Case 2: Impact of Brain Metastases in HER2+ Breast Cancer


Ruta Rao, MD: Dr Tolaney, what are your thoughts on these options, and does the presence or absence of brain metastases in a patient influence what your next treatment selection would be?

Sara Tolaney, MD, MPH: As Dr Jhaveri alluded to, it’s a problem with having multiple effective treatment options, which is a nice situation to be in. In this third-line, post–T-DM1 [trastuzumab emtansine] setting, the presence or absence of brain metastases influences my decision-making for now. We have impressive data from the HER2CLIMB study suggesting a survival benefit in patients with brain metastases. That is not something we have with another agent at this time. We have to be careful, though, with what we mean by brain metastases because this particular patient had radiation, so she has what we would consider a stable treated brain metastases. This patient would have been eligible for the trastuzumab deruxtecan trial with an appropriate washout with stable treated brain metastases, and there were 24 patients in the trastuzumab deruxtecan single-arm, phase 2 trial that had stable treated brain metastases. Their PFS [progression free survival] was 18 months. This is similar to what we saw in the overall population, which is reassuring.

In my mind, both options are appropriate in a stable-treated brain metastases patient. However, if a patient had active brain metastases, progressive brain metastases, postradiation or de novo untreated brain metastases, we see people who sometimes have multiple brain metastases where they’re not a candidate for SRS [stereotactic radiosurgery] and would otherwise need whole-brain radiation. That’s a patient for whom I would turn to the HER2CLIMB trial regimen because I’d want to spare them whole-brain radiation, or they have progressive brain metastases postradiation. We know that there is a hazard ratio of about 0.5 after survival in patients with active brain metastases, so it’s important to think about tucatinib in that situation. In that situation, the preference would be to use the HER2CLIMB study.

Komal Jhaveri, MD, FACP: I want to add a couple of points as I’m hearing Dr Tolaney talk about this. There are 1 or 2 things we need to acknowledge and understand as a community when we’re thinking about these patients. We’re excited about these data, and we’re excited about being able to offer tucatinib to patients with active brain metastases. This is a huge leap in the way we think about these patients; we can offer therapies that are effective, and we definitely need more of that. However, it is important to recognize that the way they define active brain metastases is something that you’ll be able to see on your MRI, but it does not require immediate local intervention, meaning these patients are not necessarily symptomatic. Today, if you see a 4-cm brain lesion because the patient presented with blurry vision, a headache, or a focal neurological deficit, we’re not thinking about applying those data to those patients. We still have to resort to local interventions immediately for those patients. That’s 1.

The other thing we need to think about is what is happening to their systemic disease. The guidelines are there, and I’m sure we’ll be revisiting these guidelines as we get more data. Is the systemic disease decently controlled? What is the systemic disease burden? If there is extensive systemic disease that is also progressing at the time this patient is supposedly found to have progressing brain metastases that is not symptomatic but active with the systemic disease exploding, I’m still going to think about trastuzumab deruxtecan because it’s not a bad option given that the PFS and the responses that we’ve seen with that are significant. When we look at the subgroup analyses from the HER2CLIMB trial for the stable metastases patients, we did not see a big difference in the overall survival for that subgroup. There were small numbers; slicing the data down even further, one would wonder whether that lack of difference in the overall survival in that subgroup is driven by exploding systemic disease, meaning your brain was stable but your body disease was growing quickly, and that may be why there was not a big difference with the addition of tucatinib. This is something we have to keep in mind for the given patient we see in clinic.

Lastly, we definitely have our standard options of trastuzumab plus chemotherapy in the third-line-and-beyond setting. Those options are here to stay, and we can still utilize them eventually. These 2 exciting new options will certainly be our third-line choices for a given patient in front of us.

Transcript edited for clarity.

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