Joyce O'Shaughnessy, MD: Now we’ll talk about some scenarios; we’re in a data-free zone because we don’t have randomized trials, except what we just went over. We don’t have any clear guidance on how to sequence. We have to go in part by the patient populations that were studied in the phase 3 trial. We have to go in part by antecedent therapy they had, maybe in the adjuvant/neoadjuvant, and what the disease-free interval might be. We have brain metastases, we have toxicities to consider. What are you doing? This might be a good time if you had any interesting observations or anything like that, it would be interesting and to hear about it. Who wants to start? How do you think about sequencing?

William Gradishar, MD: I can start. If you build off what is viewed as standard, and you’re more likely to use a CLEOPATRA-like regimen, then follow it by T-DM1 [trastuzumab emtansine]. The reality is that in the adjuvant setting some people get TH [paclitaxel, trastuzumab]. If they develop progressive disease, would that make you not give a taxane with HP [trastuzumab, pertuzumab]? It would be dependent on how recently the patient progressed and last received their therapy. I wouldn’t exclude the possibility in that kind of scenario of using HP with a taxane.

As for the newer agents, it’s to a large degree influenced by whether CNS [central nervous system] disease is present. That certainly would influence my thinking. We’ve used a lot of trastuzumab deruxtecan, and I’ve been impressed with its activity. Obviously if somebody had bad pulmonary disease for whatever reason, I’m not talking about cancer-related disease, it may be somebody who I would avoid it in, but not because they have cancer in their lungs. There’s also, obviously if somebody has active brain metastases, tucatinib would be very attractive. I’ll stop there so others can comment.

Joyce O'Shaughnessy, MD: Thank you. Who else?

Claudine Isaacs, MD: I’ll go. I do start with the CLEOPATRA regimen, and typically if somebody had a lot of CNS disease or something going on, I might think tucatinib, it’s approved as second line and beyond. There are instances where I might think a bit, but I would typically do T-DM1 next. It’s a really well tolerated drug, and we have good data for it.

In the third-line setting, I think it’s going to really depend on the patient. I have to say I was a little bit skittish about trastuzumab deruxtecan because of the interstitial lung disease and because it came just as coronavirus disease 2019 was hitting. Getting more used to everything, I’ve used it as well. I would probably think of tucatinib in the third line and then trastuzumab deruxtecan. Which way we do it, I don’t think we have evidence for; it ends up being individualized on the patient’s adverse effect profile, what’s more tolerable. It’s a lot of medication to take with the tucatinib and the capecitabine. There’s diarrhea with it, so it carries with a very different adverse effect profile. As usual, we now have 2 good, very solid options for third and fourth line, and it’s an individualized decision in my mind with the patient in terms of their preference, their adverse effects, their comorbidities, and other things that come into play.

Joyce O'Shaughnessy, MD: Let me ask you Claudine because you make the point about the tucatinib being FDA approved and on National Comprehensive Cancer Network guidelines in the second line, which distinguishes it from the trastuzumab deruxtecan in the second line, which distinguishes it from the trastuzumab deruxtecan and the neratinib, not that we have to rigidly follow that. Sometimes we don’t for individual patients. Nonetheless, it’s nice to know where the guidelines and FDA stand. Having said that, is there any patient for whom you might consider the tucatinib in second line? Would you ever consider any kind of a brain MRI? We have a little ostrich effect here; we’ll look at the liver every day, but we’re not looking at that brain, we’re not going there. The question is, is there anybody we should, if you think they may be at particularly high risk for CNS metastases?

Claudine Isaacs, MD: I’m not aware of what would predict for a higher risk of CNS metastases with HER2-positive disease. I don’t know if my colleagues are?

Joyce O'Shaughnessy, MD: Yes, Nancy Lin, MD, taught me. I don’t know that it really pertains to the sequence of metastatic, but for those who recur in the brain, or who start off, it’s probably the same, it’s T3/T4 disease and ER [estrogen receptor]-negative. If you’re T3/T4, even ER-positive, you can be at risk, or if you have more sizable cancers, ER-negative—like node-positive, ER-negative. So, ER negativity and the bigger cancers would be the ones that would tend to seed back when these things were developing.

Claudine Isaacs, MD: There you go. I always listen to what Nancy Lin says, so I’ll take that one home too. I’m debating whether we should be doing scans. I have to say, I have had that ostrich-like response. I didn’t want to know, and now that we have a drug that’s active, I think we need to rethink that strategy. I haven’t quite figured it out yet. I don’t know whether it’s something that we should be doing every X-period of time, whatever that might be, and to do it when it’s time to change therapies. It feels a little different when we know that we have something beyond repetitive local therapies for these patients to think about something. That could influence me if I had a patient who had CNS disease in the second line, and I thought I could spare and push off radiation if I chose a systemic therapy that had CNS penetration, that could influence things. I haven’t quite figured it out. I’d be interested to hear what my colleagues have to say about, if they’ve developed an algorithm for this. I’m still trying to get used to this playing field and figure out how to best strategize around that.

William Gradishar, MD: I don’t know that I have an algorithm, but I think it’s like alpelisib. We wouldn’t be looking for PI3 kinase mutations if we didn’t have something to do with the information. The practice is going to be as time goes on, we will be looking for more brain metastases, even in the absence of symptoms. But it does raise the issue, if there’s lead time that we’re creating, and we’re starting therapies that may or may not impact on very tiny or very indolent CNS disease. I don’t know the answer to that, but I bet we’re going to be looking more than we have in the past.

Joyce O’Shaughnessy, MD: There was that subset analysis. It was Nancy Lin who did this one too, where she looked at a combination of patients who did have brain metastases and those who didn’t have brain metastases, and then looked on the tucatinib vs placebo for time to development of new brain metastases. A little preventive. There was a real nice separation in that curve where it certainly gives us hope in the curative setting. That’s helpful, but probably for right now I think if people have brain metastases, we’d all be thinking about tucatinib sooner than later, probably. Sometimes, even in my practice, leapfrogging over the T-DM1 if they had substantial brain metastases. I don’t mean necessarily 1 brain met. How about you, Lisa, how do you sequence these so far?

Lisa Carey, MD, FASCO: I have to say, I share the sequence that Claudine just outlined. I’m fairly conservative about that way. There’s some reassurance in that when they’ve done many of the trials, like EMILIA for example, they did include patients that had stable brain metastases. They did have some of them for whom they could see a response rate, and it didn’t look terribly different from the parent trial.

I suspect for a variety of reasons that tucatinib is going to outperform all of them, specifically in the CNS compartment, but I’m not so worried about it that I’m leapfrogging or rearranging my normal lines of therapy at this point. I do share Bill’s concern about routine screening in asymptomatic patients. If you look, you will find. Once you find, then you’re stopping and reconsidering, and you’re doing stereotactic radiosurgery here, there, and everywhere. I’m not sure that we’re helping patients if we do that. We might be, but I always get a little leery of it. You’re right, there is a disconnect because I’m imaging the systemic compartment all the time. But I typically don’t image asymptomatic patients for the CNS.

Joyce O'Shaughnessy, MD: Thank you. How about you VK?

Vijayakrishna Gadi, MD: I echo what Claudine put out there as the framework. I am thinking about this disease now as a today problem and a tomorrow problem. The today problem is a lot of my patients have been through 1 or 2 lines of therapy. It’s a slam dunk to say I’m going to use tucatinib or deruxtecan, and maybe there are small, subtle reasons why I might pick one over the other, certainly brain metastases being present, one of the big ones. My concern is as we project forward, the patients who recur, those who had residual disease after THP [paclitaxel, trastuzumab, pertuzumab], and then we know that the patients who get T-DM1 in the adjuvant setting are still the ones having the events, right? Now they’ve taken out my first 2 lines of therapy, and if you’re recurring within 1 to 3 years, as many of these patients will, then I’m worried about going back to these agents.

Now we’re looking at in the first-line metastatic setting trying to get access to drugs like tucatinib and neratinib as well as deruxtecan. I don’t know how this is going to shake out. I’m just throwing out my hands with concern about what the near future is going to look like in these patients who are heavily pretreated in the adjuvant setting. Now we’re delivering them, and certainly if they get neratinib, like I said earlier, I’m a little worried about cross-resistance to tucatinib. Neratinib is a very potent HER2 inhibitor, it just inhibits a lot of other stuff as well. Now if you try to go back to the well and target HER2 kinases with tucatinib, will it work? We don’t have these data of course. It doesn’t exist. These are my fears and my worries for the coming days.

Claudine Isaacs, MD: Can I ask VK a question on that? You go all the way out to; I’ve taken myself to a year, a year-and-a-half out and said after that I can think about reusing old agents. Does that?

Vijayakrishna Gadi, MD: I’ll use them, I’m....

Claudine Isaacs, MD: You’re just worried.

Vijayakrishna Gadi, MD: I’m just worried. My anecdotal experience is that these drugs don’t maintain the same way as if it were a pristine patient in the metastatic setting who gets these drugs. I think that patient, you can very easily say, this is a person who’s going to be on these drugs for 2 years. But when those patients have been that experienced in that early phase setting and they have a metastatic event, I might, just my back of the envelope sense, is that they’re not getting that type of mileage.

Lisa Carey, MD, FASCO: Well the good news is that as we get better and better in this adjuvant setting, and we’re already seeing this in some of the modern things, they’re all de novos. All of these metastatic patients, there are like 45% in the most recent studies. That’s a testament to what we’re doing in the adjuvant setting. I share VK’s pessimism about patients with early relapse following poly-HER2 targeting, although I have to say I retry things unless there’s a compelling reason not to.

Transcript Edited for Clarity