Paradigm Evolving in HER2+ Breast Cancer With CNS Mets

Shannon L. Puhalla, MD

Central nervous system (CNS) metastases remain challenging to treat in patients with breast cancer, and incidence and outcomes have been found to vary depending on subtypes of the disease.

Recent developments in systemic treatments for HER2-positive disease, such as neratinib (Nerlynx) and tucatinib (ONT-380), have demonstrated an improvement in disease control. Positive data have also been reported on ado-trastuzumab emtansine (T-DM1; Kadcyla) which, according to Shannon L. Puhalla, MD, is challenging the dogma that the blood—brain barrier is impenetrable.

For example, a phase Ib trial that evaluated tucatinib in combination with T-DM1 in pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, found that the 2-drug regimen showed encouraging antitumor activity.

In the study, 50 patients were treated with tucatinib at a recommended phase II dose of 300 mg twice daily plus T-DM1 at 3.6 mg/kg intravenously every 3 weeks. In patients with CNS metastases, the objective response rate was 47% and the median progression-free survival was 6.5 months. The combination was determined to be well tolerated, with the majority of adverse events categorized as grade 1.

However, there have not been similar advances in patients with triple-negative breast cancer (TNBC) who have CNS metastases. Larger studies are necessary to better understand subtype- specific outcomes, and novel treatments are needed to control CNS metastases and systemic disease, Puhalla explained.

OncLive: What are the key takeaways from your presentation on brain metastases in breast cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Puhalla, an oncologist at the University of Pittsburgh Medical Center, discussed some of the advances being made in systemic treatment for patients with brain metastases from breast cancer.Puhalla: Part of what is important to know is, historically, how often do brain metastases from breast cancer happen? What are the differences among the different subtypes? Are there differences among HER2-positive brain metastases compared with TNBC brain metastases compared with estrogen receptor [ER]—positive brain metastases? The short answer is, “There are.”

Although patients who have HER2-positive disease have a higher incidence of brain metastasis, they do better [on treatment for brain metastasis] than, for instance, someone who has TNBC or ER-positive disease, where the brain metastasis happened very late in the disease course and treatments are more limited afterward. I also provided a brief overview looking at different treatment strategies, specifically local therapy and systemic therapy, which is our [challenge] as medical oncologists. What can we get from a drug standpoint?

Historically, there has been this idea that the blood—brain barrier keeps everything out and there’s no way to deliver systemic therapy; however, there are actually data showing that this is not the case. Particularly for HER2-positive disease, there is an interesting study looking at radiolabeled trastuzumab [Herceptin] where you can actually see uptake within the CNS. There are also some data with T-DM1, which we thought of as this big bulky trastuzumab molecule that wouldn’t get into the brain; actually, there can be some efficacy. Therefore, it is really challenging that old dogma that the blood–brain barrier is impenetrable; certainly, it’s different from systemic circulation, but when you’ve got a leaky blood tumor barrier, and you have the blood–brain barrier in a postradiation setting, there probably is some drug there.

I highlighted some of the advances made in systemic treatment in my presentation, as well. Really, where we have seen a lot of advances is in HER2-positive disease. One example is the small-molecule tyrosine kinase inhibitors [TKIs], such as neratinib and ONT-380; we have the data for those. There have also been many interesting studies looking at brain metastasis and, in particular, not looking at the treatment as something that happens after local therapy, but in some cases, in lieu of local therapy. Could you start with systemic therapy instead of jumping right into radiation therapy?

What is the prevalence for the different cancer subtypes?

What is the biggest clinical utility of neratinib and tucatinib?

Could you explain how some of these agents are challenging the belief that the CNS is impenetrable?

I also spoke a bit more about TNBC. Unfortunately, with TNBC, we haven’t seen advances in the brain metastasis population; it’s very difficult to treat in general. However, there are also some studies looking at CDK4/6 inhibitors as therapy for brain metastasis as well as in ER-positive disease. I tried to provide an overview of where we are now, in 2018, with new studies evaluating how we can look at systemic treatment for brain metastasis.There was a registry study that was conducted, which looked at 400 women with brain metastases as well as the breast cancer subtype, and more than half of patients were HER2-positive. Within that HER2-positive group, 26% of patients were ER-positive and 31% were ER-negative. Then a much smaller population were ER-positive, HER2-negative at about 20%, and about 24% had TNBC. Then, there was a registry study done by Adam M. Brufsky, MD, PhD, which suggested that about 35% to 40% of women with HER2-positive disease will develop brain metastasis at some time in their disease course, and so in that population, it is a big problem.That’s a great question. The utility is multifold, and what we have seen very truly in the brain metastasis studies is that you have to have a drug that’s systemically active or else you won’t get any mileage at all with brain metastases. If people are progressing outside of the CNS, it doesn’t matter as much how well a drug works in the CNS, and that has been a limitation with lapatinib [Tykerb]—it just didn’t work well enough. With that now, we’re looking at more irreversible HER2 TKIs, or TKIs that have a stronger affinity.The idea of challenging the dogma of agents getting into the CNS is very important, and we certainly have data with a number of agents. The challenge is, it’s not at the level of the systemic absorption, but it certainly can get in—even with big, bulky drugs such as trastuzumab or T-DM1—and those data are there. It’s no longer a situation of not being able to count on systemic therapy to help.

With regard to both local and systemic therapies for metastases, are there any adverse events to be cognizant of?

There’s an ongoing SWOG study looking at that in TNBC with platinum agents and with veliparib [ABT-888]. There are a number of studies out there; the problem with those studies is identifying patients who have progression and trying to hold off on that immediate stereotactic radiosurgery or the immediate referrals to get radiation so that they can potentially try these systemic agents instead.The biggest challenge is that whole brain radiation therapy can be quite toxic, and if we have an opportunity to avoid it with sequential stereotactic procedures—with medical therapy—that’s extremely important. I am always frustrated to see a patient who has had whole brain radiation and then it limits what we can do down the road, particularly if it’s something that could have been treated with stereotactic treatment, so that’s another thing where I urge patients and oncologists to seek out those opportunities when they’re faced with a brain metastasis diagnosis.

Borges VF, Ferrario C, Aucoin N, et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ meta- static breast cancer (MBC), including patients (pts) with brain metastases. J Clin Oncol. 2017;34(suppl 15; abstr 513). ascopubs.org/doi/abs/10.1200/ JCO.2016.34.15_suppl.513.