Ian E. Krop, MD, PhD

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I have a couple of questions that will be highlighting the ways in which the availability of HER2-targeted therapy has required adaptations to clinical practice. For my first question, how do you incorporate patient preference in treatment selection?

 I think we touched on that a little before. The advantage of having multiple options now for HER2-directed therapies is that we can tailor our therapies for individual patients. We certainly take into account things, as I mentioned, like hair loss. There are regimens like T-DM1 [trastuzumab emtansine] and the HER2CLIMB regimen, which don’t cause any significant alopecia; and we use those if patients are averse to losing their hair. Drugs like trastuzumab deruxtecan cause hair loss in about half of patients. Those are some of the considerations; also whether patients are able to travel to your infusion center easily, or an every-3-week infusion drug versus a weekly drug. There are big medical issues, like brain metastases, which I think would steer us more toward drugs like tucatinib-based treatment. Other inpatients who don’t have brain metastases can use this very effective agent trastuzumab deruxtecan, which has about a 97% disease control rate. Those are the medical issues, layering on top of patient preferences. The good thing is we have lots of options; most patients are going to get all of these drugs at one point or another, and it’s a matter of sequence.

How have you changed your practice to accommodate patients on targeted therapy in terms of patient care, and what are some of the challenges that may have come about?

 In the COVID-19 era, those kinds of practical issues have to be thought of even more than in the past. There is not a big difference between giving an infusion of trastuzumab versus an infusion of vinorelbine, or chemotherapy versus targeted therapy. In other words, there’s not a huge difference in terms of practical infusion issues. Particularly during the COVID-19 pandemic, we’ve been trying to minimize the number of visits patients have to have; using longer-acting therapies is helpful there. We’ve been trying to avoid using immunosuppressive regimens; that’s a reason to try to avoid immunosuppressive chemotherapy for patients, especially when COVID-19 was flaring in each of our areas. Those are some of the things we’ve been thinking about to try to make it easier for patients, cutting down visits, avoiding immunosuppression. I think those are the main things. The other issue is some of these are oral regimens, meaning you need to have nurses be able to call patients to make sure they’re taking the drugs appropriately at home, and they’re not having real problems managing things like diarrhea or mucositis. It helps to have more outreach to patients now that they’re taking more medications at home versus getting infusions in the infusion room.

As you mentioned the pandemic, did your use of HER2-targeted therapies for patients with metastatic breast cancer change during the COVID-19 pandemic, and if so, how? Do you think these changes will continue now that the COVID-19 vaccines are available?

 Yes, particularly when COVID-19 was really surging, we did our best to try to minimize the number of trips patients had to make, and used therapies that only required once-every-3-week visits or therapies that patients could take largely at home. There has been a push to try to use fewer infusions. There’s an interest in subcutaneous formulations of antibodies, which we now have with trastuzumab and pertuzumab. That’s been helpful because it means that if they have to come in [to the infusion room], it can be for a short time. There are people who are investigating whether you can get these drugs at home as subcutaneous formulations, and have nurses go to people’s homes to give them their subcutaneous injection, so they don’t have to come in at all. That’s going to require a whole new set of infrastructure if it scales, but it’s worth thinking about that. COVID-19 gave us a nudge that we needed to try to explore some of those things. Whether they’ll prove to be cost-effective and feasible for everybody post–COVID-19, we’ll have to find out. But it certainly made us think creatively, and we’ll probably come up with some kind of happy medium where we’re requiring patients to come in fewer times, and for shorter amounts of time, as much as possible.

Thank you so much, Dr. Krop, for your time. This has been an excellent discussion, and we hope you found the information to be valuable to your clinical practice. Thank you all for watching this 

Videos

The impact of the COVID-19 pandemic on the utilization of newer targeted therapies for HER2-positive metastatic breast cancer and considerations regarding their adoption into clinical practice based on the availability of vaccines.

COVID-19 and the Use of HER2-Targeted Therapy for MBC 

What is the rationale for the use of dual HER2-targeted monoclonal antibody therapy?

: There are now several different ways to do dual HER2 therapies. The one we first figured out was the combination of trastuzumab with pertuzumab, as you asked about, 2 different antibodies. That’s based on the fact that even though they both target HER2, they target different spots on the molecule, different epitopes on the HER2 molecule. That allows them to block the different types of signaling of HER2, and different methods of dimerization. That’s relevant because it looks like one of the ways cancers were getting around the effects of trastuzumab was activating a pathway, whereas HER2 would bind to other similar molecules that trastuzumab doesn’t block, but pertuzumab does. By combining trastuzumab and pertuzumab, you can block both of those signaling pathways and overcome resistance. That was shown in clinical trials to be advantageous with a big survival benefit compared to either one alone. There are also data combining antibodies like trastuzumab with tyrosine kinase inhibitors, like lapatinib or tucatinib. That’s a part of the rationale for the HER2CLIMB regimen, using both trastuzumab and tucatinib along with capecitabine. Because of synergistic effects on HER2 signaling, you get better efficacy than using one of those alone.

What are the data that led to the incorporation of dual HER2-targeted therapy as part of the treatment landscape for metastatic disease?

 That’s the data we were talking about. In the first line, we had this CLEOPATRA trial that compared chemotherapy and trastuzumab versus chemotherapy and dual therapy of trastuzumab and pertuzumab. There was a 16-month survival benefit by adding pertuzumab, showing unequivocally more efficacy when you use those dual approaches. There have been smaller studies looking at combining antibodies with tyrosine kinase inhibitors, including this HER2CLIMB trial, which used trastuzumab and chemotherapy with or without the tyrosine kinase inhibitor tucatinib. It showed a benefit in terms of survival by adding 2 HER2 therapies versus 1 alone.

Can you please describe some of the issues surrounding administration of dual HER2 therapy in the metastatic setting?

 There are some practical things. When you’re combining an oral therapy with an antibody, it’s more complicated for patients. They have to come in to get their infusions, and have to take oral medications at home. They need a lot of coaching for that to make sure they are taking their oral regimen correctly, and having to come in as well. There is a problem with using 2 different antibodies, each with its own infusion time, leading to longer times that patients have to stay in the infusion room. That’s being addressed in part by products combining trastuzumab and pertuzumab into 1 drug, which cuts down the infusion time. There are also subcutaneous versions of the combination, which completely get rid of the infusion time. The market is working to get around some of the hassles of using multiple HER2-targeted therapies. But until that problem is completely solved, it is more complicated, both for patients and providers, to use multiple HER2 therapies as opposed to 1; there is a cost.

As you mentioned cost, how do cost considerations factor into your treatment decision-making?

 Fortunately, I’m an academic oncologist, and I work in a state that has a relatively high number of patients who have good health insurance. But at least in the HER2 therapy world, cost hasn’t been much of a direct challenge for patients. It’s been a long time since I’ve had a patient have a problem with out-of-pocket payment for these drugs. Even the oral agent tucatinib, I haven’t had that issue so far. That’s what patients are experiencing; it hasn’t been a problem. These drugs are incredibly expensive, and it’s a big challenge for the health care industry and our society. We are combining more than 1 of them; obviously, that’s more expensive than using 1 drug alone. It is a societal problem that we’re going to have to deal with. But at least at the individual patient level right now, cost, in my experience, has not been a real problem in this particular arena.

The rationale for treating metastatic breast cancer with a dual HER2-targeted therapy approach. 

Dual HER2-Targeted Therapy for MBC

I know some of these targeted approaches may be used at different times. You mentioned a few examples. In general, when should target approaches be used in the metastatic setting?

: That’s a great question. I think unlike most other areas of breast cancer, in which sometimes we use target therapy, sometimes we use conventional therapies, in HER2-positive disease, it’s not really a question of when to use it. Because we’ve now shown in multiple studies that when you use a HER2-directed therapy, it’s always better than not using HER2 therapy. In every line of therapy we’ve looked at, using a HER2 therapy either by itself or with chemotherapy or endocrine therapy is always better than using the chemotherapy or endocrine therapy alone. In practice, what happens is, at least in the United States where fortunately these drugs are all available, we always have at least 1 HER2 therapy in everybody’s regimen. I think the data really support that. As we talked about, there are lots of different options, and how you sequence them can differ depending on patient preference and other factors. But I think the general sense is you should always have at least 1 HER2-directed therapy in your regimen, be it an antibody or a tyrosine kinase inhibitor, or a combination, or an antibody-drug conjugate.

Thank you. What are the considerations for deciding which targeted therapy is appropriate for a given patient?

 I think that’s where things are evolving and where clearly a one-size-fits-all approach doesn’t make sense anymore. As I was talking about earlier, I think whether a patient has brain metastases at least helps me decide whether you’re going to use trastuzumab deruxtecan versus tucatinib-based therapy. We didn’t talk about neratinib, which also seems to have some effectiveness in the brain. My opinion about this is that we should probably use tucatinib in most of those patients first, along with capecitabine and trastuzumab, and then you could consider using neratinib after that if they have progression. But with the caveat that we really don’t have any data yet on whether neratinib does work after the use of another tyrosine kinase inhibitor like tucatinib. I’m hoping we get some data on that.

Those are the kind of things that we should think about, whether they have brain metastases. Somebody who has prior significant pneumonitis probably would like to avoid using trastuzumab deruxtecan, at least until you’ve tried other regimens. People who have problems with their GI [gastrointestinal] tract would like to avoid the drugs that cause significant diarrhea. I think those are things that should be considered. Some of these drugs cause less hair loss than others. For a patient who’s averse to hair loss, trying to use a regimen that doesn’t cause hair loss first would make sense. It’s definitely something where you have to consider lots of different variables. But it’s nice that we have all these different options.

Ian E Krop, MD, PhD, elaborates on which treatment settings are most appropriate to use HER2-targeted therapies in to manage metastatic breast cancer.

Sequencing HER2-Targeted Therapies in MBC

 We have 4 new drugs, all of which are now approved, mostly in these patients who have had at least 2 lines of prior HER2-directed therapy. The question would be, how do you decide which one to use? For first-line and second-line therapy, we still use the tried-and-true standard of taxane, trastuzumab, pertuzumab in the first line, and T-DM1 [trastuzumab emtansine] in the second line. In the third line, we have these 4 new drugs. How do we decide which ones to use? I think different oncologists probably have different views. There’s no right answer here.

In my mind, it makes sense to use trastuzumab deruxtecan in patients who do not have brain metastases, or who had brain metastases treated a long time ago and never had another problem. The reason I think it makes the most sense to use that drug is because the efficacy of trastuzumab deruxtecan, which we really haven’t talked about yet, appears markedly more active than any of the other drugs we’ve had so far. The response rate in heavily pretreated patients is over 60%, and progression-free survival is approaching 20 months, which is roughly 3 times longer than what we’ve seen with other drugs in the pretreated setting. It works very effectively, very uniformly, and it tends to have very durable responses. I think it’s very nice to be able to tell a patient that you have a drug that’s going to work in the vast majority of people to some extent, and it’s going to likely work for a long time. One [adverse] effect of trastuzumab deruxtecan that we have to pay attention to is that in about 15% of people, you can get pneumonitis or interstitial lung disease, which can be serious and can be fatal in a small number of patients. That has to be monitored when you use that drug.

For patients who have significant brain metastases, using tucatinib-based therapy in the third line, to me, makes the most sense because the drug clearly shows activity in that setting. In the fourth line, you can switch to whichever one the patient didn’t get. After that, you can use this new drug margetuximab along with chemotherapy to take advantage of its immune effects. That’s in my mind how we integrate all of these new drugs, at least one approach for patients now that they’re all available.

Considerations regarding how to best integrate newer targeted therapies available for HER2-positive metastatic breast cancer [MBC] into clinical practice.

Ian E. Krop, MD, PhD

Articles

COVID-19 and the Use of HER2-Targeted Therapy for MBC

Dual HER2-Targeted Therapy for MBC

Sequencing HER2-Targeted Therapies in MBC

HER2+ MBC: Integrating Newer Targeted Therapies Into Practice