best we can around that, we can start to answer some of these important questions without the trials, which, as Bill mentioned may be very difficult.

Dr Gradishar: This is “pie in the sky” stuff, but we’re collecting [circulating tumor] ctDNA on patients fairly frequently. As the assays become more sophisticated, we may find signals there that dictate what signature would suggest a particular drug or sequence makes the most sense in an individual patient.

Dr Rao: Bill, looking forward, can you briefly describe to us the newer ADC that we've been hearing a lot about, Dato-DXd?

Dr Gradishar: This is another antibody drug conjugate, datopotamab deruxtecan. The development of these drugs, the trials look almost the same. There are always a monotherapy with the new drug versus a physician's choice of a limited number of monotherapy chemotherapies. This drug, the initial results from this drug also look encouraging, and again, one of the problems is, as these drugs are being developed, they're not direct comparisons. You have to look at efficacy, trial to trial, but they're not direct comparisons.

It has good efficacy from the standpoint of response and PFS compared to monotherapy with chemotherapy. And there's a suggestion that, in fact, the toxicity profile might be a little bit more favorable in some respects, particularly with GI toxicity. At least that's my takeaway from it.

Dr Rao: Any toxicities with it that you were surprised to see or concerned about?

Dr Gradishar: Not that I remember.

Dr Wander: No, I agree with everything Bill just mentioned. I think of this drug as the sort of child between T-DXd and sacituzumab [govitecan]. It has the sacituzumab antibody with the T-DXd payload. And again, you can modify both of those components. You can also modify the linker in terms of how tightly the payload is bound to the antibody. All of those things can change the therapeutic index. The tighter the payload is bound, the harder it is to drop off, and so perhaps the less systemic off-target toxicity, but also the more you need the antibody to really be expressed. I think the looser the connection, the more bystander effect, the more permeable the payload is, the more you can hit some cells that might not express your target with risk of more toxicity. As we design these drugs, we're going to see a shift from effectiveness with less target to potentially more systemic broad toxicity, and the happy medium is going to be somewhere in between.

And we're seeing that. To compare TDM-1, to T-DXd, to sacituzumab [govitecan], to Dato-DXd, you see a whole spectrum of these phenomena, and it has to do with how much antibody you have expressed, how permeable and toxic the payload is, and how tight the linker is.

Dr Gradishar: One of the things, again, there are multiple things one has to look at, but we're sort of getting into a discussion about how we're pushing chemotherapy farther and farther away, which is everybody's dream, but we're still giving chemotherapy. It's just getting there in a different way. Part of the issue is going to be the cost of these things, not that that's the focus of our discussion today, but there may be an argument for not completely abandoning chemotherapy, because there may be situations where it's potentially equally efficacious and doesn't necessarily mandate that we stick with sequential ADCs, one after another.

Dr Rao: Based on everything you've said, what do you see as the role of Dato-DXd in breast cancer?

Dr Wander: I think this is also an important unanswered question, and we don't know anything to my knowledge yet about sequencing in terms of Dato-DXd relative to the other two [ADCs]. And that's going to be an important point because these other agents are, as Bill mentioned, briskly moving into clinic now. Many patients are receiving one or both of these agents regularly. How Dato-DXd fits into the mix will depend a little bit, not just on how it performs compared to those 2 agents, as Bill was saying, kind of apples to oranges comparisons between the studies, but also how it's going to fit in sequence as we start to mine these larger real-world data sets.

I think it's great to have more options. You hope that there are patients, just like with conventional chemotherapy, who may respond better to one versus another for reasons that are not totally clear to us. Having more options affords the opportunity to give patients these kind of choices. But I think right now, it's still a bit of a black box from my perspective.

Dr Gradishar: I agree.

Dr Rao: Well, thank you very much for summarizing what we know about the 3 ADCs that we've talked about. I think we all have a lot of questions still remaining about how to use these in sequence, but thank you for sharing your insights and thank you to the audience for watching.

Please join us for part three of this discussion on T-DXd and HER2-positive metastatic breast cancer.

Sources:

Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X

Bardia A, Jhaveri K, Im S-A, et al. LBA11 Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015