Evolving Treatment Strategies for HER2+ Metastatic Breast Cancer

Megan Kruse, MD, discusses the evolving treatment landscape for patients with HER2+ metastatic breast cancer.


Megan Kruse, MD: Hello, everyone. I’m Megan Kruse, breast medical oncologist at Cleveland Clinic, and today I’ll be providing an update on the management of HER2-positive metastatic breast cancer with key updates from our national meetings.

In terms of selecting how we sequence agents for the treatment of HER2-positive metastatic breast cancer, things have become more complicated in the last couple of years because of the approvals of multiple drugs in this space, specifically in the second- and third-line metastatic treatment after initial treatment with the CLEOPATRA (NCT00567190) regimen, or taxane, trastuzumab, and pertuzumab. In the second and third line, we’re really thinking about 2 main regimens that were newly approved, and that is trastuzumab deruxtecan or T-DXd, and then the tucatinib-based regimen of tucatinib, capecitabine, and trastuzumab, which we call the HER2CLIMB (NCT02614794) regimen. And they are really trying to figure out where to position them amidst our prior standard of care in the second-line therapy, which is T-DM1, or ado-trastuzumab emtansine.

The clear standard of care right now for first-line treatment of HER2-positive metastatic breast cancer remains the combination of a taxane with trastuzumab and pertuzumab, as per the CLEOPATRA regimen. After that, we have a couple of different treatment options in the second-line setting. The treatment option that I often reach for these days is that of trastuzumab deruxtecan, or T-DXd. And this really is because of the results from the DESTINY-Breast03 (NCT03529110) trial where T-DXd was compared head-to-head with T-DM1, or ado-trastuzumab emtansine, and showed a significant improvement in progression-free survival, as well as an improvement in overall survival. That changed my practice and is also now reflected in the NCCN [National Comprehensive Cancer Network] guidelines as a preferred second-line regimen.

When I think about treating a patient with HER2-positive metastatic breast cancer, some of the factors that go into that decision for me are: How well a patient is doing overall, what’s their global health status, what other medical conditions might they have that influence our choice of therapy. And, how quickly do I need a response, in terms of where their cancer is and the complications it might cause? For patients with general visceral disease, we have multiple different options in the second-line treatment, but for those patients who have more of a visceral-crisis-type picture, where I need urgent response in their disease in order to maintain organ function, that is where I’m reaching for trastuzumab deruxtecan because it has extremely high response rates, over 60%, near 70%, for women with HER2-positive metastatic breast cancer in the second line. We see great responses in women who have visceral involvement, including those who we’re most worried about with liver involvement. The other group that comes to mind here is patients with brain metastases. And for those patients with brain metastases, I’ll often reach for the tucatinib-based regimen of tucatinib, capecitabine, and trastuzumab. This is because in the HER2CLIMB regimen that got this combination of treatment approved, that study included patients with active brain metastases and was powered for end points, specifically looking at the groups of patients with brain metastases. So, this is a patient population I’m very comfortable with using [a] tucatinib-based regimen. We know that trastuzumab deruxtecan also has activity in the CNS [central nervous system.] The patients who were included in the DESTINY studies with brain metastases had stable, treated brain metastases rather than active metastases. And that’s really what differentiates the 2 groups from the HER2CLIMB study versus the DESTINY studies.

Patient preferences play a huge role in treatment selection and treatment sequencing, and that can be on a variety of fronts. And I think when we’re trying to decide between the main treatment options in the second-line setting for HER2-positive metastatic breast cancer, we have to keep in mind that we have IV-based options and an option that is mainly oral treatments, although there is still an IV or subcutaneous drug that is included in there with the trastuzumab. Patients feel very differently sometimes about whether they want to receive IV agents versus oral agents. The schedule also matters. Medications like trastuzumab deruxtecan or ado-trastuzumab emtansine are IV once every 3 weeks, which despite being inconvenient because they are IV, they can actually be easier from a scheduling perspective than the HER2CLIMB regimen of tucatinib, capecitabine, and trastuzumab, which has a lot of moving parts. That regimen has the IV once every 3 weeks in addition to 2 different pills that are on 2 different schedules. There has to be some patient comfort level with managing those pills at home. There’s often a different financial burden, as well, with having those pill-based medications. So, those 2 things come into account from the logistics of therapy. We also think about how active the treatments are, which, thankfully, the treatments that I’m talking about in this setting are all very active against metastatic breast cancer. We can assure our patients that, in terms of anticancer efficacy, they’ll have a good option either way, and over the course of their disease, they’ll probably receive both of these options in due course.

For most patients, what they [decide] to do in terms of treatment selection or sequencing of treatments, has to do with the side effects of treatment. There are a couple unique side effects of each of these regimens that I would say patients really keep in mind. With trastuzumab deruxtecan, there is the risk of interstitial lung disease, and that is a toxicity that a lot of patients fear and should be educated on. There’s also quite a bit of hair loss that we see, and that can be very meaningful to patients in this setting. GI toxicity, nausea, vomiting, diarrhea: These are all things that can really impact day-to-day life and quality of life. So, those are the things that I’m focusing on when I’m counseling a patient. If they’re thinking about the tucatinib-based regimen, for sure, diarrhea. That is the thing that we talk about first, because managing tucatinib-related diarrhea early can make a big difference in a patient having better quality of life and being able to stay on treatment. That regimen is not so bad for hair loss, but it does come with the risk of hand-foot syndrome, which is a particular skin toxicity that can have a very large quality-of-life impact. So, there’s a lot to go through here in terms of treatment selection and sequencing for patients. Thankfully, we have really great options in this setting. We’re able to dive into the nuances, and many of my patients will have specific ideas of what they’re willing to go through and where they fall on that risk/benefit calculation.

Transcript edited for clarity.

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