Breast cancer experts exchange thoughts on the treatment of HER2+ breast cancer with CNS involvement, particularly the use of trastuzumab deruxtecan in this subset of patients.
Dr. Charles Geyer: I guess one thing that always comes up in- when we're talking about HER2-positive metastatic breast cancer are, that it- that need, that unmet need, so to speak, of brain metastases. So there's always- you will generally see updates, particularly now with T-DXd where people are trying to get a sense of the activity. There's been clear reports of it, CT scans showing regressions. And there was one study that- from Japan where they went back and basically just tried to gather data on patients who had developed brain metastases, had imaging and had received T-DM1. And on their poster, they had 51 patients with brain imaging who had a response rate of 63% with a- and a median intracranial progression free survival of 16 months. So I- it's clear that the drug is active in the CNS. And so I think one common challenge as always, the HER2CLIMB data was also very impressive with tucatinib capecitabine, HER2 showed survival advantage, showed advantages in patients who CNS disease had not been treated. So in a sense, the level one data is stronger for that. So how do you incorporate the two, and I guess that- one of the things that people always like to hear is, how are you making that call. What sort of things are you using in your clinic when you have a patient with brain metastases?
Dr. Ian Krop: I think it is a tough question. My algorithm had been that in the second line you would be using T-DXd in most patients except those that have progressive brain Mets, because as you just pointed out, the one area where we didn't have large scale data with T-DXd was in the progressive untreated brain met population. And we did have those data from HER2 Kline with tucatinib, which clearly is a drug with activity in the brain. So I think up until recently that's- that was my- the dogma, or at least my thinking process was that if you had progressive brain Mets you still would use the HER2CLIMB regimen first because of the phase three data and survival benefit, and then you would use T-DXd after that. But as the DB03 data become more and more compelling with time, and as we're starting to see small study after a small study clearly showing activity of T-DXd in the brain, I think it's hard, at least for me, it's starting to get harder and harder to kind of stand on this soapbox and say, you have to go with where the phase three data are and use tucatinib. So I think in practice, what I'm kind of trying to do is if you look at not only the- what's going on in the brain, but also looking what's going on extracranially. And if you have patients who are having a tough time outside the brain with progressive visceral disease and had a short time for disease control on their- in their first line CLEOPATRA type regimen, those are patients we all know- we all worry about and you want to get control of this. And so that's a patient, given the incredibly high response rates we're seeing with T-DXd would lean towards using T-DXd, even with some evidence of progressive brain Mets. In contrast, if you have a patient who's having a- their- most of their trouble is in the brain. They're having innumerable brain metastases, they're symptomatic. Either they've already had radiation or you're trying to forgo using radiation or delay using whole brain radiation, and their extracranial disease is more quiet, that might be a patient to use tucatinib based therapy on. I think in general you're going to use both at some point. And I think it's just that right now I would tend to hedge one versus the other based on the overall picture of the patient, which is more of a problem, brain versus extracranial disease. But as the brain met data continue to evolve with T-DXd, it very well may be that it's a drug that's more active in the brain as well as extracranially compared to TD- compared to tucatinib or probably compared to anything else.