Joyce O’Shaughnessy, MD: So here she is, she's going along and then she's on the TDX about a year and now she's got a couple more brain lesions that you pick up and she's doing very well otherwise, pretty asymptomatic so you treat those. You treat those with SRS, probably a consensus there on that and then let's just say here she is six months later, she's got another two brain mets. I'm beginning to feel like it might be time to think about changing therapy to, you know, there's only so much SRS we can do. I mean it's not scot-free, is it? I mean you can start getting all kinds of issues, right, with radiation necrosis, you get the edema and so I mean I don't know, what do you think Heather? When do you bail out? Focusing on the brain.

Heather McArthur, MD: These are luxurious challenges, right, because we have options now which a couple of years ago, we didn't have any of these options, but I agree with you with recurrent brain metastasis on trastuzumab deruxtecan. I would be concerned that something that's more CNS directed is indicated and I would think about the HER2CLIMB issue. What we haven't talked about is toxicity monitoring, trastuzumab deruxtecan and interstitial lung disease and the frequency of monitoring and how we coincide that with brain metastasis monitoring for those patients and I'd be interested to hear your collective thoughts. But I agree with you Joyce, I would think about switching with recurrent brain metastasis at that point.

Joyce O’Shaughnessy, MD: It comes a point where the site of metastasis is the life of the brain could become the life limiting site. I guess that's kind of where we might be willing to, you know, we hate to give up on a systemic regimen that's still working but if something really is beginning to wave the red flag, this could be the life limiting site of metastasis, then we have to... And quality of life though too.

Andrew Brenner, MD: Yes, that raises a very good point. For patients who develop brain metastasis from HER2 positive disease, 70% of those will die from CNS progression. So, it is an important point to continue to treat them systemically if you feel like their local options are running out.

Joyce O’Shaughnessy, MD: How about you, do you have a certain number, when do you start to get that gut feeling that you should switch over?

Virginia Kaklamani, MD: You're getting the gut feeling when I think every time you do a scan, which is usually every three months, you're starting to see the brain disease just taking on a life of its own, in a way. And I think regardless of how much we love believing our systemic agents, because that's what we do for a living, at some point you realize that you're not controlling this disease. And so, at that point, even though I try to continue it for as much as I can, deep down I know that I'm not really helping the brain. And I might be able to use SRS, but at some point, if you use enough SRS, it's like doing whole brain RT, you might as well do it.

Joyce O’Shaughnessy, MD: And you know, if somebody pops up after, you know, she's been on it a year and she's got a couple brain mets SRS, and six months later a few more, you could, do you ever do this hand, you could like not do SRS and just come in with the tucatinib triplet?

Andrew Brenner, MD: Yes, if there's a reason, if a patient's not terribly symptomatic and they have active brain metastases and you know, you're worried about doing more local therapy, yes, I have and I will do that. I do switch patients to CNS active regimen like the tucatinib triplet. And I've seen very good results. The question becomes, you know, when you're getting good control intracranially and they have been on the capecitabine for an amount of time, they're getting the hand foot syndrome, you know, they're dealing with, you know, some level of diarrhea over time, when do you drop the capecitabine?

Joyce O’Shaughnessy, MD: I was just going to ask you that. How do you manage the toxicity? Which one do you get down on? Which one's better for the brain? You're trying to treat the brain, right? So how do you do it?

Andrew Brenner, MD: So, what I usually do is I drop the capecitabine once they start to develop that toxicity. I keep them on the tucatinib and the trastuzumab. Sometimes I get, you know, very good ongoing control with that.

Joyce O’Shaughnessy, MD: Wouldn't even have to stop the capecitabine, not just drop the dose, but have to drop the whole agent, huh?

Andrew Brenner, MD: Yes, sometimes when you get, when you're really getting PPE and the patient's just getting worn out, they just need a break. And then I do, if I drop it and they start to progress again, I do reinstate it and I do see responses again. What my personal experience has been that the responses aren't as long lived or as deep as the first time around. But you still are able to get back some level of control by resuming the capecitabine.

Joyce O’Shaughnessy, MD: What has your experience been about the toxicity management with the Tucatinib triplet?

Heather McArthur, MD: I have to be honest; I have been administering the capecitabine backbone in one week on, one week off fashion, which is based on the dose-dense modeling by Dr Norton and colleagues. And they did a study at Memorial Sloan Kettering looking at the one week on, one week off regimen. And I do find that it's much better tolerated than the two weeks on, one week off.

Joyce O’Shaughnessy, MD: Interesting. So, you're not getting into toxicity issues, that's your first move, huh?

Heather McArthur, MD: That's actually my starting point, quite honestly, and accepting that that's not how it was administered in the HER2CLIMB regimen. But given that these patients do so well for so long on average now, that making that investment upfront and mitigating toxicity risk has been my strategy.

Joyce O’Shaughnessy, MD: Interesting, yes. You know, get the success going here. Exactly. How about you, Virginia? What do you do to try to make sure the patients can take it?

Virginia Kaklamani, MD: So, I obviously will bring them back very quickly to make sure that they're taking it correctly and make sure that their adverse events are manageable. I typically continue the capecitabine until I start seeing the fatigue. And the fatigue is not necessarily just fatigue, fatigue from taking the drug. Whether it is Hanford syndrome or whether it is diarrhea or whether it is just a little too much. Whenever I get to that, I realize that especially with HER2 positive disease, these patients live for more than five years with metastatic disease. And so, this is a marathon, not a sprint. And they're gonna be in a lot of chemotherapy in their lifetime. And we have to pace ourselves. And the minute I start seeing that they're running out of patients, that's when I'll stop it. If I do have to give it and a patient has had quite a bit of toxicity, I do switch to the one week on, one week off. There's some data from the GI world suggesting that they're as efficacious, which is great. But I will start them with the original two weeks on, one week off regimen.

Joyce O’Shaughnessy, MD: I always start with the full dose tucatinib because I'm usually at that point quite interested in making sure we get the best thing for the brain. But even if they don't have brain, I'm in the third line. I just want the best non-cross-resistant drug. So, I'll start a little lower. I don't start at the HER2CLIMB, 1,000 per meter BID. You don't want to have too much at once. So, I start a little lower on the CAPE. And I push it up as much as I can. It's so funny, different people are so different. I have an older patient; she couldn't take the capecitabine. But she's doing fantastic. And just on the tucatinib test, Tuesday, another gal, she was on TDXD for quite a long time. She was doing very, very well. She had CR, or almost CR, but she got some ILD. Little bit early grade too. And gosh, oh darn. So, I was like, well, no, we better follow the rules. We better stop, et cetera. So, she's on the tucatinib triplet. And she's on a good dose of the capecitabine in addition to the full dose tucatinib. She's doing fine. It's so funny, different people are just simply different with it. But it sounds like we've got some consensus that we're gonna modulate the capecitabine dose and schedule to try to keep the tucatinib as high as possible. I haven't had too many problems doing that. The diarrhea of tucatinib doesn't seem that much. It really seems that it's the capecitabine, tucatinib combination that really is more of the challenge there.