Relapsed/Refractory HER2+ Metastatic Breast Cancer - Episode 1

Best Practices: HER2+ MBC With Brain Mets

Adam M. Brufsky, MD, PhD: Let’s do a polling question for the audience. What factors are important when deciding whether to continue current systemic therapy vs switching or recommending local therapy for a patient who develops CNS [central nervous system] progression after starting frontline therapy? Is it disease extent and location, rate of progression, presence of symptoms, patient age, availability of a clinical trial, or other?

The poll has ended. About half say rate of progression, 25% say disease extent and location, and 25% say presence of symptoms.

I’m going to open this to you guys. The analogy I like to make with this is to pediatric leukemia. In the 1960s, our predecessors did a great job of combination chemotherapy at the NCI [National Cancer Institute]. That’s how the NCI got started—pediatric leukemias and combination therapy with Dr Emil Frei, Dr George Canellos, and Dr Emil Freireich. Dr Gordon Zubrod was kind of part of it. They were really good, but then everybody had sanctuary sites. They all had brain metastases and the disease was not cured. It was considered cured, with 80% or 90% long-term survival, until they figured out the sanctuary sites.

This disease is kind of like that, right? We’re doing such a good job now systemically that we’re seeing people getting brain metastases. We all have those patients who we give a ton of radiation and then the patient gets radiation toxicity. They live long enough to see the long-term adverse effects of whole-brain radiation. I’m just curious. Let’s start with VK on this 1. What is your overall plan when someone presents with a brain metastasis? How do you handle it? If a woman with HER2 [human epidermal growth factor receptor 2]–positive breast cancer comes in with a brain metastasis, what do you guys usually do? You have a multidisciplinary practice. What do you usually do with it?

VK Gadi, MD, PhD: First, multidisciplinary is the right answer. We definitely enlist the opinions of our neuro-radiation oncologists and, if necessary, neuro-oncologists. We have more tools than we’ve ever had. Just to be clear, I’m not going to discuss leptomeningeal. This is the actual brain metastasis. In that setting, if a patient has symptoms, then you need to address the symptoms and that forces your hand to ask, “Do we need to excise this? Do we need to radiate this?” We go down that pathway. If the patient doesn’t have symptoms, it’s an incidental finding, or something that could be well managed with stereotactic radiosurgery [SRS], that becomes a viable option as well. That’s certainly what we had been doing: stereotactic radiosurgery. If you can salvage the systemic agents for below-the-neck disease, we’d continue those. But if we need to shift gears to an agent that has CNS activity, we can certainly make that shift as well.

Now things have changed. Obviously, we have tucatinib. We have a clinical trial clearly showing control of disease, treatment of disease, and treatment of active disease in the brain, and that’s become an option. How this is going to sort out over time is not clear in my practice. It’s still a case-by-case basis, but it gives us a pretty powerful tool to proactively manage the CNS metastasis with or without SRS. Maybe you try the systemic agents—especially if someone is having progression in other places like the liver, the lungs, etc. This makes a lot of sense, and then you could revisit the idea of SRS. Obviously, if somebody has a lot of lesions, we’re still getting backed into the corner of having to use whole-brain radiation with all the long-term toxicities that might impart.

Adam M. Brufsky, MD, PhD: That’s a good question. Have people started using this? To me, it seems like HER2CLIMB is where the bang for the buck is for people who don’t get therapy, initial local therapy for their brain metastases. Those are the ones who seem to have the progressive or untreated brain metastases. I’m curious: Neil, have you started using tucatinib-based regimens for the patients you don’t get on trial for whatever reason? Do you usually use tucatinib before you use SRS in these people?

Neil M. Iyengar, MD: I certainly have that conversation. There’s a lot to be said there. We know from HER2CLIMB that although it’s a subset and a bit of an exploratory analysis, we do know that there was a protective effect in terms of CNS progression with the tucatinib-based regimen for patients who did not receive local therapy to the brain.

That is an intriguing discussion to have with patients, whether one can forego local therapy. If it’s a question of something like SRS to a single lesion, my preference and the preference of our neuro-radiation oncologists is generally to proceed with SRS to the single lesion. But if we’re talking about more diffuse, maybe multiple parenchymal metastases and the question is whole brain vs something like tucatinib, that’s more of a discussion. We do tend to err on the side of local therapy followed by perhaps a switch of systemic therapy until we see more data for that cohort of untreated brain metastases population.

That being said, this ties together a couple of things that both Sara and VK have said about how we are seeing the natural history of this disease being changed. Adam, almost 10 years ago, you published that the prevalence of brain metastases in de novo HER2 metastatic disease was around 20%. We’re now seeing closer to 50%, at least in HER2CLIMB. As our tools evolve and we start to look at what is truly the definition of a first-line metastatic patient, given all the changes in the adjuvant setting, do we define that by minimal residual disease [MRD]?

Now that we’re looking at circulating tumor DNA assays on a research basis, 1 of the things we’re very interested in is whether we can look at MRD or circulating tumor DNA in cerebrospinal fluid, for example, and use that as a basis for assessment. This is all research based, and we can’t make any clinical decisions based on those assays as of now, but the field is moving in that direction. I certainly have that discussion because I see the field moving in that direction. I certainly do have that discussion with patients who are presenting with CNS disease. We do have a systemic therapy that is an option, although labeled in the second-line setting and beyond. With all those considerations, it is worthwhile to at least have that discussion with the patient before embarking on therapy.

Adam M. Brufsky, MD, PhD: It’s really cool. You reminded me of something. At last year’s ASCO [American Society of Clinical Oncology Annual Meeting], they looked at people’s response to trastuzumab deruxtecan. It had to do with the amount of circulating HER2 amplification they found. It was from cells or it was from circulating DNA. They figured out some assay they could look at amplification of the circulating DNA, and they used that to prognosticate people. That’s kind of cool. That’s where we may be going, right? I totally agree. Sara, what do you think of this whole thing?

Sara A. Hurvitz, MD, FACP: It’s interesting. A lot of research needs to be done. These are really exciting topics and times, and we’re just getting back on the clinical aspect from a patient perspective. We’ve got to improve the outcomes for patients with brain metastases, because study after study, including your register data, our sister’s data, and EMILIA data show that patients who have brain metastases have a worse PFS [progression-free survival] and OS [overall survival]. It’s a very consistent story, so we have to do better. I’m looking forward to clinical trials that will hopefully interrogate how to sequence locoregional therapy with systemic therapy.

Tucatinib is not the only agent. It’s the only approved agent with this substantial response in the brain: a 47% objective response rate in the brain. That’s pretty phenomenal and an overall survival benefit in those with brain metastases, but it’s not the only 1. There are drugs in development that are also HER2 selective and penetrate the blood-brain barrier. More and more, we’re going to have to try to figure out from a clinical trial standpoint how to optimally sequence these drugs in order to preserve patients’ quality of life and cognition, which is an important factor in quality of life.

I would like to point out that on the HER2CLIMB study, if you recall, patients who were on tucatinib or a placebo and had a CNS progression on study were allowed to have SRS or radiation and continue on study as long as they didn’t have an extracranial progression event. We can do that in clinical practice where patients are started on tucatinib-based therapy, and if they have an isolated CNS progression, you have data to support treating it locoregionally and continuing systemic therapy.

Adam M. Brufsky, MD, PhD: I agree. Before we go to the case, I want to raise 1 thing. Neil raised this, and that is the prevention of brain metastases. In other words, keeping them at some sort of micrometastatic state so they don’t bother people. This field is crying out for some sort of algorithm—clinical, molecular, whatever—to tell us up front when a woman walks in with de novo disease if we can get a sense of whether she’s going to get brain metastases, because those are the people we should apply the HER2 TKIs [tyrosine kinase inhibitors] to, right? But we’re waiting. I’m really struck by some of the data from neratinib—the NEfERT-T trial that was done a number of years ago, in which they treated people with neratinib and paclitaxel or trastuzumab and paclitaxel. The neratinib-paclitaxel cut the incidence of a first brain metastasis in half, as the first site of disease. That just tells us what these things probably have the capability to do.

Sara A. Hurvitz, MD, FACP: Yes, we’re seeing that with NALA and ExteNET as well. Hopefully the HER2CLIMB-02 trial of T-DM1 [trastuzumab emtansine] with or without tucatinib shows that we can delay CNS progression events and new CNS events. That would be great.

Adam M. Brufsky, MD, PhD: That would be great. That would be tremendous if we can do it. I want to ask you guys 1 last thing before we go to the case. This goes back awhile. I think Sara was involved in this. I don’t know if Neil and VK were. I was involved a little in this whole concept of T-DM1 [trastuzumab emtansine] preventing brain metastases. Now people are talking about trastuzumab deruxtecan somehow interfering with brain metastases. Do you think there’s something to that? Let me start with VK. This huge molecule doesn’t cross the blood-brain barrier as far as we know. Do you think it somehow influences the course of brain metastases? Do you think there’s anything to it?

VK Gadi, MD, PhD: I believe there are 2 theories behind this. There’s the idea that you have brain metastases that are established, and then you somehow sterilize the brain of those brain metastases when you do SRS, whole-brain radiation, or whatever. Then the goal then is to prevent new additional lesions from finding their way into the brain. If you have a drug that is very good at maintaining systemic disease at a low level where you don’t get new opportunities, then you would interpret that as an effect in the brain. In fact, you see it not just with this study, with T-DM1 [trastuzumab emtansine] in the EMILIA trial, but you also see it with trastuzumab and pertuzumab as well in the first-line studies, right? So that’s 1 theory.

But there’s some emerging evidence that these molecules are actually crossing the blood-brain barrier. They’re detectable in the central nervous system, and maybe they’re actually getting there in enough quantity that you’re imparting an effect directly on brain metastases in the brain and that these could be therapeutics for the brain. There’s a little bit of both kinds of thinking going on in this space.

Adam M. Brufsky, MD, PhD: Yes, I wonder how they get there. That’s the question I’m asking. How do they get there? Is it active? Is it passive? It’s an interesting question, but that’s more of a scientific question for later.

Transcript edited for clarity.