HR+ Metastatic Breast Cancer: What is the Role of Antibody-Drug Conjugates?

Centering discussion on antibody-drug conjugates in HR+ metastatic breast cancer, panelists consider the selection and use of these agents in practice.

Eva M. Ciruelos Gil, MD, PhD
: Second question is the obvious one: how do we introduce sacituzumab govitecan [Trodelvy]? Yesterday, we discussed some data of sacituzumab govitecan and its efficacy irrespectively of HER2 status. It has been trying to help in the algorithm. When to use sacituzumab govitecan: before or after T-DXd [trastuzumab deruxtecan] in the HER2-low space? T-DXd works for HER2-zero and HER2-low. Maybe that is why this analysis was done and presented yesterday. In direct comparison between 2 trials, what would be your optimal sequence when sacituzumab govitecan is approved for this indication as well?

Sara M. Tolaney, MD, MPH: First of all, I was very excited to see the data from TROPiCS-02 with regards to overall survival. We saw the initial data comparing sacituzumab to the treatment of physician’s choice at ASCO [American Society of Clinical Oncology] with regards to progression-free survival [PFS] showing modest benefit. The PFS Delta, just about 2 months, was not as large as I think we wanted to see it. Seeing that there’s over a 3-month Delta in terms of overall survival, favoring sacituzumab, makes me think that it should be a standard option for our patients, but it is for a population of patients though that were pretreated more than DESTINY-Breast04 with 2 to 4 prior lines of chemotherapy for their metastatic disease. I tend to think of sacituzumab as a later-line agent, as was used in TROPiCS-02, meaning that I would think about using T-DXd probably in a second-line chemotherapy setting. Then, post-T-DXd, if they’re HER2-low, they could get sacituzumab. But if they’re HER2-zero, and not a candidate for T-DXd—which is about a third of our hormone receptor-positive patients—then it could be used as a second- [or] third-line chemotherapy agent. I think it just depends on their HER2-low status to make that decision.

Eva M. Ciruelos Gil, MD, PhD: Would you recommend retesting HER2 status when you have to make that decision? In our first-line patients, we didn’t used to biopsy and rebiopsy but it may be the next recommendation: to biopsy and rebiopsy to look for this dynamic X person on the targeted antigens. This may be a problem or an issue to be addressed when we plan to use particular ADCs [antibody-drug conjugates] because we’ll have many options. Maybe if it’s striving because of expression levels, we’ll have to biopsy, and rebiopsy. HER2 and HER3 is a very dynamic biomarker.

Sara M. Tolaney, MD, MPH: I think this is a question I’m struggling with in clinic currently because HER2-low status is dynamic. We’ve seen some publications where if you go from a primary setting to a metastatic setting, you can see it go either way. You can see it go from HER2-low to HER2-zero, or HER2-zero to HER2-low. Even in the metastatic setting, we’re seeing the same dynamic trend. We don’t have as much data about how it trends through the metastatic setting, but just anecdotally in the clinic, I’ve seen this, and I have started biopsying more. The question I have is if I biopsy someone and they’re HER2-zero, but their biopsy in the prior metastatic setting it was HER2-low, what do I believe? Because 1. it’s dynamic, but 2. it’s probably also heterogeneous, so where I biopsied may also impact one, if another location is actually a HER2-low. In truth, I’ve been giving the patient the benefit of the doubt that if they’ve had 1 biopsy that was HER2-low, even if it’s not necessarily the most recent biopsy, I’ve been using T-DXd. But I think your point is super important. We need to understand this better because I don’t know. Does it matter, at the time that you start, if the biopsy is HER2-low, especially because our testing is not even so accurate? That is what worries me to make that decision.

Eva M. Ciruelos Gil, MD, PhD: No, sure. Maybe activity won’t depend on that. Let’s wait for it.

Sara M. Tolaney, MD, MPH: That’s true. What if ultra-low works too?

Eva M. Ciruelos Gil, MD, PhD: Maybe this hasn’t been so much the “magic bullet” but has been the driver. In fact, maybe these drugs are so effective that for some reason, they can be administered on patients with a wider therapeutic window when compared to conventional chemotherapy, but maybe they are not so dependent on the antigen or antibody. Maybe the antibody has its own mechanism of action, but the level of antigen doesn’t mean anything. We have data from–

Sara M. Tolaney, MD, MPH: From DAISY.

Eva M. Ciruelos Gil, MD, PhD: Patritumab deruxtecan [Enhertu].

Sara M. Tolaney, MD, MPH: Oh, that too.

Eva M. Ciruelos Gil, MD, PhD: This is the very earliest scenario, pre-surgery trial, and activity of patritumab, biologically speaking, through CelTIL [tumor cellularity and tumor-infiltrating lymphocyte] score that does not depend on IHC [immunohistochemistry ] expression, but mRNA expression, on this gene on HER3. I just know that I don’t know anything.

Sara M. Tolaney, MD, MPH: I think the question is unknown. The DAISY data, I think, is what really threw that into the mix because if you’re seeing responses in HER2-zero, is it that it doesn’t matter what your HER2 IHC 4 is, or that you’ve captured some HER2-zeros that have HER2 expression that’s not enough to be 1+, but it’s that sort of 10% faint staining that’s getting them to be HER2-zero, yet still getting responses. I think we really need to understand if HER2 quantitation matters or not.

Eva M. Ciruelos Gil, MD, PhD: Sure. And we need more translational approaches and projects. Are you performing biopsies at your clinics because you’re using a disease? I think that it’s relevant for clinicians to perform biopsies the most they can because we do need those samples, just to have that ready for new investigational projects or collaborations so we can see what’s happening when a patient progresses to a particular ADC. This will help to take decisions in the clinics.

Sara M. Tolaney, MD, MPH: It’s so interesting that you bring that up because our institute started a biopsy protocol for pre- and post-ADC. Particularly with this idea, as you pointed out, we don’t know for what biomarkers or for who’s going to respond to ADCs, but the resistance mechanism is going to be critical to understand.

Eva M. Ciruelos Gil, MD, PhD: Sure thing.

Sara M. Tolaney, MD, MPH: We talked about maybe using sacituzumab post T-DXd, but clearly, we have no data what the efficacy is going to be when you’re using topA. What if the ADC mechanism of resistance to T-DXd was that the tumor developed resistance because it was resistant to the deruxtecan? Does that mean that you’re not going to respond to an SN38 payload with sacituzumab because you have a topA-I resistance? We have a very small case series. One of my colleagues, Aditya Bardia, MD, MPH, had published literature looking at sacituzumab resistance, where they saw it could either be the target, or the payload that led to the resistance. This clearly shows that we need to learn a lot more in order to think about ADC sequencing, especially as there are so many new ADCs that are coming out.

Eva M. Ciruelos Gil, MD, PhD: Sure. That’s impressive. It’s like cooking. You combine different ingredients and you can make your own ADC. Please stop and let’s review what we have on how to move forward.

Transcript edited for clarity.

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