Joyce O'Shaughnessy, MD: It’s very important, tucatinib for the brain. Does anybody have any pearls or words of wisdom in terms of cutting down toxicity? So many of these things have more toxicity when we start them in the first month or two, and then there is tachyphylaxis, or we tweak the dose. Does anybody have any particular thoughts? Anybody using any escalation strategies, for example, rather than going in with the full dose as they did in the protocol?

Vijayakrishna Gadi, MD: With neratinib, I feel very comfortable with an escalating strategy, and it does seem to increase or maintain compliance. I don’t know that we have that option with tucatinib yet. I haven’t seen data, and I’m still a little worried about starting with 1 tab instead of 2. They come in different increments, and I don’t know how we’re going to fix that. It’s so much easier with neratinib, where you can go 3, 4, 5, 6 pills. The other drug I have a hard time with is capecitabine and what’s the dose of capecitabine here in these regimens.

It’s slightly a little bit on the higher end of what I like to use in the metastatic setting, and we’ll use it, but a lot of the toxicity from the regimen that’s described in the studies is from capecitabine. It’s hand-foot syndrome, it’s diarrhea. Some of that could be tucatinib, but I think it’s really the capecitabine. If you look at the data deeply, the patients who are on capecitabine longer are more likely to have those toxicities. Big surprise. That’s the drug I struggle with the most in these combinations.

Joyce O'Shaughnessy, MD: Yes, thanks. Lisa, what were you going to say?

Lisa Carey, MD, FASCO: I agree with VK. Tucatinib is an easier drug because it is a much more HER2-specific drug. So you don’t have, in this sense, off-target effects with the GI [gastrointestinal] toxicities. I haven’t had that struggle, where you do have it with neratinib. We’re all looking for strategies to manage neratinib better, and we think dose escalation is a good one because it’s proactive, and we need it to be proactive.

I haven’t had that need, and I think that a good deal of the toxicity is capecitabine. We’re going to have tucatinib added to T-DM1 [trastuzumab emtansine]. We’re going to have tucatinib added to trastuzumab deruxtecan. There are going to be all these trials; we may have other options that allow us to avoid capecitabine if we want to. But I think you basically strategize around capecitabine the way you always do.

Joyce O'Shaughnessy, MD: Yes.

Lisa Carey, MD, FASCO: Start, and go down. But nobody gives it at the same doses that the FDA thinks we do.

Joyce O'Shaughnessy, MD: Right, and I can start a little low on the capecitabine and try to get the full dose of tucatinib in because we’re trying to get to the brain, and then work my way up on the capecitabine. Sometimes I’ll do that to have a better experience, a more positive win for the patients early on.

Transcript Edited for Clarity