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Banu Arun, MD: Hello. I'm Dr Banu Arun. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today we will discuss challenges that relate to HER2/neu-positive breast cancer. Historically, breast cancers with HER2/neu overexpression were associated with an increased risk of disease recurrence and an overall worse prognosis. Since the early 1990s, with the discovery of trastuzumab, the treatment landscape has evolved tremendously. Now we are seeing targeted and personalized therapies, which is translating into women living longer with a good quality of life. First, let me introduce my guest. Dr Avan Armaghani is an assistant member in breast oncology at the Moffitt Cancer Center. She has a strong interest in medical education and mentorship. Her project and research interests are focused on medical education and on discovering new ways to use digital technology to optimize healthcare delivery. Welcome to InDiscussion. I want to start by asking you, what do you believe is the most relevant issue in advanced metastatic breast cancer nowadays?
Avan J. Armaghani, MD: Hello, Dr Arun. Thank you very much for having me. I'm very happy to be here and speak on this very important topic. I think there are a couple of challenges or maybe really exciting developments in HER2-positive metastatic breast cancer. As you had mentioned earlier, I think we've come a long way in the treatment of HER2-positive metastatic breast cancer, starting with trastuzumab, and now we have antibody-drug conjugates (ADCs), which are focused on more personalized and tailored therapy. I think we are continuing to evolve in the type of treatments that we have, but I think we also face challenges, particularly with brain metastases and finding ways to prevent brain metastases from developing in HER2-positive metastatic breast cancer patients, but also how do we treat them?
Arun: Yes, that sounds really good, Dr Armaghani. Before we go into all of these details with the studies and brain metastases, as well as tackle the issue about access for our patients, I want to remind our listeners that our first episode dealt with ADCs. We had a lively discussion with Dr Lynce, so I encourage our listeners to go back and listen to that episode as well. The floor is yours, Dr Armaghani. Would you like to start with the ADCs that relate to HER2-positive breast cancer and go chronologically? How did this start, and where are we now?
Armaghani: Yes. The first ADC that was approved in the treatment of HER2-positive metastatic breast cancer was T-DM1, and I think that was huge in the treatment for HER2-positive metastatic breast cancer. We had trastuzumab pertuzumab in combination with chemotherapy with the CLEOPATRA trial, but I think after that, it was a little bit unknown in terms of what to do in second-line-and-beyond therapy. I think the approval of T-DM1 in second-line therapy for HER2-positive metastatic breast cancer was groundbreaking and, of course, practice changing. That was the first ADC. More recently, we saw the development of another ADC, which was trastuzumab deruxtecan (T-DXd). The first display of efficacy in this space was with DESTINY-Breast01, and that was a phase 2 study that looked at heavily pretreated patients with HER2-positive metastatic breast cancer and with an objective response rate of over 60%. That led to the initial approval of this ADC for our treatment of patients with HER2-positive metastatic breast cancer who had progressed on two or more prior lines of therapy. This was another huge development, and then that led to other questions that were asked. We were questioning the standard that was set for so long, which was a taxane plus Herceptin or trastuzumab pertuzumab followed by T-DM1. But what about having T-DXd? Maybe it's better than T-DM1. We had that answer in DESTINY-Breast03.
Arun: Thank you, Dr Armaghani, for this introduction. Where do you see the next set of studies going? Also, how do we position these agents in our clinical practice? We are thrilled that they are increasing options, but sometimes it's confusing. What do we use second and third line? How do we sequence? There will be more ADCs. There are many more Phase 1 and phase 2 studies going on with other ADCs, actually similar antibodies or similar payloads.
Armaghani: Absolutely. I think DESTINY-Breast03 led to the new standard where second-line therapy now is with T-DXd. In DESTINY-Breast03, this was a direct head-to-head comparison between T-DXd and T-DM1. The response rate with the T-DXd was far better than T-DM1. That's what led to our new standard. The question still remains, is the CLEOPATRA trial still number one? Because that's what we still use. We use taxane in combination with trastuzumab and pertuzumab as first-line therapy in HER2-positive metastatic breast cancer. What's really exciting is that we have a trial underway with DESTINY-Breast09. This is a phase 3 study with HER2-positive metastatic breast cancer patients. They have received no prior chemotherapy or HER2-targeted therapy. This would be first-line T-DXd alone or with pertuzumab, and that would be in comparison with the standard of care, taxane plus trastuzumab and pertuzumab. I'm looking forward to the results of that study because maybe after all these years of what our first-line standard of care was, maybe that'll change with the results of DESTINY-Breast09.
Arun: Right. DESTINY-Breast09 is really awaited. The results can indeed be practice changing. We have mentioned that there are other ADCs on the horizon as well. How about agents and studies that are targeting HER3? There are recent developments in that area as well.
Armaghani: We have a new ADC that targets a different protein called HER3 — it's called patritumab deruxtecan. That's certainly a mouthful, but this is a HER3-directed ADC in patients with HER3-expressing metastatic breast cancer. We've seen a good percentage of metastatic breast cancers that express the HER3 protein. I think there is a lot of exciting preliminary data about the efficacy of this new ADC across all subtypes of metastatic breast cancer, including HR-positive, HER2-negative, HER2-positive metastatic, and triple-negative metastatic breast cancers. There will be more to come.
Arun: Yes. Thank you. It's indeed a complicated biology. There are not too many studies right now, but — and I am going a little bit off the topic — HER2/neu or trastuzumab resistance has been tackled in the past, and there are some studies looking at adding other targeted agents. Do you think it will become an issue with these ADCs as well, or because the mechanism of action is different? It's not really the HER2 receptor and biology.
Armaghani: We just have to wait and see. I think that resistance could certainly develop over time with any of these drugs. I think if we have different ADCs that are targeting different markers on the cancer cells, then I think that would be a way that we can circumvent potential resistance.
Arun: Right. I think it's a good thing that we will have all of these different agents, the antibodies and the payloads, and not solely depending on trastuzumab in the very early days and then having to deal with trastuzumab resistance when there was nothing else that we were able to use. Thank you for that insight. Now I want to switch to another important topic that relates to all breast cancers but more so for HER2 positive: brain metastases. From the very beginning, we knew that brain metastasis is seen a little bit more often in patients with HER2/neu-positive disease. In fact, many of us have seen patients where the progression is only in the brain, and there's no systemic disease. How do we approach it? What is the standard? What studies are ongoing to tackle this?
Armaghani: Yes. I think this continues to be a challenge not only in HER2-positive disease but also in other subtypes of breast cancers. How do we develop therapies that are able to effectively cross the blood-brain barrier? That continues to be a challenge. I think something that was really groundbreaking in HER2-positive metastatic breast cancer was with the HER2CLIMB data, and that was evaluating the addition of tucatinib in combination with trastuzumab and capecitabine for HER2-positive metastatic breast cancer. What was unique about this study was it included patients not only with treated brain metastases but also with active brain metastases. These are patients with untreated brain metastases, or they had progressive brain metastases. We saw that the addition of tucatinib to trastuzumab and capecitabine prolonged progression-free survival, overall survival, and reduced the risk of disease progression or death, particularly in those patients with active brain metastases. This was huge. I can also touch on the role of the ADCs like T-DXd, because there is some data to suggest crossing the blood-brain barrier. Typically, what I prefer in those patients with brain metastases and HER2-positive disease is to choose first the tucatinib, capecitabine, trastuzumab combination because we have that data in the HER2CLIMB data. I think in the second-line setting, we have both of those options that are appropriate. I think if we're considering that there is a patient in front of us who has brain metastases, I would probably choose the HER2CLIMB regimen first over T-DXd with the data that we have available to us right now.
Arun: That is a really natural segue into the discussion that we have these two options. With brain metastases, you would choose the tucatinib. How about the combination of tucatinib and deruxtecan in the HER2CLIMB-04 study?
Armaghani: That is a phase 2 study looking at this combination, and this is in patients who have received two or more prior HER2-based regimens in the metastatic setting. That will be really interesting to see. Rather than using them by themselves, what about trying to combine them? I think that would be very interesting to see what that data turns out to show.
Arun: Do we have quality-of-life data, especially for patients with brain metastases? I think we have data from the whole study population, but is there a subgroup analysis that is available?
Armaghani: One thing that's interesting is there's another study: HER2CLIMB-05. I know we haven't talked about prevention of brain metastases because that's just equally as important. One of the endpoints is looking at quality of life. With HER2CLIMB-05, this is interesting because this study is with patients who are receiving first-line taxane, trastuzumab, and pertuzumab. Then, after stopping the chemotherapy and continuing trastuzumab pertuzumab, you're adding in tucatinib and seeing if those patients can remain on first-line therapy longer and whether you can actually decrease the incidence of brain metastases in the future. I think that also translates toward improving quality of life as well, especially trying to prevent the brain metastases from developing.
Arun: It will be a first because there are no studies or agents that are used for prevention of brain metastasis. The only old-fashioned way we know is whole-brain radiation. Beyond that, in terms of agents and drugs, there is actually no data. The HER2CLIMB-05 study will be very interesting and important in that regard as well.
Armaghani: It's always a challenge. I think one of the other challenging things is those patients who just recur in the brain, and their scans are showing no evidence of disease otherwise. I think that's also a challenge and a constant question of, are we just treating the brain itself? Do we incorporate systemic therapy even though there is no evidence of disease elsewhere? I think that's another challenge that we always struggle with.
Arun: Yes. Absolutely. Finally, I want to touch base on what we mentioned very briefly at the beginning of the episode — access to these drugs for everyone. We just all came back from the American Society of Clinical Oncology (ASCO) [Annual Meeting], and the theme was access and treating everyone everywhere. In line with that, do you have any comments about access to treatment with these agents?
Armaghani: I think that science is great, and it has led us to the development of so many amazing therapies and effective therapies. As we mentioned earlier, these therapies allow women to live longer with metastatic breast cancer and maintain an amazing, excellent quality of life. We continue to struggle with cost and drug costs with all of these sophisticated therapies. I think that continues to be a challenge that we have to address and ensure that our patients are able to have access to these drugs without major hurdles to go through. It's really hard when I see patients who come into my clinic, and let's say they're on the HER2CLIMB study, and we're trying to get them their capecitabine and tucatinib, and there's multiple issues that they have in terms of obtaining the drug. I always think the last thing that patients should worry about is how they get the treatment for their breast cancer. I think that's something that we all have to continue to work at and continue to be an advocate for our patients.
Arun: Absolutely. I agree that access to treatment should be the last thing patients should worry about. Financial burden and financial damage are a reality. Thank you for your insight about that as well, Dr Armaghani. I think we have really come a very long way in the treatment of metastatic HER2/neu-positive breast cancer. Trastuzumab was the first groundbreaking discovery that revolutionized the treatment of HER2/neu-positive metastatic breast cancer. That also served as a catalyst for a number of therapies to follow, including pertuzumab, tyrosine kinase inhibitors, and ADCs. Now we have come so far that [we are] even talking about prevention and treatment of brain metastases and maintenance therapy, but obviously the study results are awaited. I would like to thank you again, Dr Armaghani, for joining us. And I would like to thank our listeners for tuning in. This is Dr Arun for InDiscussion.
Tucatinib Versus Placebo Added to Trastuzumab and Capecitabine for Patients With Pretreated HER2+ Metastatic Breast Cancer With and Without Brain Metastases (HER2CLIMB): Final Overall Survival Analysis
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Cite this: Targeted Therapies in Advanced and Metastatic Breast Cancer: Risk Factors, Quality of Life, and Treatment Access - Medscape - Sep 06, 2023.