Selecting and Sequencing Therapy in Patients with HER2+ mBC and CNS Metastases

Vijayakrishna Gadi, MD, PhD: One of the things I often get asked about is, what’s going on with brain metastasis in this particular disease. [There are a] few basic rules. Biologically, if any cancer is HER2-positive, it has gained a proclivity or tropism to get into the central nervous system [CNS]. Unlike many diseases where the longer you have the disease, the brain just happens to be a site that the disease crawls into, with HER2-positive disease, it is a preferred site. This happens pretty early in diagnosis. When I ask and query trainees and colleagues about what they think this number is, often they are underestimate the number. Based on historical data, half the patients within the first 2 lines of therapy will developed brain metastases in HER2-positive metastatic breast cancer. It’s a very common early event. That’s the importance of having brain-penetrating molecules and interventions, in terms of being able to prevent those things from happening, but also to treat it when it does happen. It’s a very common problem.

As an extension of this idea of brain metastases being common, what is the granularity of the data with molecules like tucatinib and trastuzumab deruxtecan in managing the brain metastases? Reflecting on the HER2CLIMB trial [NCT02614794] , the investigators not only included patients who had stable treated brain metastases, but they also included a large number of patients who had active brain metastases. What we saw in that population was multiple things. One of the primary end points that was coded into the study was to look at progression-free survival in patients with brain metastases. And that was achieved. Then, in the exploratory studies, you see survival benefits in that group, [and] you see patients who actually have responses. [The] cancer’s getting smaller after being treated with this. Then, [as] an additional exploratory end point, you see the delay of onset of new brain metastases. This is a very clearly active agent inside the central nervous system.

Of course, when you have brain metastases, we think about the blood-brain barrier being disturbed. One thing you’ll see, even historically, looking at other large bulky molecules, [such as] trastuzumab emtansines [and] pertuzumab, you do see a hint of a signal of being able to control disease in the brain, but it’s not very clear. The studies were certainly not set up to specifically answer that question head-on. One thing that people have seen in some studies looking at the patients who have brain metastases in the studies with trastuzumab deruxtecan is a hint [at] a signal of improvement of the disease in the brain. This is a little challenging because some of the patients entering those studies had just had treatment for the brain metastases. While that disease is continuing to shrink, we might inadvertently ascribe that as a positive association with the trastuzumab deruxtecan. We can’t exclude that possibility, but the early signals are that this is potentially a disease that can have some impact through trastuzumab deruxtecan. I think the principle still holds true, in general. The better our disease control below the neck, the less likely patients are going to keep showering the metastases into the central nervous system. It’s a pretty complicated space. The most robust data is around the tucatinib molecule, but certainly, we see evidence that we could get control with some of these others.

The real challenge now is, when a patient has brain metastases, as a doctor, not just looking at the data and saying, “No, it says do this.” How do you actually take care of those patients? It’s much more complicated than you would think. There [are a] lot of options available. I’ll just share with you what my personal approach might be. Although it’s not hard coded, it could be very different and dynamic depending on what’s going on in the patient. If I have a patient with an isolated brain metastasis or a handful of brain metastases that I can target and capture with very focused radiation therapy, such as SRS [stereotactic radiosurgery], I would do that and then consider using a very strong or potent agent that might control all the disease. In this case, it may be trastuzumab deruxtecan. However, if the decision-making is being driven by what’s going on in the central nervous system, I might still treat with SRS, but then I’m going to be more inclined to use a tucatinib-based regimen because I want to make sure that I don’t have to deal with those events over and over and over. That might be my option there.

This is also, of course, a negotiation with a patient. They might look at the toxicities that we explain to them, and they may make a choice, “Hey, I want to be on that one, or I want to be on that one.” That’s fine. I think we should have that discussion. Unfortunately, the trial populations are different enough that they’re just guideposts; they’re not very prescriptive about [whether] this is actually what we need to do. That takes real deep consultation with our patient, [and] certainly our other colleagues such as the neurooncologist, the neuro-radiation oncologist, and of course, the medical oncologist.

An extension of the brain metastasis, of course, is what is the status of the brain metastasis? If, for example, we’ve done radiation therapy, we assume a dead brain metastasis at this point. The high energy associated with radiotherapy is actually very effective, so it gives you the ability to continue to monitor the central nervous system but maybe select an agent that is more potent for systemic disease [ie, trastuzumab deruxtecan]. If a patient has active brain metastasis that you’ve not treated, that might be an option, especially for small brain metastases, [then] I think the only therapy we have that’s been proven in a properly done clinical trial for that question is the HER2CLIMB study [NCT02614794]. That’s tucatinib in that setting in combination with capecitabine, which is also a CNS-penetrating drug in combination with trastuzumab. For patients who have larger brain metastases [and] more disease burden, I think those are all considerations we might take that tilt us one way or the other.

Transcript has been edited for clarity.