Introduction

DR LOVE: I’m Neil Love from Research To Practice and welcome to Key Questions in Clinical Research in the Management of HER2-Positive Breast Cancer. We’re really excited today to be able to spend some time with Dr Lisa Carey and Dr Ian Krop today to go through a bunch of cases and new data sets to consider.

We’re going to focus on HER2-positive breast cancer, and like a lot of our programs, really try to get into clinical management issues. In order to do that, as we’ve done in the past many times for live meetings, and today we’re going to try this as a virtual meeting, we work with a bunch of general medical oncologists in community-based practice and asked them for cases and questions that they would like to see our faculty address, and we’ll show you those as we go through this exercise.

Here’s where we’re heading. We’re going to spend about the first half of our time talking about localized HER2-positive disease, neoadjuvant/adjuvant, post-adjuvant therapy. In the second part we’ll talk about metastatic disease. So much going on, newly approved agents, lots of new options to be talking about.

Localized HER2-positive breast cancer

DR LOVE: So, first we’re going to localized disease and to begin we’ll go through a few of the data sets. And, Lisa, in her talk, goes through all of these in detail; I really recommend you check out that lecture once we get it posted. But, Lisa, this is a great slide, you started out with, kind of summarize some of the key trials in local therapy that have come out over the past couple of years. Maybe you can talk a little bit about these trials and we’ll take a brief look at each one, but globally the direction that we’re taking in the management of localized disease, Lisa.

DR CAREY: It’s a pleasure, Neil, and thank you. Yeah, I liked putting this slide together. It reminds all where we’ve had successes, that it’s really quite rewarding. And I think it also brings up to the challenges. So among the issues is, as we got better and better at treating HER2-positive breast cancer — and what I don’t have on there is the really amazing transference of one of the poorest prognosis subtypes of breast cancer to the one of the best through the advent of all these things — but what you also see is many, many, many drugs.

And I think in the middle of that, so we have the — many of us remember the standing ovation in 2005 for adjuvant trastuzumab and then some additional incremental benefits added on, added on, added on, to the point that we were pretty routinely seeing patients with relapsed-free survival and disease-free survival event rates that were well into the 90s. And that brings us to the efforts to try and parse out risk, right, so now you’re escalating with a much more thoughtful approach. And that’s were KATHERINE and KATHERINE-type studies come in.

And then, of course, Sara Tolaney’s work with the APT and then subsequently the ATEMPT, run through the TBCRC, as a similar effort to try and now de-escalate when you know that the outcome is likely to be good, and both of those were quite successful and I think that’s where the direction is going.

And I had the question mark about the extent to which we are going to get smarter. To be honest, all we’ve done here is escalate everybody, then we started de-escalating according to anatomy. We haven’t really brought in biology, outside of HER2, and so I think that’s going to be the next kind of mountain to cross.

DR LOVE: Ian, any comments about that last thought that Lisa had in terms of looking at biomarkers, biology of these diseases — of these patients and these situations to try to parse out how much therapy you need?

DR KROP: I think — and hello to be on the call. Certainly, using anatomic features, such as size, has paid dividends and that we know clearly know that treating Stage I patients with combination chemotherapy is not necessary. They have excellent outcomes just with TH and that’s clearly the standard of care.

I think the next big advance was this realization that, while biomarkers in the standard sense, haven’t really been very helpful yet, other than HER2, response to preoperative therapy, or a functional biomarker, has clearly changed the game in terms of allowing us to identify who needs T-DM1, the patients who don’t have such a good response to neoadjuvant therapy. That was a clear advance and the benefits of T-DM1 are quite marked. And then, it’s now opened the door to studies using de-escalated neoadjuvant therapy to see who we can do less with, even if they have larger, extensively high-risk cancers, and that’s where COMPASS and CRESCENDO come in to, kind of leverage that biomarker of response to neoadjuvant treatment to say, okay, this is a good actor, even if we couldn’t tell upfront. We can now tell because they responded well to neoadjuvant therapy and we can potentially do less.

I think that’s the next big frontier, is using that neoadjuvant functional biomarker to say who we can get away with de-escalation there.

DR LOVE: So, what I really want to do is make Rounds with the two of you and go through a bunch of cases, but let’s get the data out on the table. I’m also starting to see some good questions coming in the chat room that we can deal with. But, Lisa, to get the tools out on the table, pertuzumab’s been out there for a while. In your talk, you commented on the fact that now we have the updated data from the use of pertuzumab. Any comments there? And particularly the fact that now it looks like ER is not much of an issue.

DR CAREY: Right. And I think that was the update just continued demonstration of the effectiveness of pertuzumab. I think it became clearer. And you can see here really not a lot of difference in the node-negative population, but pretty clearly the node-positive. I mean when we do focus groups with patients, typically they start to say clinically meaningful is somewhere around 3 or 4% and I don’t think too many people would argue that with a well-tolerated drug, and you start getting close to 5% in node-positives. And you’re absolutely right, unlike the first analysis, the benefit, that there wasn’t really a differential between ER-positive and ER-negative, which I think simplifies decision making.

DR LOVE: So, Ian, another tool I want to get out on the table, and then we’re going to see how this plays out in terms of cases — and we just had a case that was just emailed in that I want to ask you about — is post-adjuvant neratinib. Where are we today with that, Ian? One of the issues in the past, of course, was toxicity. I’m hearing that that’s much better controlled now in terms of diarrhea. I also see that when we poll people, people are much inclined to use this ER-positive/ER-negative. Where are you today, Ian, in terms of post-adjuvant neratinib?

DR KROP: So I mean the ExteNET study, as you alluded to, did show a benefit in the overall population. But, when you look at subgroups, it was exclusively in the ER-positive/HER2-positives. There was no benefit in the ER-negative/HER2-positive population, which was a surprise and we’re still not exactly clear why that is. Perhaps because of crosstalk between blocking HER2 and blocking ER, since all those patients area also getting endocrine therapy. But at least, if you look at the subsets, the benefit’s only in the ER-positives. And it is true that if you use primary prophylaxis for the diarrhea, it definitely helps. It doesn’t get rid of it, but I think, for most people, it ends up being manageable.

I think the concern or the challenge here is how do you apply the neratinib ExteNET data in a world that’s changed a lot since when this trial was done? This trial was only in patients who had had adjuvant trastuzumab. Now, all the high-risk patients are getting pertuzumab in a neoadjuvant setting and they’re getting T-DM1 if they don’t have a good response and does neratinib still provide benefit in patients who got 2 different drugs than the patients on their trial.

And I think that’s where I think we’re all struggling, because, of course, there is no data. And, at least personally, I kind of fallen to the place where for very high-risk, ER-positive patients who have substantial residual disease after neoadjuvant therapy. I give them T-DM1 and talk about potentially doing neratinib after, in the second year. And if they tolerate it, continue it. If they don’t stop.

But it really is a small group of people at this point. And again, you have to tell them that we don’t know whether it’s providing any benefit in that situation.

DR LOVE: So we call that the “art of oncology.” Lisa, of course the other issue, as we were talking about, is this de-escalation of therapy that we’re seeing, Lisa, beginning with the APT trial, again coming out of Dana-Farber, showing really great results just using that regimen, TH. But more recently, the ATEMPT trial, Lisa. Can you just comment on that and how it affected your thinking about the de-escalation of therapy?

DR CAREY: I think ATEMPT was really an effort to see if you can get rid of a free cytotoxic altogether. And I think, as you can see, the 3-year disease-free survival in this trial is approximately 98%, which is a pretty resounding success in that regard.

There are some toxicities to T-DM1, so it’s not as if omitting the free cytotoxic saves you all of the toxicity; the truth is it saves you neuropathy, it saves you hair loss, but it also buys you some other things over a longer duration. So, I think, separate from reimbursement, I think it is a drug that many people would probably reach for and I think patients — you ask patients what they want to get rid of, it’s the free cytotoxic. And having put quite a few people on this trial, it’s very well tolerated. I think one of the cases I sent to you, I have a patient who actually ran the Boston Marathon while on therapy. So she was the poster child for TBCRC-33. So I think that’s the reality of it.

Now I think from a cost effectiveness/healthcare policy standpoint, there’s a very important question that we didn’t ask in APT or in TBCRC-33/ATEMPT. And that is, do these patients need anything? Do they need any anti-HER2 therapy? Because this ended up being a very small, all node-negative, all had to be T1s, and, in fact, nearly half were very small T1s.

So I think there is a potential additional de-escalation which are questions we haven’t yet asked and that’s, I think, a topic for the future.

DR LOVE: So, Ian, we were talking about 2005, when the trastuzumab came in in the adjuvant setting. I actually remember interviewing George Sledge the day after that data was presented in Orlando, that was when ASCO was not just in Chicago, and, wow, what a moment. But for me, the next best moment was this, KATHERINE, in terms of the natural history of the disease. And I already see a question in the chat room about, is there, for patients with just a small amount of residual disease, microscopic residual disease, Ian, are you still going to take this approach? And any comments about the trial itself?

DR KROP: I agree. When these data were presented, it was quite moving. And we had been moving with T-DM1 for many years and were trying to figure out how to move into the early disease setting. And this was one approach. And KAITLIN, which we may talk about, was another approach that we had come up. And I think this was quite — I think you have to hand it to the team who did this trial since it was the first real trial to look at this post-neoadjuvant approach and it turned out to be a really — an excellent place to look at a new drug, since it’s automatically selected for higher-risk patients. Again, because of this functional biomarker of lack of pathologic complete response.

In terms of, if you look at the subgroup analysis, if you look at the forest plots, the benefit is absolutely uniform essentially all subgroups. And this particular question of well, how low do you go, comes up a lot, but if you actually look at the data in the anatomic subgroups, meaning how little — depending on how much residual disease there was at time of surgery and how that predicts benefit of T-DM1, it’s really hard to find a group that doesn’t benefit. I mean even in the subcentimeter, node-negative group, there’s a 6%, I think, absolute benefit of T-DM1.

So I mean I pretty much give T-DM1 to anybody who’s got macroscopic residual disease after neoadjuvant therapy because I can’t find a group that doesn’t seem to benefit, and the tolerability of T-DM1 is pretty good.

DR LOVE: Well, I really want to get into some cases. I just want to show you slide without discussing it, that’s in Lisa’s talk. Check out Lisa’s talk. She goes through all these things in detail. It will take about 15 minutes now, but let’s see how it plays out in terms of actual patients. That’s really what I want to get to.

So first, we’re going to talk about some cases that were brought to our attention from the general medical oncologist. And actually, we’re going to ask you all to kind of vote on this. So we’re going to put up this as a poll question, a survey question. We’d like to know how you think through this case. So here’s the case. You’ll hear the doc talking about it in a second. A young woman presents with a big triple-positive tumor. Gets a path CR to neoadjuvant TCHP. Gets adjuvant trastuzumab. This is about 4 years ago. She gets endocrine therapy as well. But 4 years later she has the same thing happen — she’s got a 5-cm local recurrence. The doc again uses neoadjuvant TCHP, again has a path CR.

So our question is, now what are you going to do in terms of adjuvant therapy for this local recurrence, so to speak? Are you going to use trastuzumab? Trastuzumab/pertuzumab? T-DM1? And then are you going to use neratinib? This patient’s ER-positive, 6 cm. Do you think might be thinking about neratinib in this situation?

And actually, let’s get to this in a second. But I’ll just ask you, Lisa, let’s take a look at the video first of the doc asking you the question.

DR CAREY: Then let’s ask Ian the question.

DR LOVE: Okay, we’ll ask Ian. Ian likes to have hard questions. Okay, let’s hear what Dr Leasure’s question, Nick, while we see how they’re voting.

DR LEASURE: She was 35 years old and had a very large, 5 or 6 centimeter triple-positive tumor and we gave her neoadjuvant TCHP. This was about 4 years ago. And she had a rapid, like an immediate clinical response. Her tumor went away within a month. And 4 years later she came back and had actually a fairly sizable in-breast recurrence. She was a large breasted woman, and by the time she got back to us her tumor was almost as big as it was before.

I actually gave her TCHP again and she, once again, had a rapid response and proceeded to bilateral mastectomies, and again was a pathologic complete response. She’s never had metastatic disease.

So I could have given her a year of pertuzumab and then it would have been a second year of trastuzumab. It just seemed like it at that point I felt like I needed to expose her to something different...

DR LOVE: So, of course, there’s no perfect answer and you can see that in the votes of the audience. It looks like there’s 50/50 about whether to use neratinib. And you can see pretty much of a split between trastuzumab/T-DM1. Ian, any thoughts about you might do in this situation?

DR KROP: So, as you said, there’s no perfect answer because there’s no data. And actually, I don’t remember what I put in response to this. But I think the dilemma here, the particularly complicated situation is, clearly this is a cancer that’s quite sensitive to HER2 therapy — she’s had a good response now twice to trastuzumab/pertuzumab-based treatment, but the problem is it wasn’t good enough. She had a recurrence. And we know that patients who have recurrences of cancer are at substantial risk for distant metastatic disease in the future.

So, I think I’m a little torn between saying, well, she responded well to HP-based therapy, so I’m going to give more trastuzumab and pertuzumab. But I also kind of agree with Dr Leasure, that I feel like there needs to be something more. And even though she doesn’t fit the KATHERINE data, because she had a pCR, I probably would give her T-DM1. Lisa?

DR CAREY: Yeah. I have to say, there’s nothing magical about the pCR residual disease. I mean it probably selects a certain biology, but the truth is what it mostly selects for is risk and that’s the reason for KATHERINE. So I actually tend to agree with Ian, in a 35-year-old woman I’m not really looking for a reason to de-escalate. And even though she had pCR, she’s already shown that her pCRs don’t confer a good risk tumor and so I would probably reach for something that gave her additional bang for the buck.

I do think the neratinib question is an interesting one because she did this on an AI. She did this while receiving active endocrine therapy. So in addition to optimizing endocrine therapy, I might, in this case, actually this may be one of the few ones that I would say, listen, whatever tools in the toolbox might help. Because an IBTR within 4 years on active therapy after well delivered drugs is a high-risk situation.

DR LOVE: I’m just going to run through a bunch of other clinical questions that were posed by this group of GMOs and we comment on. This is another case, a 77-year-old, 2-cm triple-positive, node-negative tumor. We asked the faculty what’s the smallest tumor where you would use neoadjuvant therapy. Most people say 2 cm, although you see Hope a little bit on the lower side, or a lot on the lower side. You see there’s a pretty big split about whether people would use neoadjuvant therapy in this situation or not.

We presented this situation, again based on another case, 80-year-old woman with a 1/2-cm tumor. What adjuvant therapy would you use there? Again, interestingly, a split between paclitaxel/trastuzumab, T-DM1, if we could use it, which was what you said, Ian. TCH. Any comments, Ian, about elderly patients with small tumors? You say T-DM1 ideally for a patient like this.

DR KROP: So I think both of these 2 cases you presented are kind of tricky because they’re kind of both right at the border. The previous one was 2-cm is about where we start thinking about neoadjuvant therapy. In her case, that’s a Stage I cancer and I think you should use the APT regimen.

In the 80-year-old patient, how low do you go before you stop using HER2 therapy? I think our group feels that somewhere around 5 mm for an ER-positive/HER2-positive cancer, maybe 4 mm, somewhere in that range, we still tend to use TH and less than and in an ER-positive/HER2-positive, definitely not in the T1A range. The reason I picked T-DM1 in this case was because in the era of the COVID pandemic we’re really trying to avoid myelosuppression, and given the ATEMPT data showing very good outcomes, I think that would be one reason why I would reach for T-DM1 in that particular case rather than TH. But I think you could certainly argue that no therapy would be very reasonable. It’s just, to me, again, that’s right on the border for treatment.

DR LOVE: So I want to go to another case to be presented by one of the general medical oncologists, but I did want to show you this other question we asked the faculty, about the subcutaneous formulation of pertuzumab/trastuzumab and hyaluronidase-zzxf. Lisa, can you comment on it? It looks like there’s a lot of interested in that in the faculty in using it.

DR CAREY: Yeah. I mean any time you get away from infusional therapy and to a, at least theoretically, much easier, more patient-friendly administration regimen has got to be a win. And so I think that’s reflected by the general amount of enthusiasm that everybody was having for this thing that few of us have had the opportunity to use outside of trials.

DR LOVE: That’s how we do consensuses. We ask 25 people what they do. If they all say the same thing, well, we call that a consensus. But I don’t think there’s going to be a consensus on this one. It’s funny, we were arguing back and forth about T-DM1/pertuzumab, etc, but interestingly, we go back to a doc in practice — and Dr DeFusco actually specializes in breast cancer — and she had a question I think a lot of people are thinking about. I’ll let you watch that in a second. Basically, the case was a young woman with a 3-cm tumor that was biopsy-positive in the neoadjuvant situation. And so our question —well, here’s Dr DeFusco posing her question. While she poses it, you all can vote on how you think you would manage this patient.

DR DEFUSCO: I think when we talk about the ones that are greater than 2 cm or positive nodes, I think we still run into the debate sometimes about do we use an anthracycline or not. So I think when you talk to the investigators from the West Coast there’s a greater tendency not to use anthracyclines, although if you’re kind of in the Memorial Sloan Kettering web or area, catchment area, they’ll tend to still use an anthracycline-based regimen.

I think if you have a 38-year-old whose got a 3 cm node-positive, HER2-positive breast cancer, you’re always looking to go with curative intent, but especially in a younger patient, is there an advantage to using an anthracycline in that patient over somebody who’s older and might have comorbidities.

DR LOVE: So, really practical question, Lisa. I guess there’s also the option to use an anthracycline after surgery. It looks there’s a consensus in the audience here — just kidding –- there’s a lot of difference. TCHP is the most common answer. Actually, a quarter of the audience says anthracyclines. However, our faculty says TCHP. Lisa, in what situations, if any, you’re not from either Boston or the West Coast, but what situations, if any, right now are you using anthracyclines, Lisa?

DR CAREY: I use anthracyclines in situations where I’m worried that the tumor is not going to behave as a HER2-driven tumor, so I’ll use something where, heterogeneity, for example, if I’m concerned about it a high-risk situation. I think the truth is that TCH and ACTH in the BCIRG trial were very close to each other, there was a hint of a difference that was about offset by the hint of difference in toxicity in long-term, significant cardiac and leukemogenesis.

So if you had “P” in there, it seems like the backbone of the chemo becomes even less relevant and I think many of us have, for that reason, pivoted towards TCHP, which, to be honest, is not an easy regimen. And so, I think, during the regimen it’s not an easy one for patients but has fewer of these long-term consequences and I think people reach for that.

When do I get nervous about it? I get nervous about it when I see a fair amount of heterogeneity in a high-risk tumor that normally, if they were HER2-negative, I would give an anthracycline/taxane-based regimen. Sometimes you see a patient that has either known heterogeneity or more than one cancer and that’s the sort of situations where I use an anthracycline. To be honest, I don’t use it very often though.

DR LOVE: So actually, in a second, I want to get Ian’s response to one of Lisa’s cases. But I’ll just mention that there was a presentation at ASCO, the so-called TRAIN-2 study, which was looking at the issue of anthracyclines that you can check out. And interestingly, in terms of side effects profile and cardiovascular — I think there was a couple of cases of acute leukemia as well.

But I want to actually get to another case. This actually is from Lisa, Ian. So we’re going to see what the audience and you think about this case. A 46-year-old woman presents with extensive DCIS, gets a right mastectomy, sentinel node, and is found to have 6 mm of ER-negative, HER2-positive invasive disease, negative sentinel node. We want to know from the audience, okay, you’ve got this young woman whose got 6 mm of tumor, what would you likely do in terms of adjuvant therapy? It looks like we see, regulatory issues aside, so theoretically maybe you’d consider T-DM1. Lisa, can you tell us what happened with this patient? This is your Marathon runner, I guess, huh?

DR CAREY: Yes. So, well, she’s doing great. So she actually went on ATEMPT and was randomized to the T-DM1 arm and she did have a little bit of neuropathy, which was interesting. A rash. Nausea. All these were very low grade, not particularly bothersome, but she did notice them. As I said, she ran the Marathon. And she’s now more than 5-years out and is doing fabulously.

DR LOVE: So, Ian, again if you could, would you use T-DM1 in a patient like this? The audience seems to be more inclined to use paclitaxel/trastuzumab.

DR KROP: Well, I mean it’s hard to answer this question because Lisa didn’t tell us her Marathon time. And obviously, that impacts your decision making a great deal. But I think we’re trying to write up the ATEMPT data right now and exactly what the right way to interpret how the data should be used I think is a little ambiguous. We do think that it provides a very good outcome, albeit, only with 3 years of follow up. And, in general, it’s more tolerated, particularly compared during the 12 weeks the patients are getting the taxane in the TH arm. But, the overall toxicity wasn’t better. Quality of life again really was only better mostly during the first 12 weeks. But the toxicities are different, you don’t get the neuropathy, hair loss and neutropenia. You get fatigue and some transaminases and thrombocytopenia, which seem to be gradually more of a problem as you get towards your end the year of your T-DM1.

So, I think for select patients, particularly patients who are going to be really bothered by the neuropathy or the hair loss or myelosuppression, that T-DM1 should — it would nice to have that as an option, again, regulatory issues aside. For most patients, I think TH still should be the standard.

DR LOVE: We’re going to move on now and talk about metastatic disease. But one more question, back to you Lisa. I see in the chat room — we actually had a couple of cases but we didn’t present them — so the question in the chat room is, in terms of tumor heterogeneity, do you check HER2 on both the primary tumor as well as nodal disease, but, also, in terms of pre- and post-neoadjuvant therapy? Do you check it again for the residual disease? We actually had a couple of patients that flipped, went from HER2-positive to HER2-negative. Do you pay attention to that, Lisa, or you just keep going?

DR CAREY: I pretty much keep going. I think it’s super intriguing, the idea of subtype switching that we see. And we saw it in our CALGB 40601 neoadjuvant study, too, where we looked at the residual disease biology and what appears to be happening, there’s some subsequent data from Alex Pratt and the Spaniards, that you do see a shift. And we saw it our study and other subsequent studies saw it, but it tends to revert back in many cases or it looks like it can. And I have to say, there aren’t enough data to say that you treat what’s left, nor that that’s even stable. So, in my mind, I treat what I started with and if there’s HER2 in there anywhere, they get anti-HER2 therapy.

HER2-positive metastatic breast cancer

DR LOVE: So we’re going to move on and talk about metastatic disease. I’ll say I see a really great case in the chat room of local recurrence, ER2-positive, HER2-negative. We’re going to present the case when do our ER-positive one — because I can’t wait to hear what people have to say about adjuvant CDK, based on press releases we’re hearing. Pretty interesting situation. But let’s stick with HER2 and talk about what has instantly become really interesting choices, particularly in the third-line setting. And, Ian, you went through this in your talk. And I love this slide that you started out with, Ian, kind of talking about where we were in the past, i.e., 2019, before all these new options came up. Maybe talk about where we were and kind of where we are right now, Ian.

DR KROP: So I think up until December of 2019, so way back when — I think everybody knew the landscape — we gave a taxane and trastuzumab and pertuzumab in the first line, based on CLEOPATRA. We used T-DM1 in the second line. And then in the third line we just used dealer’s choice of chemotherapy and continued the HER2-directed therapy.

So there were plenty of options for those third-line patients, it’s just they didn’t work very well. The response rates were less than 20% in most of the trials. Progression-free survival were like in the 3- and 4-month range for the most part. So we had options, but they weren’t great and it was clear that we needed more novel therapies here. And as you alluded to, Neil, now we have a veritable cornucopia, as you would say, of new agents, all in the same line of treatment, or at least all the trials were slated in that third line or greater setting. So the question is, now how do you optimize the sequence of all these different agents?

DR LOVE: And of course, again, Ian goes through this in detail in his talk. We’re not going to spend a lot of this time going through the data. We all know that the options on the table, first of all, tucatinib, trastuzumab, capecitabine from the HER2CLIMB study. We actually have one of the patients we’re going to present was actually on the study. WE know what was seen there.

I guess one thing, Ian, maybe you can comment on is the issue – and of course, this is the issue that we were hearing from oncologists, is the CNS activity. Can you comment on what was seen there, Ian?

DR KROP: I mean the reason it’s the issue is because somewhere between 40 and 50% of patients with HER2-positive advanced breast cancer will eventually get brain mets and our treatments up until now, haven’t been great. And yet, this is the HER2CLIMB study was the first big trial to allow patients with active brain mets, not just treated brain mets, but actually progressive brain mets, onto a big study. And they showed these really wonderful data of 9-month survival benefit with the addition of tucatinib in those patients specifically with progressive brains mets.

So I think it’s clear. I think tucatinib has now demonstrated its chops in terms of treating patients with HER2-positive brain metastases, where 47% in-brain response rate, with pretty decent durations of response. So I think we have a clear winner right now for patients who have progressive brain mets.

DR LOVE: So a quick question from the audience, Lisa. What’s the role of tucatinib in someone who’s had progression on capecitabine/trastuzumab?

DR CAREY: So I think one of the challenges for tucatinib is to show that it has equal chops when you give it with other regimens, particularly other backbones. They’re in the midst of studying it. So I suspect that it works as well as all these other anti-HER2 therapies do, combined with other things.

So, again, regulatory and reimbursement issues aside, I probably wouldn’t give it with CAPE again, but I would certainly try and wedge it in there somewhere if you have a patient where that’s the appropriate drug to use.

DR KROP: I think the only issue is, we don’t know how much of the benefit in HER2CLIMB is because capecitabine itself gets into the brain well or whether it’s — clearly, part of this is the tucatinib, a lot of it is tucatinib. Whether you’ll still get that brain effect with a non-CNS penetrating chemotherapy I think is really open to question and we need to look into that.

DR CAREY: We do.

DR LOVE: Another quick question from the audience, Lisa. Can you give tucatinib during whole brain radiation therapy? Or would you?

DR CAREY: I probably would not during whole brain radiation. I usually stop all of these therapies during whole brain.

DR LOVE: So, of course the other big story or another big story, Ian, that you go into in your talk — I could never pronounce this one — trastuzumab deruxtecan.

DR KROP: T-DXd.

DR LOVE: I like that. I think I can do that one. But I just can’t do the deruxtecan too well. But anyhow, what an exciting agent, but also kind of provocative. Ian, can you talk about what this is? And what we know about it right now?

DR KROP: So, T-DXd, or trastuzumab deruxtecan, is a second-generation antibody drug conjugate. it’s got the same trastuzumab-like backbone as T-DM1, but it uses a different payload. It’s a topoisomerase 1 inhibitor instead of a microtubule inhibitor. There’s more of them per antibody and it has this interesting feature of what we call bystander effect, meaning that once the antibody binds to a HER2-positive cancer cell and gets internalized, the payload can go into the cytoplasm of that cell, but it also can diffuse out and kill neighboring tumor cells, regardless of whether they have HER2 on them.

So, that’s the bystander effect and maybe can improve outcomes when you’re dealing with a heterogeneous tumor, kind of like Lisa was talking about earlier, because those neighboring cells don’t need to have the HER2 to still be killed by the payload here. And that may be one of the reasons why we see this waterfall plot, it shows virtually every patient had some benefit, either regression or stability, when treated with it. The disease control rate was 97%. And again, that may mean that it gets those heterogeneous cancers that other drugs weren’t able to target.

So the efficacy is very impressive. But then there’s this other issue we need to talk about.

DR LOVE: Yeah, so the other issue. Yes, that is the other issue, Lisa, the interstitial lung disease. Can you talk about that, Lisa, and have you ever observed it?

DR CAREY: I have observed it. I have had one patient that we needed to take off drug, I want to say 2 or 3 cycles in. It wasn’t terrible. They got a cough. And to be honest, it was just before the COVID-19 pandemic, also complicated all of your evaluations of anything happening in your patients’ lungs, which was sort of a blessing for us right then. But right now, I’m not sure how I would have interpreted these things. And I think it’s a real thing and it’s showing up consistently. The data that Ian showed — there’s still not a lot of data about this drug. It’s still kind of emerging and I think the company is still working very hard to figure out ways to identify risk of this and also to ameliorate it better. But it’s such a fantastic drug, this is the thing that they have to figure out how to manage.

DR LOVE: So provocative too. So we’re getting a lot of really great questions from the audience. I want to interject a couple of them and also get into the other alternative out there that people are talking about. Just real quick though, Ian, I think this is Dr Karen Green that we work with a lot, do investigators recommend doing screening brain imaging for brain mets at regular intervals in the absence of symptoms with HER2-positive metastatic disease because it’s more amenable to treatment now, for example, stereotactic radiation? And someone else wants to know would you use trastuzumab/cape and tucatinib first line in a patient with brain mets, Ian? Do you want to handle those 2 questions?

DR KROP: Those easy questions? Sure.

DR LOVE: Yeah, I give you all the easy ones, Ian.

DR KROP: So I think the routine use of brain MRI is something that’s kind of gone in and out of favor over the years. I don’t do it. When someone has symptoms I image, but I don’t routinely do it. And again, I think there’s pros and cons. Once you start finding them and they’re very small, you feel the need to treat, and we don’t really know that treating it when it’s 2 mm versus 6 mm or 8 mm makes a difference. And it then brings up questions of what you should do with their systemic therapy. So I generally don’t do routine testing.

But the second question you ask, whether we should start moving up drugs like tucatinib that clearly have good brain penetration, move up in the lines of therapy is a very interesting one and should be tested and fortunately, is going to be tested. Right now there’s a study of T-DM1 plus or minus tucatinib, so that’s looking in the second line. The TBCRC is planning a trial to look at whether tucatinib can be effective at secondary prophylaxis in earlier lines of treatment.

So I think the caller raised a very good question and it needs to be tested. But outside of a trial, I’m not doing that.

DR LOVE: So I still want to get to some more cases, but we’re really getting some great questions. Real quick, Lisa, first of all does trastuzumab deruxtecan penetrate the brain? And the other question is, somebody has a patient who’s on it and the bilirubin’s rising a bit to 2. No liver disease. Is this a toxicity? So do you see CNS penetration and do you see any hepatic toxicity. Lisa?

DR CAREY: So the brain penetration question is a really good one. I think there are emerging data that in — well, again, we don’t have a lot of data. The data that do exist suggest that they allowed stable brain mets into the DESTINY trial and those patients, as I recall, seemed to do as well. They had the same proportional benefit as anyone else.

We have to separate a little bit the brain mets question into patients with brain mets, where the blood brain barrier is already disrupted. And the truth is that by the usual parameters of blood brain penetrance, gadolinium shouldn’t cross, right, we shouldn’t — so, when you already have existing brain mets there’s a lot of things that “shouldn’t” cross the blood brain barrier. But, since it’s not there to the same degree, they do, versus prevention of development of brain mets which, of course, is a rational endpoint for these kinds of drugs as we’re thinking long-term. And as Ian pointed out, because such a high proportion of patients, if you control the disease, will, in fact, end up with CNS involvement.

DR LOVE: So I want to get back to some cases and of course, tons of cases about third-line therapy. Just to mention again, check out Ian’s talk. He gets into the issue of trastuzumab deruxtecan in HER2-low. In some of our other programs this summer, we’re going to talk about this agent in GI cancers, HER2 amplified, in HER2-mutant lung cancer. What an interesting situation.

I’ll just remind you again, Ian goes through that. The potential role of neratinib, particularly neratinib/capecitabine in patients with brain mets. And again, like Lisa, really goes through a really detailed and astute “how I do it” type thing.

But let’s just see how it really plays out in terms of actual cases. So we’re going to start with a case from Dr Justin Favaro, a neighbor of your in North Carolina, Lisa.

DR CAREY: I know him well. Hi Justin.

DR LOVE: A 38-year-old woman. Gets THP for metastatic disease, but now — and again, this is really the question we’re getting in the chat room, we’re getting from the docs in practice — here’s Dr Favaro’s question, and we’ll put it up to as a survey also.

DR FAVARO: So this is a 38-year-old lady and she presented with breast cancer about a year and a half ago. And she had bone mets at the time of presentation. She’s been treated, actually on and off for the past year with trastuzumab, pertuzumab and docetaxel. And she’s had a lot of complications from that. She’s had to be taken off for C. diff 3 times.

About 3 months ago she got brain mets, multiple brain mets. And she was treated with whole brain radiation therapy.

The question is what to do for patients that have progressed through standard first-line therapy for HER2-amplified breast cancer? Do you move to T-DM1? Do you move to the newer agents for metastatic HER2-amplified breast cancer? And the question is whether or not the brain mets play into that at all.

DR LOVE: So, it’s interesting, there’s a lot of variability in the audience and I’d say there’s a pretty interesting variability in the faculty as well, split completely, except you 2 both seem to agree. So, Ian, you said for this situation that you stick with typical second-line therapy. Any way to indirectly compare the CNS activity of T-DM1 to the HERCLIMB regimen, Ian?

DR KROP: You’re right, it’s indirect. As Lisa alluded to, there are some data now emerging to suggest that in patients with preexisting brain metastases. It does look like the blood brain barrier is degrade and large molecules can get in. We know that there are case series of patients responding to T-DM1 in the brain.

So we did an analysis of the AMELIA trial, which was capecitabine/lapatinib versus T-DM1, and we looked at the patients who had brain metastasis at baseline and we also looked at patients who progressed in the brain. And in that analysis, there still was a substantial benefit to T-DM1 over capecitabine/lapatinib in both those groups.

So, again, I think the previous caller raised this question of should you move tucatinib up in the earlier lines of therapy? Maybe. But I think we need data on doing that. And I would still use T-DM1 in this situation because we do have some data showing that there is reasonable disease control in the brain for patients on T-DM1 in just this situation.

DR LOVE: So, Lisa, this is another clinical situation that these docs want to see an answer to, a patient who doesn’t have CNS involvement. So we said this is a case that’s based on one of Dr Favaro’s cases, a woman in her 70s who gets THP, then T-DM1, and then, what’s next? But she does not have a CNS involvement. And the faculty is pretty split between the 2 new options, Lisa.

DR CAREY: Except for Dr Krop, who dissembled....

DR LOVE: Also, Lisa, in addition to answering this question or can you also answer the question from someone in the room, would you hesitate to use trastuzumab deruxtecan in patients with lung mets? And I would add people with preexisting, COPD, etc. What about that? And also this case, Lisa.

DR CAREY: So, this is a situation. I try to go along with the lines of evidence as they’re presented to me. In this case, after T-DM1 progression, regardless of CNS, I tend to reach for tucatinib-based regimen, simply because it wasn’t just the benefit that was seen in the CNS group, it was also — half the patients didn’t have CNS mets and they had terrific outcomes. I really like trastuzumab deruxtecan, but I do think that we have a limited amount of data at this point and we do have some toxicity questions that I think need to be addressed. So I tend to reach for the tucatinib-based regimens first and then DS8201a subsequently.

DR LOVE: So here’s the final case from one of the docs and actually, for other 2 breast cancer symposia, we’re going to bring other cases from these docs and a couple of others, but this is from Dr Ma, a 75-year-old lady who gets THP, T-DM1 and now has disease progression but now has significant leptomeningeal disease. So, we’ll see what the audience think about this case. But while we’re doing that, here’s Dr Ma.

DR MA: Number 1 is, under HER2 in the metastatic setting, we’ve got so many agents now. I mean really after T-DM1, it’s kind of — I’ve got several patients I got experience on the deruxtecan. Tucatinib, I used on trial before. Then you had the neratinib, then the really old lapatinib. And I know there is some CNS penetrance differences, but, still, neratinib is supposed to have — we see good CNS penetrance too.

So I’m just curious about expert panel’s opinion on the sequencing?

DR LOVE: So this actually is the response of the faculty. I’d call that a consensus, Lisa. And you see the same thing in the audience as well. I want you to comment on that, Lisa. But also, to this question that we put out the faculty which is the patient who gets tucatinib/trastuzumab/capecitabine, responds. But then the question is what would you do to the patient if they had further progression? And you can see again a little bit split between keeping the tucatinib going or switching to trastuzumab deruxtecan. Lisa, any comments on this situation? Disease progression is only in the brain.

DR CAREY: Right, isolated CNS progression. It’s an incredibly challenging question because the don’t really exist, so they’re scant. The guidelines, what do exist, are some or a series of patients that suggest that if you treat the CNS, and that’s the only place that progresses, and you continue the same thing, many of these patients will go for quite some time before you need to change drugs. And while I appreciate Dr Ma’s enthusiasm for all the drugs that we now have, we do in these patients eventually run out of them. And so, ASCO actually has guidelines for this particular setting, which is continue, if you have isolated CNS progression and you have a local therapy — radiation, whatever — to deliver, you deliver that and you continue the systemic therapy until you see additional progression either in the brain where you need change systemically, or in the systemic compartment. And that’s why I answered that.

I do think there’s a great question to be answered here, and Ian mentioned one of the TBCRC trials that’s in development, may address the — if you have a really good drug that works in the brain particularly well should we get away from the guidelines? Should we reconsider the guidelines? But I think at the moment we don’t yet have the data for that.

DR LOVE: So another question, Ian, is the issue of whether you would use trastuzumab deruxtecan in patients with HER2-low metastatic disease? It looks like actually Joyce has already done it. You say you would for the right patient, Ian. What’s the right patient?

DR KROP: So we have limited data. There is a Phase I experience of T-DXd in patients with HER2-low cancers, and just to remind everybody what we mean by HER2-low is HER2-1+2+ plus not FISH amplified, so HER2-negative by clinical definition. And the response rate was 37% or 38% in that population and it seemed about the same whether they were HER2-1+ or HER2-2+. Small numbers of patients. And that’s led to a randomized Phase III trial that’s ongoing, comparing T-DXd versus chemotherapy in this patient population. But it certainly does look like there’s activity and if I didn’t have any other option for such a patient I would consider it.

DR LOVE: So I want to close out with one of Ian’s cases, but first, Lisa, just before we came on I got an email from Dr Nirmala Shevde, New Hyde Park, New York, of a case. Do you want to hear it, Lisa, real fast?

DR CAREY: Absolutely.

DR LOVE: And also, please, send us more cases, drneillove@researchtopractice.com. Send me more cases. We’ll present them. Here it is, Lisa. A 30-second case, okay?

A 57-year-old with a history of hemochromatosis, locally advanced breast cancer, IDC. ER-positive/HER2-amplifed. Neoadjuvant TCHP. Mastectomy. Residual disease. Two positive nodes. RT, T-DM1. Develops abnormal LFTs. A sonogram of the liver normal. PET-negative. Treatment held for a month. LFTs improved. The patient got a dose of trastuzumab. So I’m going to tell you the next part in a second, Lisa. But, first, what you’ve heard up to now, any thoughts what you think the hemochromatosis had something to do with the LFTs on T-DM1, Lisa?

DR CAREY: Well, I mean I suspect it didn’t help, but it sounds like, particularly since they improved off therapy, this was largely a T-DM1 toxicity.

DR LOVE: So here’s the tricky part. And actually, I saw a case in the chat room that’s kind of similar to that. So, again, the T-DM1 was held and gave her a dose of trastuzumab. She shows up 1 week later with multiple skin nodules over the reconstructed breast. Biopsy-positive, Lisa. Any comments and suggestions?

DR CAREY: Well, I mean they don’t tell us this, but she had radiation it sound like. So, this is probably local recurrence in a radiated field. And if they’re sort of scattered, it’s probably inoperable. So, fundamentally, you follow your metastatic or inoperable locoregional recurrent paradigm. And in this case I would probably reach for the tucatinib/cape/trastuzumab. I mean she progressed on T-DM1. You could make an argument for going back to THP. She’s probably — I’m trying to do the math — didn’t say how many cycles into T-DM1, but it’s probably a pretty quick recurrence.

DR LOVE: Six. Six cycles.

DR CAREY: Six cycles in. Yeah. So you’re talking about a pretty short interval.

I don’t shy away from reusing drugs in the metastatic setting, just because the disease-free survival is short and that’s because the goal is different. So disease control is different that eradication. So you could go to THP an reach for that and it wouldn’t be a wrong thing to do, or you could save that in your back pocket.

DR LOVE: So I want to finish out with a case from Ian and actually, at this point, I think I kind of know what the audience is going to say, but, anyhow, a young woman, metastatic disease. Gets THP followed on T-DM1. She’s got new brain mets.

But, Ian, can you explain what happened with this lady?

DR KROP: So this is a teacher who presented with a moderate risk cancer, ER-positive/HER2-positive, T2. A positive node. This is before all the KATHERINE data, so she just got adjuvant TCH and hormonal therapy. And 4 or 5 years later developed bone lesions and also was found to have liver and pulmonary. Again, biopsy same histology, ER-positive/HER2-positive. Had a good response to THP, as often is the case. But then eventually progressed. Was on T-DM1 and did well on as well. But, again, had bad brain metastases. They were innumerable, so we had to use whole brain.

We did continue the T-DM1, a la what Lisa saying, according to the ASCO guidelines because she did not have progression outside the brain, but then had further brain progression after that. And fortunately, we had the HER2CLIMB study open and she was on that. And we eventually found out, in retrospect, she was randomized to the tucatinib arm and has done well on that since then with good control of the brain. And she’s tolerating it well and still teaches. Clearly, just as what the data had shown, that this really can do wonders in patients who have significant brain metastases, whereas, in the past we really didn’t have lot to offer.

DR LOVE: Lisa, any comments on this case? And, also, your clinical experience in terms of tolerability of the HERCLIMB regimen, Lisa?

DR CAREY: It’s interesting because I think when first starting I assumed it would have similar tolerability issues as lapatinib, neratinib. It’s more similar to neratinib than it is to anything else. But it really is far less of the HER1 type toxicity and I found it to be much more tolerable for patients by quite a bit. And I think the regimen, overall, is well tolerated. I mean it’s a free cytotoxic-based regimen, tool. You have capecitabine in there so you have all of the usual toxicities that go along with that. But I actually have not found it to be hard on patients at all and quite well tolerated. I was pleasantly surprised during the course of the trials.