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Banu Arun, MD: Hello. I'm Dr Banu Arun from the University of Texas MD Anderson Cancer Center, Breast Medical Oncology and Clinical Cancer Genetics. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today we'll discuss antibody-drug conjugates (ADCs) in metastatic breast cancer, including HER2/neu-positive, HER2/neu low–positive, triple-negative, and hormone receptor–positive breast cancer.
First, let me introduce my guest, Dr Filipa Lynce. Dr Lynce is a medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Farber Cancer Institute and assistant professor at Harvard Medical School. Her research focuses on inflammatory breast cancer, triple-negative breast cancer, BRCA-associated breast cancers, and novel therapies in the treatment of breast cancer. Welcome to InDiscussion.
Before we begin our discussion, I'd like to ask what you believe is the most relevant issue in advanced metastatic breast cancer?
Filipa Lynce, MD: Hello, and thank you so much for having me. I am delighted to be here with you today.
I think that one of the most fascinating things in breast cancer is moving away from this concept of one size fits all. In the past few years, we have seen the development of very exciting targeted therapies where we are trying to take advantage of the unique characteristics of each person's tumor. Of course, if we talk about targeted therapies and therapies that try to be potent and hopefully less toxic than our old chemotherapies, we must talk about ADCs.
Arun: What is an ADC? What are the advantages and disadvantages compared with our old chemotherapy regimens?
Lynce: When I talk to my patients about this, I really like the concept of the smart bond. It's not a new concept — this idea that you are able to deliver high doses of cytotoxic chemotherapy linked to an antibody that, at least in theory, is going to deliver those high doses of chemotherapy to the cancer cells expressing the antigen that links to the antibody that is part of the ADC. Every ADC has three components: an antibody with specificity in terms of the cells that it's going to target; the payload, which is most commonly the cytotoxic regimen that you want to deliver; and, finally, a linker that connects these two. Of course, all of the ADCs have different characteristics. They have different drug-to-antibody ratios. The linkers have different characteristics. Some ADCs have more bystander effects than others. We have seen three ADCs being commonly used in breast cancer that we are all getting used to.
Arun: Thank you, Filipa. This is really a very exciting era right now, and I think we can dive directly into the main topic. Where do we use the ADCs now? Is it for a certain subgroup of breast cancer? Is it for all breast cancers? What are the studies that will help us guide through the HER2-positives, the low-positives, the triple-negatives, and the hormone receptor–positives? I know this is a very loaded long question, but we are eager to hear about this.
Lynce: We should probably start with HER2-positive advanced breast cancer. This is where we saw the first ADC used in breast cancer, which was trastuzumab emtansine (T-DM1). We have all been using that now for almost 10 years. This is very well-tolerated. It has major side effects — some nausea, some liver function test (LFT) elevation. I would say that overall, our patients tolerate it very well. We providers have easily learned how to manage its toxicities.
Then of course, in the past few years, we have seen the introduction of trastuzumab deruxtecan (T-DXd) into the field of advanced breast cancer. We first saw this in HER2-positive disease. We saw the results of T-DXd in patients with heavily pretreated HER2-positive breast cancer. More recently, we saw the results of DESTINY-Breast03. I think that we all still have those curves in our minds. There was such a huge difference between the curve of the patients that were treated with T-DXd compared with those that received T-DM1. That became our second-line therapy for our patients with advanced HER2-positive breast cancer. I think that most of us are using it in the clinic setting.
There is an ongoing trial comparing T-DXd with our current first-line regimens — the CLEOPATRA regimen — trastuzumab, pertuzumab, and the taxane. There is more to come, whether or not we will see these ADCs moving toward the first line for these patients.
Arun: For HER2-positive breast cancer, it is safe to say that we can use it as second-line therapy for now, but more to come.
Lynce: That's right. That is what we are using in the clinic for most of our patients.
Arun: Wonderful. What about HER2-low–positive patients? This is a whole new subtype of breast cancers.
Lynce: I think that we all, including pathologists, patients, and medical oncologists, have to reeducate ourselves to not only look at HER2 negativity or HER2 positivity, but to go deeper into the HER2-negative cases and try to identify the HER2-zeros or distinguish the HER2-zero cases from those that have HER2 1+ or HER2+ fluorescence in situ hybridization (FISH) not amplified. There is more to come as we see the efficacy of some of these ADCs in HER2-ultralow disease, but we will keep that for another episode.
I think that we all were very excited to see the results of DESTINY-Breast04, where we saw the efficacy of T-DXd in patients with HER2-low disease. DESTINY-Breast04 enrolled mainly patients with hormone receptor–positive, HER2-low disease. However, the efficacy was impressive not only in these patients but also in the smaller number of patients that had triple-negative breast cancer. Here, this is defined as hormone receptor–negative, HER2-negative, but HER2-low — not HER2-zero. This led to the US Food and Drug Administration (FDA) approval of these agents. It was already approved for patients with HER2-positive advanced breast cancer, but the label was expanded to include patients with HER2-low disease that had received at least the prior chemotherapy in the metastatic setting or had progressed during or within 6 months of completing adjuvant chemotherapy.
Something to keep in mind here, and in particular when it comes to a space where we have other ADCs and other agents, is the toxicity profile. If you recall, we were talking about the toxicity profile of T-DM1, at the beginning of this podcast — that it's overall very well-tolerated. I would say that overall T-DXd is well-tolerated, but you have gastrointestinal (GI) toxicities. I think that a specific toxicity that we all have to keep in mind is interstitial lung disease (ILD). ILD is another thing that we all have to reeducate ourselves about, how to recognize it, what to do, and how to act when you encounter asymptomatic ILD on your common staging scans and what you need to do if someone has symptoms.
When ILD is asymptomatic, you temporarily hold the drug and you start to initiate steroids right away. After resolution, you can resume the drug. However, the recommendation now is that if someone develops grade 2 or higher ILD, you start steroids right away and you do a long taper, but you should not resume the drug. I think that we all are now getting used to it. But it's important to keep that in mind. Always try to recognize ILD and have in mind that for our patients. It might not be easy to distinguish ILD from other ongoing issues in our patients' lungs — disease progression in the lungs, pneumonia, or COVID or so many other things that can cause some radiologic findings. It really requires the provider to have ILD as part of our differential diagnosis so that we don't miss something that, if left untreated, can be fatal.
Arun: Thank you, Filipa. I think at the end, it always comes down to benefit and risk ratio. To summarize this part of the discussion in HER2-low–positive disease, T-DXd would be the choice, regardless of hormone receptor status. Correct?
Lynce: Exactly. We have another ADC that is approved in the setting of HER2-negative breast cancer, and this is sacituzumab govitecan. This has been around for a while now, and we all have become very comfortable using it with our patients. It was initially approved for treatment in advanced triple-negative breast cancer, based on the results of the ASCENT trial that compared sacituzumab govitecan with the physician's treatment of choice. We have to keep in mind that the approval of sacituzumab in triple-negative breast cancer includes those patients with hormone receptor–negative, HER2-low disease as well.
More recently, we saw the approval of sacituzumab to expand to patients with hormone receptor–positive, HER2-negative disease. This was based on the results of TROPiCS-02 — that was also a phase 3 randomized trial comparing sacituzumab govitecan vs the physician's choice. We have different options. For those patients that have hormone receptor–positive or negative and HER2-zero disease, the current ADC that is available is sacituzumab govitecan. But for those that have HER2 1+ or HER2 2+ and FISH not amplified disease, we have two options: We have sacituzumab govitecan, and we have T-DXd.
I totally agree with you. We need to look at the toxicity profile, the benefits that were derived in each of these trials, and how many patients were treated and discuss this with the patient to pick one over the other. Although I suspect that most of our patients will receive both during the course of their disease.
Arun: Thank you so much for this very elegant and informative answer. I think it's important to point out that the recent approval of sacituzumab in the hormone receptor–positive group was for patients in whom appropriate endocrine therapy and two lines of chemotherapy had failed. Is that correct?
Lynce: Yes, that is correct. The recent approval of sacituzumab was for patients that had received two or more prior lines of therapy. I think an important point as well is that in TROPiCS-02, patients enrolled in this trial had progressed on prior endocrine therapy and CDK4/6 inhibitors. In particular, for those patients with hormone receptor–positive, HER2-negative disease, we still need to keep in mind what are the agents with less toxicity that have shown to prolong overall survival and have limited toxicities, and we should continue to favor those upfront.
Arun: I completely agree with that. I want to switch gears now and talk about brain metastases. We see this quite often now, whether it is related to the inherent subtype or because with advanced therapies, patients live longer, survival is longer, and patients have time to manifest with brain metastases. What is known about the central nervous system (CNS) penetrance of these newer ADCs?
Lynce: That's a great question. I think that people were worried that ADCs, because of the size of the molecules, would not be able to penetrate the blood-brain barrier and be effective in the CNS. However, we now have preclinical and clinical data. In fact, a recent paper that was published in Clinical Cancer Research by Kabraji and colleagues showed preclinical and clinical activity of T-DXd on brain metastases for patients with advanced HER2-positive breast cancer. We have now seen different clinical studies looking at the clinical activity of T-DXd in brain metastases in patients with advanced HER2-positive breast cancer. I would say that the results are quite impressive. These studies reported an intracranial response rate in patients with active brain metastases anywhere between 46% and 73%, and they even saw patients who had complete response. This was not one or two patients; this was up to 13% of the patients.
We do have other regimens that are active in patients with brain metastases, such as tucatinib with trastuzumab and capecitabine. But I think that we are seeing more and more evidence that ADCs — in particular, the most recent ones and T-DXd — are effective in patients with active brain metastases. That's very reassuring for our patients.
Arun: That's very important to know. Thank you very much.
Finally, what is the plan after using one ADC? Can we use another one? What are the data? If patients are progressing on one ADC, is it a sign that they will not respond to a subsequent one?
Lynce: I think this is a great question, and it becomes a broader question: Now that we have all of these novel and very exciting new agents, how are we going to sequence them? Many times, the clinician is left with this decision of which one do I pick first, especially if the agents were evaluated in similar settings and if trials were conducted in parallel or in a time when a certain drug was still not available. We can't really say, oh, look, both drugs are available, but each of them still has efficacy after progression on the other drug. We just don't have that answer for many of these agents.
When it comes to ADCs in particular, I think that it's even more challenging because, as we discussed at the beginning, an ADC combines an antibody with the payloads. At the moment when a patient develops progression, we don't know if it is because a mechanism of resistance developed that is specific to the payload. If that is the case, we can switch to a different ADC that can still have the same antibody but different payloads. If there was development of resistance to that antibody, and you keep the same payload but you change the antibody, the patient will continue to have a benefit. This is really important as we see more ADCs that are being developed that share, for example, similar payloads or similar antibodies.
For example, when you are thinking about sacituzumab govitecan and datopotamab (dato) deruxtecan, that is an ADC that we are already seeing in different clinical trials. They both share the same antibody, so they both target trophoblast cell surface antigen 2 (TROP2), but they have different payloads. For sacituzumab govitecan, it's SN-38, whereas for dato, it's a topoisomerase I (TOPOI) inhibitor; it's a different type of payload. I think that we will need to learn more.
There was a very elegant paper from Bardia and colleagues recently about how they were able to distinguish the mechanism of resistance in a certain patient, and that may in the future inform us how to pick our next line of therapy. It's important as well to know that sometimes exposure to a certain ADC can lead to changes in the characteristics of the tumor. For example, data now suggest that after exposure to T-DXd, some tumors lose HER2 expression. It's important to have that in mind and do more biopsies. In that case, we may have to adjust our treatment afterward to take into consideration some alterations that might happen in the tumor as we expose patients to certain drugs.
Arun: Thank you, Filipa. It appears that it's getting more and more complex, and I would like to add that there are now studies going on combining ADCs with discoidin domain receptor (DDR), such as PARP inhibitors, for example, or in ADCs with immunotherapy. I have seen that a phase 1 study is being planned or even started with the triplet ADC, DDR, and immunotherapy. There will be a lot of wonderful data that we will learn from and have to dissect. Thank you very much.
Today we've talked with Dr Filipa Lynce about ADCs in different metastatic breast cancer subgroups and what the future holds. Thank you for tuning in. Take a moment to download the Medscape app to listen and subscribe to this podcast series on advanced and metastatic breast cancer. This is Banu Arun for InDiscussion.
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Cite this: Antibody-Drug Conjugates and Subgroups of Advanced and Metastatic Breast Cancer: Strategies, Resistance, Emerging Data - Medscape - May 02, 2023.