Management of Brain Metastases Among Patients With HER2-Positive Breast Cancer

Margaret Gatti-Mays, MD, MPH, Ohio State University James Comprehensive Cancer Center, Columbus, discusses treatment options for patients with brain metastases from HER2-positive breast cancer as well as the data surrounding these approaches.

Transcript:

My name is Dr Margaret Gatti-Mays. I'm a Breast Oncologist at the Stefanie Spielman Comprehensive Breast Cancer Center at the Ohio State University. Today, I'm going to talk to you about the management of brain metastases from HER2-positive breast cancer.

HER2-positive breast cancer composes around 15% to 20% of all breast cancers. However, there's a large percentage of patients with HER2-positive breast cancer who will develop brain metastases over the course of their disease. Generally, only a small number of patients are found to have brain metastases at the initial metastatic diagnosis, and this is estimated around 9% of patients. However, over the course of their cancer, up to 50% of patients with HER2-positive breast cancer will develop brain metastases.

We know that patients with brain metastases do worse than those who do not have brain metastases. And within brain metastases, there are two main types: intraparenchymal and leptomeningeal disease. Patients with leptomeningeal disease tend to do far worse with a median survival of around 3.5 to 4 months.

How do we treat these patients? Dual treatment is recommended, and that's both a local therapy with either radiation like stereotactic radiation and/or whole brain radiation if there's diffuse disease, potentially surgery may be a local therapeutic option, especially if there's a large mass with a lot of mass effect. However, in combination with local therapy, systemic therapy is needed.

Now, historically systemic therapy has had limited effect. There's also been limited evaluation of systemic therapies in this setting because many clinical trials have excluded these patients with brain metastases or leptomeningeal disease.

When we think of the main treatment regimen for HER2-positive disease, we think of the CLEOPATRA regimen (docetaxel, Herceptin and pertuzumab). The initial CLEOPATRA study excluded patients who had brain metastases. However, a post-hoc analysis did find that patients who were in this trial while they did not have brain metastases to start with, that a small population of those patients enrolled on the trial did develop brain metastases over time.

What Dr Swain and colleagues identified was that patients who received pertuzumab who ended up developing brain metastases experienced longer progression-free survival,15 months vs 11.9 months in patients who did not receive pertuzumab. Also, their median overall survival was longer, with an estimated median survival of around 34 months vs 26 months in the patients who just received docetaxel and Herceptin. This suggests that with the addition of the pertuzumab, not only do we get better systemic control, but we likely also obtained better control of the development of CNS disease.

Our second-line regimen is T-DM1 or Kadcyla. Again, many of the initial studies excluded patients with brain metastases. An ongoing study called the KAMILLA trial is now looking at the evaluation of T-DM1 after first-line therapy with THP. And in this KAMILLA study, there's also a small CNS population.

Again, we found that in patients who had better systemic control with T-DM1 or Kadcyla, they also had better CNS control. I think the first point to make when thinking about the management of HER2-positive breast cancer that has metastasized to the brain, is that better systemic control leads to better CNS control.

Fortunately, in recent years, there's been a plethora of agents that have been approved for the third-line setting and beyond in metastatic HER2-positive breast cancer. One of the questions and one of the things we're going to primarily focus on today is how do you choose which regimen to use in a patient with CNS metastases?

My general approach after first-line therapy with THP and then second-line therapy with T-DM1, the third-line regimen would be involving an agent called tucatinib. Tucatinib is combined with Herceptin as well as Xeloda. And this is based on the HER2CLIMB trial. In this trial, patients who had brain metastases that were not only treated, but also ones that were active were included. In the general brain metastases cohort, the 1-year CNS progression-free survival in the tucatinib arm was 40%. Whereas those who received only Herceptin and Xeloda, the CNS progression-free survival at 1 year was 0%.

I always find this number astonishing because it speaks to how impactful a single agent can be in a setting where treatments are needed. The 1-year CNS overall survival in the brain met population in the HER2CLIMB trial, the tucatinib arm, was 70% at 1 year and in placebo it was 46.7%.

In this study, they also looked at patients who had active brain metastases, and these were defined as untreated or treated and progressing. The 1-year CNS progression-free survival in this population for tucatinib was 35% vs 0% in the placebo arm.

Something that also is interesting and important to keep in mind—this data is still very early. This is an ongoing investigator-initiated trial that's actually looking at the HER2CLIMB regimen in patients with leptomeningeal disease who have not received treatment. And what the investigators have found, and this was presented at ASCO in 2020, was that there were adequate tucatinib CSF levels. And these were similar to the plasma levels in these patients. This is the first documented evidence that tucatinib is found in the CSF and this is really exciting. This, I think, supports the clinical data that was found in the HER2CLIMB trial. But the efficacy analysis is ongoing at this point and we eagerly await it.

Once a patient progresses on tucatinib, my next line of therapy really depends on the total volume of cancer that is present. If a patient has a high volume of disease, my next selected agent would be trastuzumab deruxtecan based upon the DESTINY trial.

The DESTINY trial included patients with treated stable or asymptomatic brain mets. They did perform a CNS subgroup analysis, which was just recently presented at ASCO 2021. In this group, it was a small population, only 24 patients and 17 of these patients had brain metastases at baseline. However, they did see that HER2 does have activity in the CNS with a median progression-free survival of around 18.1 months and an overall response rate of about 58.3 months. This is very similar to the intention to treat population in the HER2 study or in the DESTINY study.

Furthermore, when they looked at the assessment of the CNS lesion, those patients who had measurable brain metastases at baseline, about 40% had a partial response and about 25% had stable disease. While this sample is small, I think it's very promising data, especially given the activity that is seen within HER2 in our HER2-positive patients.

If a patient did not have a large volume of disease after progression on tucatinib, instead of using Enhertu (trastuzumab deruxtecan), I would probably next go to neratinib, which is data from the NALA trial. In the NALA trial, they included patients with treated stable or asymptomatic brain mets. They had a secondary end point of the trial, which was the time to intervention for CNS metastases, which included radiation, surgery, or CNS-directed concomitant medications. What they found in the arm that received neratinib, the incidence of the CNS intervention was 22%. Whereas in the arm that received lapatinib, the CNS intervention was 30%.

In this study, as a reminder, both the neratinib arm and the lapatinib arm, patients received Xeloda as part of the treatment. Patients had either received neratinib or lapatinib. And so the NALA study suggests that neratinib may be a little bit more of an active agent in the CNS. And that's why I would probably use this following tucatinib.

One of the other agents that recently has been approved and has generated some excitement is Margenza or margetuximab. And this is based on the SOPHIA trial. However, in the CNS metastases subpopulation, there really is limited data and really there have been no brain metastases specific end points that have been reported to date from this trial. At this time, I do not think that I would use margetuximab specifically for patients with brain metastases. But obviously this is an option in this HER2 population that has metastatic cancer.

After we've exhausted our options with tucatinib, and then either trastuzumab deruxtecan or neratinib, it was the third-line setting in the CNS either being the opposite of if I use trastuzumab deruxtecan, I would then use neratinib, or if I had used neratinib, I would use trastuzumab deruxtecan next. Kind of the next line of therapy in CNS disease, you could consider either lapatinib and capecitabine based on some of the earlier trials or kind of our old trustee, trastuzumab plus chemotherapy. Again, I think some of these older studies did not show a ton of benefit in CNS disease, although clinically we've been using these combinations for many years.

To summarize, with patients after progression on the CLEOPATRA regimen with THP, which we do see that there is some CNS activity specifically in the delay of development of brain metastases. And then after second-line therapy with T-DM1, which again, we do see some activity in brain metastases, the next-line therapy would be the HER2 regimen or tucatinib, capecitabine and trastuzumab.

Of course, this would be a reasonable second-line option in the place of T-DM1, if the patient had active CNS disease after completing THP. After tucatinib, either if they had high disease, I would consider in HER2 treatment. If they had relatively low volume disease, I would consider neratinib and capecitabine. After patient progressed on those regimens, if I had used deruxtecan, I would use neratinib and vice versa. And then finally moving into either lapatinib or trastuzumab plus chemotherapy.

What's exciting about the treatment of HER2-positive brain metastases is that this field, there's a lot of interest and there's a lot of promising agents and also additional information about the activity of these recently approved agents is still forthcoming, but is encouraging. Thank you.