Joyce O'Shaughnessy, MD: Let’s talk about brain metastases a little bit more. We talked a little bit about possibly throwing in some screening when we’re at a decision point in the road, and you go A or B, which way do I go? That might be one piece of data, particularly in a higher-risk person who has a lot of metastatic disease, a heavy tumor burden that’s probably been seeded as she’s been progressing through a prior line. There may be times, and I haven’t done it routinely, but I’ve done it a few times recently where I’ve thought, “Oh, which way do I go?” Let’s talk a little bit about what you do. Is there anybody who you wouldn’t rush into SRS [stereotactic radiosurgery]? Do you get to see the patient sometimes if she’s developed CNS [central nervous system] metastases? Sometimes she’ll be seeing the radiation oncologist back because she’s already had SRS let’s say, but now she’s going forward and now we have the tucatinib tool. Would you generally have chance to think about tucatinib before she gets more SRS? How do you balance the systemic therapy vs the brain therapy? How do you think through that in terms of when to change? Add a few general thoughts about brain metastases and how things are evolving in their management.

Lisa Carey, MD, FASCO: Claudine mentioned this earlier. Patients with brain metastases fall into 2 categories. There are those that are symptomatic, at which point you need dedicated local therapy, particularly if they haven’t been previously treated, and that’s typically with radiation. Although Priscilla Brastianos, MD’s, paper a year or so ago suggested that the actionable mutations and DNA aberrations may be different in a brain metastasis than in the rest of the systemic compartment. We shouldn’t give up on taking them out because then you can look at them a little more carefully. Certainly for larger ones, we still do it, but for a while we were shifting away to radiating everything. We may start to see a move back to some of the larger ones, where we go back to taking them out, but some local approach.

My own impression and practice recently has been, with all the HER2-directed therapies that we have in asymptomatic patients, so we’re pivoting away from the symptomatic ones. In asymptomatic patients, my radiation oncologists are perfectly happy to let me go first and to follow what’s happening in the CNS compartment. They have some concerns. A lot of times these patients will have multiple things and if you keep going, they live so long, sometimes you’re going back to the well with SRS over and over again.

They’re OK with waiting to do a little more medical therapy up front. At least at the University of North Carolina, that’s been an evolution. It’s a good one because we watch them like hawks.

Joyce O'Shaughnessy, MD: Exactly. VK, you were going to give us some thoughts though on this.

Vijayakrishna Gadi, MD: This has changed a lot because of tucatinib. Us looking now proactively is a real possibility for these findings. The question becomes, do we try to achieve, very aggressively, sterilization of the brain environment of visible metastases, especially if there’s 1 or 2? If there’s a lot of small miliary disease, that’s a different challenge, and fortunately those are not very common patients.

What we know now from both the first-line therapy with THP [paclitaxel, trastuzumab, pertuzumab], but also in the second-line with T-DM1 [trastuzumab emtansine], is that there’s this principle of if you can keep the disease below the neck controlled, it looks like there’s a survival benefit even for CNS-related stuff down the road, just as a general theme.

If you can get to a point where you’ve used SRS, or some localized therapy, and ”cleaned up the brain,” and you get some really good below the neck therapy, these are patients who maybe do really well without additional CNS events. That was at least my initial way of practicing. But tucatinib for good reasons is throwing a wrench into this, and for those patients now I’m feeling more inclined to use tucatinib earlier in the sequence of therapies, especially if they have HER2-positive brain metastases. It’s hard to argue with data that have an overall survival benefit, and you do have an overall survival benefit even in the patients with brain metastases in the HER2CLIMB study, so you can’t exactly dismiss that. That’s a real finding.

It’s changed a lot. More of us are probably going to look. We’re going to find disease. It’s an interesting fact I think a lot of people don’t realize that 50% of the brain metastases that happen in patients with HER2-positive disease happen within the first 2 months of therapy.

It’s an early event, it’s not a late event like you might see in ER-positive, HER2-negative disease where 5, 6 years down the road there’s a brain metastasis. This is something that happens early in these patients. If they’re symptomatic, we all know what to do in that case. It’s the asymptomatic where we have to use our judgment. If it’s a bunch of small miliary lesions and you’re asymptomatic, I’m actually really worried about that patient. But if it’s prior to half a centimeter spots, maybe that’s the patient I watch like a hawk, then bring in my neuroradiation oncologist down the road to target these lesions, especially if I’m not seeing control like I want to see.

William Gradishar, MD: I was going to say one thing, and I agree with what VK said. It is nuance though too because there are those patients who he was describing, who have done well below the neck who had bad disease that the systemic therapy is holding them.

It may be in that patient, particularly if they have relatively limited brain involvement, that radiation therapy would be a first choice rather than abandoning what seems to be holding the systemic therapy completely in check. But I agree, if the disease continues, then I would switch to something that has more activity in the brain.

Joyce O'Shaughnessy, MD: Yes.

Vijayakrishna Gadi, MD: I would argue, this is a space that has to be highly personalized. It’s going to be very much a challenge to write guidelines that say do the steps in this context.

Joyce O’Shaughnessy, MD: Yes. How about Claudine? Any evolving thoughts about treating brain metastases or management strategies?

Claudine Isaacs, MD: Increasingly when this happens, we function in a very multidisciplinary way. Increasingly, radiation oncologists and neurosurgeons and medical oncologists are around this, it’s a discussion about what might be best for the patient. Increasingly, I have exactly Lisa’s experience that sometimes radiation oncologists, because they’re the ones who follow, and are ordering the MRIs, they’ll call me and they say, “Something is going on, do you have something for her?” As opposed to me calling the radiation oncologist and saying, “I have somebody, and we need some local therapy.”

I also agree with Bill. This is one of those spaces where we’re evolving, but we have those patients who had aggressive disease, it was really well controlled, you just have a few areas in the brain, do I really want to drop their systemic therapy that’s been holding things in check and go to tucatinib now? In those patients I’d probably be more likely to get the radiation oncologist to think about doing some stereotactic Cyberknife procedure and keep them on. If you had a patient where things were more significant, I would, like everyone else has been saying, I’d be thinking about tucatinib here. Everyone has alluded to this as well, many of these drugs have some CNS activity. There was some CNS activity with T-DM1. There certainly was CNS activity with lapatinib, there is with neratinib, and with tucatinib.

It is a very individualized space. The other thing is, my sense is that in general, in speaking to people out in the community, the radiation oncologists and medical oncologists are talking together about the next best step. That’s probably the most important thing because this is so individualized; nobody jumps the gun first but talk about it together.

Transcript Edited for Clarity