Treating HER2+ Breast Cancer with CNS Involvement

Transcript:

Megan Kruse, MD: Management of breast cancer brain metastases is a significant clinical issue when taking care of patients with HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer because over the lifetime of these patients, about 50% of them are likely to develop brain metastases. When we’re thinking about treatment of patients in this space, 1 thing we pay particular attention to is the activity of drugs within the central nervous system [CNS]. Thankfully, because brain metastases are a large problem in this patient population, many of our newer studies have been commenting on the CNS activity and permeability of these agents.

This is most obvious in the HER2CLIMB study, where patients who are treated with tucatinib, capecitabine, and trastuzumab or capecitabine, trastuzumab, and placebo were allowed to enroll in the study if they had several types of brain metastases. In this trial, patients were allowed to have stable treated brain metastases, which would be the most common population for a clinical trial. But patients were also allowed to have active untreated brain metastases, which is novel. It highlights not only the anticipated efficacy of the tucatinib-based regimen for CNS activity, which is what we ended up seeing in the study, but also a more progressive look at inclusion criteria for patients on clinical trials and the importance of having data that supports use in the space of patients with brain metastases.

This study was also important in that they did statistical modeling and planning for primary end points to be associated with the management of brain metastases, knowing this was an important subpopulation in the trial. When they presented their data, they’ve consistently updated patients who have intracranial involvement with disease, as well as the entire patient trial population.

Having this information has also changed the way we think about managing these patients and how frequently we’re looking at the CNS. Historically, brain MRIs did not have a major role in the staging of patients with metastatic breast cancer in the absence of symptoms. But now that we know our treatment paradigms may change based on the presence or absence of brain metastases, the importance of including brain MRI in up-front staging for patients with metastatic HER2+ breast cancer is a topic that we talk about all the time in clinic.

When we first had the results from the HER2CLIMB study, the presence of brain metastases was a big factor in which treatment we might select for patients following taxane, trastuzumab, and pertuzumab. That was because of the confidence we felt with tucatinib and the management of brain metastases. In further follow-up, we’ve seen updates from the DESTINY-Breast03 and DESTINY-Breast02 trials looking at CNS activity for trastuzumab deruxtecan. There’s also a look at this from the TUXEDO trial. With all this data combined, even though there wasn’t a group of patients with active untreated brain metastases in the trastuzumab deruxtecan studies, the data that we have shows that this drug is active in the CNS and that we get good CNS response for patients with brain metastases.

Now we’re at a point where we have 2 great treatment options, both of which are active in the CNS. We have to make a decision about what we use if we have a patient with HER2+ breast cancer with brain metastases. I don’t think you’re going to make the wrong decision in this space. Both treatment regimens would be active. It has a lot to do with other patient-related factors that you have to take into account. If I have a patient who has a lot of extracranial disease burden—let’s say they have rapidly progressing liver metastases or lung metastases—in that situation I might reach for trastuzumab deruxtecan first, knowing that they’ll have excellent response rates and potentially quick responses. If their CNS metastases aren’t the most symptomatic part of their disease, I want the agent that is going to be most active in body but also covers the CNS.

Of course, we don’t have a head-to-head comparison of trastuzumab deruxtecan or the tucatinib-capecitabine-trastuzumab regimen. This is all extrapolation from the 2 studies with the data that we have in front of us. If a patient’s CNS involvement is their primary symptomatic driver of disease, particularly if there are any challenges with getting them local therapy in terms of radiation or surgery, then I would reach for the tucatinib-based regimen, knowing that that trial had patients with active brain metastases enrolled in it. I can feel confident that for these patients, I’m using the most evidence-based strategy.

In all the data that we have about CNS metastases for HER2+ disease, there’s 1 piece that’s missing in an area of unmet need, and that’s for patients with leptomeningeal disease. Sometimes these patients present with both parenchymal brain metastases and leptomeningeal disease, or they can have isolated leptomeningeal disease alone. Finding information for these patients on the activity of all our agents— and helping them prognosticate—can be a real challenge because they aren’t well represented in studies. Thankfully, we do have a little data presented at the San Antonio Breast Cancer Symposium in 2022 on this topic from the ROSET-BM study. This was a study looking at patients with HER2+ CNS involvement consisting of active brain metastases, brain metastases that were not symptomatic or leptomeningeal involvement as defined by radiographic changes. The patients in this study weren’t required to have lumbar punctures and cerebrospinal fluid analysis to determine if there was leptomeningeal disease.

In this study, the investigators were looking at the activity of the trastuzumab deruxtecan regimen for patients with various types of CNS involvement. They found that the response rates were almost as good as what we have seen in the general DESTINY-Breast trials for patients with HER2+ metastatic breast cancer. In the study, we saw intracranial response rates for patients in the 50%-to-60% range, which is extremely encouraging. The median progression-free survival for these patients was about 16 months, which is longer than you might anticipate for patients with such a serious disease-related complication. Keep in mind that that number also includes patients with leptomeningeal disease, who are typically thought to have the worst prognosis of all. These are very encouraging data, and they provide some reassurance when I’m treating patients who are in this very unfortunate situation.

Transcript edited for clarity.