HER2+ MBC: Navigating a New Treatment Era

This transcript has been edited for clarity. Hope S. Rugo, MD: Welcome to the Metastatic Breast Cancer Center of Excellence. Here, we’re going to discuss the new treatments that are available for metastatic HER2-positive breast cancer. We’ll talk about some of the details about decision-making, which are complex because we now have a menu of additional treatment options in different patient populations, and have many questions about how to start and how to sequence therapy, and how to manage this in different countries.I’m Hope Rugo, director of breast oncology and the Women’s Cancer Center at the City of Hope Comprehensive Cancer Center. I’m joined by my colleagues, Dr Fatima Cardoso, Dr Javier Cortés, and Dr Sandra Swain. Please introduce yourselves. Fatima Cardoso, MD: Hello, everyone. I’m Fatima Cardoso. I’m based in Nice, France. I’m working at the Centre Antoine Lacassagne. I’m also the president of the Advanced Breast Cancer Global Alliance. Sandra M. Swain, MD: Hi, I’m Sandra Swain. I’m at Georgetown Lombardi Comprehensive Cancer Center in the US and also MedStar Health. Javier Cortés, MD, PhD: Hi, everyone. I’m Javier Cortés, a breast cancer medical oncologist working in the International Breast Cancer Center in Barcelona and at IOB Madrid in Madrid.Transforming Outcomes in HER2+ Metastatic Breast CancerRugo: We have an incredible panel of medical oncologists focusing on breast cancer who have been part of some of the major advances in the treatment of metastatic HER2-positive breast cancer that have completely changed outcome for these patients. Javier, tell us a little bit about what the most important advances have been over the last two to three years in the treatment of this disease.Cortés: Thank you very much, Hope. I think that we have learned from the very beginning that the CLEOPATRA-like strategy, followed by trastuzumab emtansine (T-DM1) first and followed by trastuzumab deruxtecan (T-DXd) afterward, has been the established standard of care or more available option or more frequent options to be used in the majority of Western countries. Unfortunately, not in all. It’s true that in the last 2 years, we have had so many advances that might change the way we are going to treat these patients. I’m going to highlight three very quick. The first one is the maintenance strategies, with a PATINA-like strategy adding palbociclib in the maintenance part after taxane, trastuzumab, and pertuzumab. We also have HER2CLIMB-05, a similar approach with tucatinib instead of palbociclib, both of them with beautiful achievements in progression-free survival. Very recently, we also learned that T-DXd moved from the second line to the first line in DESTINY-Breast09. In this trial, we have one arm of the trial with data, which is T-DXd plus pertuzumab. We are waiting to see the second important arm, T-DXd alone, to see if it’s good enough or not.With all this plethora of new data, wow, how are we going to treat our patients in the very near future? In some countries, how are you treating these patients today? Rugo: Such a great summary. Sandra, I think the big data that we saw recently really are exactly in those areas. How do we choose the right first-line treatment for our patients with metastatic HER2-positive breast cancer? How does the prior treatment for early-stage disease affect that, given that almost half of our patients now have de novo metastatic HER2-positive disease? How does the presence of brain metastases when patients develop metastatic disease or recur affect those decisions?Swain: I think, as Javier just said, we’ve had the CLEOPATRA regimen as standard treatment for the last 14 years. When we looked at CLEOPATRA, we found that those patients who did very well for a long period of time, and it was about 37%, did not have a PIK3CA mutation in their tumors. They did not have central nervous system (CNS) metastases. They had a long disease-free interval. They had high HER2. Those kind of things I would put into trying to decide which patients you would use first-line CLEOPATRA vs starting with T-DXd plus pertuzumab, and that would be a majority of patients, actually.If a patient has CNS disease at presentation, and as you said, over half [of cases] now are de novo disease, I would consider T-DXd for those patients. Then the big question that comes in is, how long do you give that for? I think we all agree that, in the study, it was way too long. The preference would be doing something like Javier is doing with the DEMETHER study, which is giving six or eight cycles and then switching to trastuzumab and pertuzumab (HP). There are no data right now, but that’s probably what many people are doing.Navigating First-Line Therapy Across Diverse Health Care SettingsRugo: It’s a really important question, thinking about how we treat in the first-line metastatic setting, given the differences in availability of different treatments around the world. Fatima, how do you take that into account when you’re recommending treatment in the first-line metastatic setting? Cardoso: Thank you. This is a very important question, and of course, there is probably a group of patients that could benefit from receiving T-DXd earlier. In my point of view, these are not the majority of patients. We also need to consider the cost implications, not just because of the treatment being different, but also of everything that goes with treating with T-DXd, including the monitoring, the management of interstitial lung disease, and so forth.I think we need to put that into consideration, and accessibility is going to be very different from different countries. I’m only speaking about high-income countries, because the approval of the DESTINY-Breast09 type of treatment will take quite a long time in several European countries and may not come, because, for the moment, we only have progression-free survival. We don’t have, as Javier said, the full results of the trial of the T-DXd arm alone. That will be important. Also, one last point I would like to make. With the maintenance strategies, in DESTINY-Breast09, trastuzumab, pertuzumab, and a taxane (THP) was compared with T-DXd, not THP with maintenance, obviously, because it was not the standard. We have three trials that came up more or less at the same time, and we are now assuming that we can go with a maintenance strategy after T-DXd, but that was not studied. I think there are many unknowns and future trials may help us to decide on the duration of T-DXd. Rugo: Two really important points include what we call maintenance; we’ll talk more about that in just a moment, since patients did receive trastuzumab and pertuzumab as maintenance. Endocrine therapy was allowed, but a shockingly few number of patients received endocrine therapy, particularly in the T-DXd plus pertuzumab arm. We’ve seen this also in other trials, including, even in trials that were studying maintenance with, for example, tucatinib in HER2CLIMB-05. The second area is that when we give a treatment, the duration of treatment and when you can benefit from maintenance plays a really big role. Sandra mentioned about the importance of thinking about biomarkers and who’s an excellent responder and who isn’t. Some of these data are now being taken into the neoadjuvant setting to try to deescalate or give appropriate therapies for tumor biology. I want to emphasize what Sandra said because that’s really important when we’re thinking about treatment; that trial has helped us so much, but helped us to identify the patients who might benefit the most from specific therapeutic approaches, both in intensifying and giving less-intensive therapies. When to Continue, De-escalate, or Change Maintenance TherapyRugo: Javier, that leads us into this maintenance question of how long do we treat? There were interesting data from DESTINY-Breast09 looking at patients who had a very good partial response or complete response, defined as 80% or greater shrinkage. I think of that as patients who do well, do well, so that it may be just really an indicator of biomarkers. How do you decide how long to treat? Would you ever use, if you could, a T-DXd plus pertuzumab followed by maintenance approach, given that we don’t have T-DXd alone right now? Lastly, what’s your preferred maintenance strategy? If you could have all drugs approved, all available, what would you do? Cortés: First of all, I think the data you are referring to are very interesting, but I do not know if we are understanding the results properly. Of course, the better the response is, the better the progression-free survival might be. That’s nothing new. The point is, if we stop today the treatment or we stop the treatment tomorrow, are we going to have a deeper grade of response? I’m not sure. I can tell you something. I have patients who stopped T-DXd because of toxicity, and I was unable to re-treat the patient again, and 2 months later, without any treatment, the response was better than before. Maybe there is a delayed response even without continuing treatment. My point is, which is the optimal duration of treatment? The answer is clear: I don’t know. The point is how to treat the patient in the clinic. We designed the DEMETHER strategy. Let’s see how it goes. There are other strategies similar to that with different durations. Also, let’s see the outcomes of these strategies. The point here, which is very interesting, Hope, is what you said before: the optimized maintenance strategy. If we do something like an induction, with T-DXd or whatever the induction is — wow, a very important and very interesting question also. I would love to see in the future clinical trials with T-DXd with or without pertuzumab as an induction, looking at the optimization in the maintenance, maybe inavolisib in the future or maybe other endocrine treatments. I don’t know. I think there are many questions here and just a few answers. We are starting to know much better how to treat our patients.Rugo: That’s great. Great point, and I think well said that, you know, I think now with the PATINA regimen using palbociclib, that’s really become, in some ways, a standard for our maintenance approach, giving palbociclib plus the endocrine therapy and HP, and it emphasizes the importance of endocrine therapy, which apparently is underutilized in general.We’ll have tucatinib coming up, and as you mentioned, inavolisib being studied in patients with PIK3CA mutations. Sandy, how do you deal with the next treatment steps? How do you sequence therapies now? If you were going to start with T-DXd plus pertuzumab or the CLEOPATRA regimen, what’s your sequencing strategy?Swain: I think the data are very clear that T-DXd is extremely active second, third, fourth, and fifth line. I would prefer to try with THP or the CLEOPATRA regimen first for most patients. If, for some reason, for example, if they had CNS disease, if their tumor had the PIK3CA mutation or something like that, I might start with T-DXd.I would not treat until progression. I would use the DEMETHER approach or the DB-Guide approach, which is coming up, and do it that way, and use HP. The next treatment, the question is, do you do T-DXd again if they’ve had a response or do you go to something else? We don’t have an answer for that. The DB-Guide study is looking at that, basically giving a few cycles of T-DXd, then following it with HP and then on progression, going back to T-DXd. It’s not a randomized study, but it will give us some answers there. That could be one consideration if the patient did respond initially, to go back to T-DXd, or use any of the other combinations, tucatinib or whatever else is out there.One other point I wanted to make: We were talking about trying biomarkers and trying to figure out who to treat with what. I think HER2DX is something we’re looking at, and have looked at in CLEOPATRA. With the higher mRNA ERBB2 score, those patients did very well within CLEOPATRA with the THP. I think using something like that could be helpful, and it also shows that those patients’ tumors that are very sensitive to HER2-targeted therapy are going to be sensitive to something else. That’s what we see in practice. I’ve had patients who are on [therapy] for 10 years and are sensitive to the next treatment. I think what we need to figure out is which ones truly are driven by this HER2 oncogene and can respond to further treatments. Rugo: That’s such a great point and a really important direction to go in as we look at these data, so that will be very informative. I think that the other question really is you get these patients who have fabulous responses, and then they show up with a brain metastasis. The question as we look forward is going to be as we see further data with DESTINY-Breast09, both with and without pertuzumab, if we’re delaying the emergence of brain metastases or decreasing them may be an important outcome point in looking at these biomarkers to try and understand who’s at risk.Fatima, when do you incorporate the tucatinib triplet now into your treatment regimen? Is that the next sequenced treatment that you would use? Cardoso: Regarding the treatment of patients with brain metastases, I think we may even consider even if somebody has immediately a brain metastasis. T-DXd is obviously an option, but to do the THP, so the CLEOPATRA regimen, followed by maintenance with tucatinib, I think it’s also something very good. We need more data to understand if the maintenance with tucatinib also delays the appearance of brain metastases, the same as we need to understand from DESTINY-Breast09 if it also delays the appearance of brain metastases. I think all the longer follow-up of these trials will help us take that decision. In general and independent of this discussion, I tend to favor an earlier use of tucatinib when there are already brain metastases. Let’s say if I have estrogen-receptor (ER)-positive, HER2-positive disease but already with brain metastases, instead of maybe the maintenance with PATINA, I would favor maintenance with tucatinib. We need to take that into consideration. Also, I think it’s important to discuss about the local management of brain metastases. As medical oncologists, I hear sometimes people just over-optimistic about the effect of systemic therapy and forgetting how the techniques have advanced in radiation oncology and how we can treat so well, with very little toxicity, limited brain metastases — not extensive, but limited brain metastases.Rugo: I think that’s an important point, too. I find that if we’re treating people for a long time and keep radiating, it does tend to have a little bit more effect. That’s one of the things about maybe reducing the amount of radiation we need to give over time is so important.When Should Endocrine Therapy Be Added to HER2-Targeted Treatment?Rugo: Javier, as we come to a close now, our last questions. Do you use endocrine therapy with HER2-targeted therapy as a treatment approach? When do you employ the tucatinib triplet in terms of your sequencing? The third part of that is, do you continue trastuzumab or HER2-targeted therapy throughout the entire duration of treatment for metastatic HER2-positive disease?Cortés: I don’t know if I use trastuzumab for the entire treatment. In general, if I think that the patient is doing as good as we might expect in HER2-positive metastatic breast cancer, I would consider continuing with anti-HER2 therapies. I do not consider to rebiopsy the tumor, but the other way around, if something is not clear to me.Regarding tucatinib or T-DM1 after T-DXd, I do not have strong evidence. That’s my personal opinion that one approach is better than the other after T-DXd. When you look at the real-world evidence, it’s not that different. I think that both approaches are good, tucatinib-based or T-DM1. I think that we have to discuss with the patients the pros and cons, but both approaches are good enough in my opinion. The other way around, in the fourth line of treatment, I would go to the other approach. I think that in general, yes, I would continue for the majority of strategies with anti-HER2-based therapy during all times, but it is not 100% or 0%. I think that sometimes there are, of course, exceptions that we have to address properly.Cardoso: Hope, if I can just say one thing. For the ABC guidelines, we did a study on purpose to look into valid data to allow for use of trastuzumab beyond progression, which is not allowed in many countries. We clearly showed using real-world data that if you stop blocking the HER2 pathway, the progression is much faster. Hence, if you are in a country and you don’t have access to all these anti-HER2, continuing trastuzumab beyond progression is better than just stopping any anti-HER2 therapy to just give chemotherapy. Rugo: That’s a really important point. The other key point here is that we are seeing some changes in HER2 positivity potentially after T-DXd. It’s hard to know because there’s so much heterogeneity depending on where you biopsy and how much tissue you have. If a patient isn’t having the response that you expect, it is worthwhile to go back and recheck HER2, because occasionally, you know, as I think Sandra mentioned in the very beginning, HER2 2+ with a low copy number and a low ratio, those patients may lose HER2 very early. We don’t really know how that affects our decision-making, but it is something to keep in mind as you’re thinking about sequencing therapy. We’ve come, unfortunately, to the end of our time, but we’ve had an amazing discussion. This has been so interesting. I want to ask if you have a one-sentence conclusion about your take on this right now. Sandra, do you want to start? Swain: One other comment that we didn’t really talk about was the CDK4/6 inhibitors, and there’s a large amount of activity with those in HER2-positive disease, so I would just make that comment. We have the MINI trial and some other trials showing very good responses. I think using those later on, even though it really hasn’t been studied that much, is something to think about. I’ve had personally a patient who had an amazing response in that situation. Rugo: Yeah. I have a patient who’s still on 4 years later with a combination of endocrine therapy, CDK4/6 inhibitor, and trastuzumab in the later line who didn’t have access to those new drugs because [her disease] was diagnosed so long ago. Fatima? Cardoso: My point would be that we didn’t have much time to go into toxicity and just to highlight that when we have two options, and in this case we are fortunate to have two options for the first-line and also different options for the further lines, it’s important also to present the toxicity to the patients and have shared decision-making regarding the toxicity.My other point is obviously for those who live outside the countries that have access, to fight for access for some form of anti-HER2 because, as we know, this was a complete change of the natural history of one of the most aggressive subtypes of breast cancer. Rugo: Yes, and in many ways now the most treatable, which is an amazing shift over the last three decades. Toxicity management, indeed, we didn’t have time to cover; it’s our next webinar. It’s incredibly important, as you pointed out, not just managing toxicity when it occurs, but being proactive with preventive strategies. We really have a large amount of data on optimal preventive strategies. Now, Javier, you’ll end our webinar.Cortés: One final comment. I think that we address the most important things, in my opinion. We have great drugs, great strategies, but we have to understand what is best for our patients. I think that sometimes crossover is very important to understand how to treat our patients. It’s not just to have the good drug. It’s where these drugs should be better used. In the future, we have to design clinical trials that are also thinking about how to help patients at the end, not only how to approve drugs. Rugo: That’s such an incredibly important point to end on. As we know and didn’t mention in DESTINY-Breast09, actually a rather surprisingly small percentage of patients received an antibody-drug conjugate as second-line therapy regardless of the arm. Obviously, longer follow-up is going to be required to understand the exact percentage, but thinking about sequencing is key as we incorporate crossover of approved drugs already shown to improve survival into our clinical trial designs. Thank you very much. It’s been a fabulous discussion. I also want to thank our listeners for listening to our discussion today, and I hope that you find it useful.