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HER2-Low Breast Cancer Roundtable: Navigating Latest Guidelines & HER2-Targeted Treatments in Metastatic Breast Cancer
This video highlights the latest clinical practice guidelines for HER2-low breast cancer, explores the role of HER2-targeted ADCs, reviews pivotal clinical trial data, and discusses the implications of NCCN guidelines on the HER2 treatment landscape.
This video highlights the latest clinical practice guidelines for HER2-low breast cancer, explores the role of HER2-targeted ADCs, reviews pivotal clinical trial data, and discusses the implications of NCCN guidelines on the HER2 treatment landscape.
This roundtable discussion is sponsored by Daiichi Sankyo.
Dr Adam Brufsky: So now let's turn really to HER2 low. We're all very familiar with DESTINY-Breast04, and the publication came out in the New England Journal. I think some of us are co-authors on the article or named authors of the article. And so the thing is that, I'm just curious, I think that it was really a quite interesting abstract. I think that we all thought, and I think based on the phase I data, the phase Ib data that had initially come out, that there was going to be activity. And I think that the surprise to me was in the phase I trial, I think the response rate to HER2 1+ was like 38% and then HER2+ was like 50% or something like that. And there were PFS benefits based on the HER2 positivity. But I think what struck me, and I'm curious to hear what the rest of you have to say, is that when you finally get to DESTINY-Breast04, you see the randomized data, you see a survival, you see a PFS advantage of, I think it's 5-and-a-half months to 10 months, and an overall survival benefit of 17 months to 24 months or something like that, as second-line therapy, second-line chemotherapy and beyond.
So I'm curious to hear what people have to say about the DESTINY-Breast04 trial and what they thought of it. I mean, they'd like us to talk about that a little bit. I think it's a reasonable thing to do. So let's start with Bill. I think that, was this data worthy of a standing ovation at ASCO 2022, which is what most of us are going to remember? Although Shanu gave a tremendous, Shanu Modi gave a tremendous, that was really, really good presentation. I have to say it was one of the best ones I've ever seen, and it was really, she just did a tremendous job with it. But is it worthy of a standing ovation? Is it that much of an advance, the DB04?
Dr William J. Gradishar: Well, I was standing up for the presenter, that's what I was clapping about. But no, in all seriousness, I think the data was great. I mean in our careers, all of our careers, there's probably only been a few times where you're struck by either something that's really changing how you do things or something that's a leap forward in things you've been doing. And I think in the case of DB04, it was really changing how we think and it also impacts significantly on patient outcome based on the data you just described. So whether you needed a standing ovation, I don't know, but I think it was one of the most impressive presentations based on the data that we've had in breast cancer in a very long time. It only happens a few times. I wish it was more frequent.
Dr Adam Brufsky: Right. Maryam, what do you think? What's your impression of DB04?
Dr Maryam Lustberg: The data absolutely speak for themselves. This was completely practice changing, and I think in many ways these older traditional chemotherapies, which it was being compared to, is what we had for years and years. And suddenly we had a HER2-targeted therapy that we could treat both hormone receptor positive, HER2-low tumors as well as, the study as you know included a smaller group of what had been traditionally classified as triple negative. So yeah, I think impressive and that we were able to see an overall survival advantage being presented at the same time. So yeah, I mean, data were strong.
Dr Adam Brufsky: Fair enough. Komal?
Dr Komal Jhaveri: Yeah, no, I think these were very impressive to me. I think they were impressive at two fronts in some ways, right? Because when we think about HER2-targeted therapies, we're thinking about HER2-positive breast cancer. So this was the very first approval for a HER2-targeted agent in a, not a HER2-positive breast cancer subtype, what we now call as HER2 low. So that's one; that's new, that's different. And so that goes beyond the 15% to 20% of patients that are HER2 positive. We're talking about 45% to 55% of breast cancer that can be HER2 low. So the impact that this data had is for more than 50% of our patients with breast cancer in the metastatic setting. That's one. So that was exciting. And the second part that was really, really exciting was that we have not seen overall survival benefits, right? The only other drug that we have seen median overall survival benefit in the metastatic setting was in the EMBRACE trial with eribulin. And we saw that there in that study we saw a median overall survival of about 13 months. This was predating the CDK4-6 era. So this is truly the very first time where after CDK4-6 inhibitor progression, we have a progression-free survival benefit, which is unprecedented, but a median overall survival as you pointed out of about 24 months. So way more than what we had ever seen with the eribulin dataset, which was the only chemo, and more, and in the post-CDK setting for a new entity. So I think together with that, the presentation that was eloquently presented by my colleague Shanu Modi, I think, I was really excited and was part of the standing ovation. It just happened. I didn't have to think about it.
Dr Adam Brufsky: So anyway, so Giancarlo, what do you think? I mean I think that in your practice, is this something now that you consider as practice changing?
Dr Giancarlo Moscol: Yeah, yeah, yeah. This is absolutely fantastic. During fellowship, we are so used to be micro dissecting the Kaplan Meier curves to try to see if they really overlap or not. And then here you don't need to be a biased decision to understand that clearly there is a benefit. The separation is very strong, it doesn't disappear over time. The OS is fantastic and you don't need to be trying to go over your subgroup analysis to try to explain if one of them is doing better than the others. To me, it's very clear that all of them are doing sensationally well, and this clearly works on everybody. So it's my preferred treatment for patients that are refractory, endocrine refractory after chemotherapy.
Dr Adam Brufsky: Yeah, and that's good. I mean, I think the interesting thing about DB04, too, that we should probably talk about a little bit before we get into resistance and NCCN guidelines, et cetera is, they started with a pure ER-positive refractory group, right? You'd been through one chemo, you've been ER positive. Probably a few targeted agents beforehand, but I think they added in if I'm not correct, if I'm not mistaken, correct me if I'm mistaken, they added in 60 triple-negative, HER2 1+ patients, 1+/2+ patients, and the curves look spectacular. They're even better I think, than the ER-positive ones, right? And so the question is, is that enough data? I mean, people are asking this question, they ask me a lot, is that enough data to use it in triple-negative disease that’s HER2 1+/2+? Anybody wants to answer that, go for it.
Dr Giancarlo Moscol: Well, I'll tell you what is my perspective. I still believe that the data from ASCENT, from sacituzumab govitecan, is higher quality, right? It’s a phase III, 600 patients, and it was looking specifically for the triple-negative subset. So to me, in the triple-negative setting, I still prefer to do TRODELVY first in second line. And now with the data that was presented at ASCO that using them back-to-back, and when used two ADCs back-to-back, you're not getting the strongest response with the second ADC. I prefer to put a chemo in between those two. So that's how I've been treating my patients in the specific triple-negative setting.
Dr Adam Brufsky: Yeah. Can I ask a little bit about that? Because I've started to hear that. We'll get to the triple negative in a minute. Back to that, but you really raised a really important thing that I just started hearing about, is this whole thing with using chemo in between ADCs and I'm just really curious about what's the rationale for, what's the preclinical data that supports chemo – one ADC, chemo, and then another ADC as opposed to one ADC after ADC. Is there a preclinical rationale for it?
Dr Giancarlo Moscol: There is only an observational data from Brigham and Women's. I mean it does show that when you use your ADCs back-to-back, it doesn't matter if you use first your sacituzumab and then your trastuzumab, your Enhertu or if you use Enhertu first and then sacituzumab later, the responses with the second one are poor, probably as poor or even worse than chemo. We don't know yet why, because the whole mechanism of resistance is being studied. So is this a problem with the payload? Remember both are topo-1 driven? Is this a problem with the target? Could it be a gene expression like top1 for the topoisomerase, et cetera? We don't know that yet, but potentially by washing them out with chemotherapy, you have a higher likelihood of achieving a response, especially if you're dealing with a patient that is dealing or progressing in the liver for example, and has higher risk of impending visceral crisis, for example. So it's not a common occurrence, but that's something that I've been implementing since I saw that data presented in the post.
Dr Adam Brufsky: Yeah, a lot of people are talking about it, and I have to admit, I wasn't as familiar with this whole idea because I'm still trying to figure out in my mind the preclinical rationale for it. I mean, does anybody have any comments, Komal, Maryam, Bill?
Dr Komal Jhaveri: I think it's probably going back, at least in my mind, if I simply were to think about it, when we're thinking about utilizing various chemotherapeutic agents in the metastatic setting, we're just using different mechanisms of drugs, right? And there's no magical sequencing of utilizing vinorelbine, gemcitabine, eribulin, liposomal doxorubicin. I think we do different things with different patients. We discuss the side effects, we discuss the administration schedules, but we're thinking about unique mechanisms of those drugs, and I think while we are waiting to figure out the exact mechanisms of resistance, I think it does seem like when payloads have similar-ish activity, and so we know that the sacituzumab payload is SN-38 a topo-1 inhibitor, and we have the exatecan derivative of T-DXd, again a topo-1 inhibitor. It's possible that if they are payload resistant, then maybe using another chemotherapeutic agent with a distinct mechanism of action might hopefully help resensitize the tumor to be reintroduced to another topo-1 inhibitor in the past. Do I know that for a fact? I don't, but I think that's where this idea potentially is stemming from, that should we be sandwiching a chemotherapy between the two unless there are two distinct payloads that we are utilizing. Now T-DM1, for that matter, is a distinct payload, and we have already shown that T-DXd is superior to T-DM1. So that logic doesn't necessarily apply there directly, but maybe T-DM1 might still have activity as a drug later down the line when we've used some other mechanism potentially. And that's why I think all of us do tucatinib first, is how I'm thinking about it.
Dr Adam Brufsky: Okay. I get that. Any other comments from anybody about that? Because I want to get into resistance a little bit too before we talk a little bit more about early-stage and NCCN guidelines.
Dr William J. Gradishar: These are excellent questions for which there's no data but no shortage of speculation, I would say. So I don't think we know.
Dr Adam Brufsky: TD01 just got presented at, literally, what is today, Thursday? Yeah, three days ago.
Dr Maryam Lustberg: Different cohorts have been presented at different times as you all know, but I believe that there was a small number of patients in TROPION-01 which had previously been treated with sacituzumab and then went on to receive dato DXD, and many of them still had responses. So this challenge of sequencing, I think this is going to be an evolving story and comes back to the resistance point that you were just making, which is, at what portion of the ADC is the resistance happening, is it at the target level, is it at the payload level? So I think we'll have definitely much more to say about this in the next one to two years.
Dr Adam Brufsky: Yeah, I mean the hope is we have preclinical models that will help us out. I mean I'm really scouring the literature trying to find people with preclinical models of this sort of drug, maybe a PDX model of some sort where people get serial antibodies or whatever. I think it's really important because we're going to have probably three or four or five ADCs on the market, and we're going to have to figure out how to use them when and in what sequence? But it sounds like everybody on the call, I mean generally when we get to HER2 low and obviously the triple negative, do most people use it in triple negative right now, that's HER2 1+ or 2+? I mean, right now, triple-negative breast cancer either before or probably mostly after sacituzumab I'm guessing?
Dr William J. Gradishar: Yeah, I would use it and I have used it, but as you pointed out, and as Giancarlo pointed it out, the data from the ASCENT trial is more robust for triple negative at this point. So I would probably preferentially, until we have more data, use that as the first ADC, and then in the appropriate patient consider T-DXd later.
Dr Adam Brufsky: Yeah, got it. So that'll get us now. So let's talk a little bit then Bill about guidelines. You being very involved, I won't say who, but very involved in the NCCN breast committee. I think there are others on this call that may be on the NCCN breast committee too. So the issue is when you look at the NCCN guidelines for endocrine refractory disease as second-line therapy, if you're HER2-low, 1+ or 2+ with a negative ISH, trastuzumab deruxtecan is actually the preferred agent. Is that correct in NCCN right now?
Dr William J. Gradishar: That is correct. Yeah, in the past we had a laundry list of things you could do, but we've tried to make an effort to give a thoughtful process. So we still think that at least based on the FDA approval and all the other things that go along with it that a line of chemotherapy would be appropriate, but thereafter it would be a consideration to use T-DXd second line.
Dr Adam Brufsky: And so how many endocrine therapies would most of us go through before we started thinking of chemo? Would most of us go through, obviously I think most of us will go through probably a CDK4-6, but would anybody start chemo right after failure of CDK4-6?
Dr Komal Jhaveri: Unless it's primary endocrine resistant, meaning your first-line durability on a CDK4-6 inhibitor is extremely short, and I'm talking less than six months, right?
Dr Adam Brufsky: Yeah.
Dr. Komal Jhaveri: That's when you know that this tumor is not behaving the way it should be if it's truly endocrine driven, and when you probably are thinking about calling it endocrine refractory sooner and utilizing chemotherapy first. But short of that, I feel like for the other traditional ways of treating ER-positive tumors, you would, potentially, at least use two and many a times three. And if there's a germline carrier, a patient, you would also use a PARP inhibitor before you get to chemo. I use that as a line before I start chemotherapy. And if it's not a germline patient, I would say two or three before I get to chemo.
Dr William J. Gradishar: Yeah, if the typical PFS you saw with the CDK was mirroring what we saw in the registration trials, I would certainly try more endocrine therapy until there was demonstrable diminishment in the PFS and/or you had just bulky, visceral whatever going on. But I would certainly not abandon endocrine therapy after a single treatment.
Dr Adam Brufsky: Yeah. Okay. Any other comments? Maryam, do you have any comments about anything?
Dr Maryam Lustberg: Yeah, so similar to after CDK4-6 inhibitor progression, I think many of us are very quickly going through these endocrine therapies. So I think the second line and third line endocrine therapy primarily we're using clinical trial-based strategies versus if they have a target such as a PI3K or ESR1 mutation, but obviously to the patient's disappointment, because many of them are not aware, the responses are never as long as the first-line CDK4-6 inhibitors. So I think there have been arguments about whether we should be maybe perhaps switching patients maybe a little bit earlier than we were trained maybe 10, 15 years ago about continuing to push these endocrine therapy strategies. So this is something that is continuing to evolve as well.
Dr Adam Brufsky: Yeah, I mean especially when we see DB06, which is a first-line, HER2-low trial, right? So we will see what happens. No, I agree with you. I mean I think it's a really interesting and fascinating question. I guess a few more things before we go on to the last section. What do you think about toxicity here? I mean I think the one big non-ILD thing I found is the nausea. I think the nausea is probably the surprise for me. There was nausea, I think it was 76% of all-grade nausea in the clinical trials. So it's something we should have expected, but I was really a little bit surprised about the degree of nausea we're getting. Did other people feel the same way? I mean is it usually responsive to the typical agents we use like olanzapine, et cetera? Any comments on that?
Dr Komal Jhaveri: I think with the triple antiemetic regimen, given that this is a moderately emetogenic regimen, and now there are guidelines, including guidelines in the US, we have guidelines from ESO and the supportive cancer community as well. The triple regimen works so well that I haven't necessarily now had patients really have a very severe or a high-grade presentation with nausea because we're now giving the triple regimen with 5-HT3 antagonist, NK-1 antagonist, and steroids already. So I feel like that has really helped in my patient population. Not sure if others feel the same way.
Dr Giancarlo Moscol: I usually dose olanzapine and I keep it for probably seven, 10 days tops, 2.5 at night helps them sleep quite well and they don't get as sick. So I haven't really seen much toxicity. If I don't include olanzapine because the patient has some other comorbidities or QTC prolongation or whatever, then I need to maximize Zofran and sometimes even bring them back for fluids.
Dr Adam Brufsky: I like the low-dose olanzapine at night. That's a good idea. I'm going to try that. Thanks. I learned something today. I'm going to try that. It's a really good idea. So the next question for you guys is ILD, which is clearly, I mean this drug is tremendous and its use is skyrocketing because of it, especially in the surgery load space. I mean what are your feelings about ILD? Lemme give you an example of a patient. So eighth-line therapy, she's had everything. She's eight years of metastatic breast cancer and finally T-DXd gets approved for HER2 low, what was it, about a year ago? Something like that. The FDA approved that, so insurance started paying for it, and I gave it to her and she had a complete response in her liver. Complete. But, six months into it, she began to develop haziness in her lung. What do you do? What would you guys do? I mean, this is a real-life case. What would you do? Haziness in her lung, asymptomatic, completely asymptomatic, and you of course get the “could be inflammation” on the report from the radiologist. What do you guys do with that?
Dr Komal Jhaveri: Hold treatment and consider steroids and do some additional work.
Dr Adam Brufsky: She's type 1 diabetes so she can't get steroids. So steroids out of the questions. So what would you do?
Dr Komal Jhaveri: Well, you can optimize the diabetic regimen. It's not like she can't get steroids, she just has to be monitored more stringently.
Dr Adam Brufsky: Right, really closely, right, on her diabetes regimen. But the question is complete response in her liver. All right, you would stop, everybody would stop and just maybe use steroids depending on how they feel?
Dr Maryam Lustberg: Run repeat imaging, typically, in four weeks, and these grade 1 ILDs we have good data in terms of rechallenges. So as long as she was asymptomatic and we didn't have to bump her to grade 2, I think we have options. I think it's when they have some symptoms that then we're in a data-free zone where we are not quite sure, we don't have safety data for rechallenging grade 2.
Dr Adam Brufsky: Got it. Okay. So the consensus is anything weird on the CT, you stop, you may use steroids depending. Symptomatic disease definitely stop and that's it. You would not rechallenge a symptomatic patient, is that what I'm hearing?
Dr Komal Jhaveri: Yes. And then for the symptomatic patient, the dose of the steroids would be higher. So for your asymptomatic ones it's 0.5 milligram per kilogram of prednisolone or an equivalent, but for your grade 2 it would be higher. 1mg per kg prednisolone or higher and then a longer taper. You definitely want to make sure that they get enough taper and they're resolved, and you wouldn't rechallenge.
Dr Adam Brufsky: You wouldn't rechallenge. Okay, interesting.
Dr Maryam Lustberg: There's still a lot of hesitation that I'm actually seeing, maybe not so much by breast specialists, but about rechallenging even grade 1 ILD. So patients who had been having remarkable responses are not given the opportunity to be rechallenged. So I think it's important to kind of raise awareness on that front. And where I'm seeing it is that patient could have been having a wonderful response, and then they have progression in the brain on, typically patients are switched to tucatinib-based therapy and then they progress in the brain on tucatinib-based therapy, and then you're left in a quandary. And obviously we know T-DXd also has CNS penetration, and so to be able to raise awareness that some patients can be safely rechallenged is really important.
Dr Adam Brufsky: Yeah, I'm really thinking more of somebody who has had a complete, and HER2 low, we believe that you can add it, because we don't really know if it works in HER2 low, and we do know that there is some CNS activity, these drugs, do we think, let me stop. We need to move on to the next session, the last session, in a minute. But we know there's activity in HER2 3+ patients, and we know there's a little bit, from DEBRA and some of the other trials, some very small experiences right now that there's CNS activity in HER2-low patients. Have any of you seen CNS activity in HER2-low patients right now? Someone who has HER2-low disease with a brain met, have you seen activity of this drug in that setting? Any of you, you want to comment on that?
Dr Komal Jhaveri: I haven't. Fortunately, I feel like, unlike the HER2-positive patients where CNS progression is a little more common and you'd end up seeing that early on in the disease course as well, and you can see that late of course, with ER-positive tumors specifically, I feel like regardless of HER2, you kind of see that later in the disease course. So I feel like now that we're utilizing per label this in the second line, I don't think I've come across a situation where I've seen patients with brain met. I'm not saying it's not possible, but it's probably not as frequent or as prevalent.
Dr Maryam Lustberg: I had one clinical situation where there was actually a tremendous amount of CNS disease both in the brain as well as epidural extension, she had had extensive radiation and there were really, she was starting to have motor compromise. Additional radiation could not be given. And we reviewed her goals of care and she really wanted to try one additional therapy line, and she actually has had a remarkable response to T-DXd, with improvement in motor symptoms, improvement radiographically, and we were able to see this within two to three cycles.
Dr Adam Brufsky: Right. Okay, good. I think that we're just done. One last question before we move on to testing, and that is early-stage disease. I personally was not that impressed by the TALENT trial, the TRIO, I don’t know what it's called, TRIO 03 or whatever it was called. I was put at San Antonio. I mean it had a response rate in the neoadjuvant setting, I guess T-DXd plus anastrozole. I think it had a response rate of 60. I don't remember about the PCR rate, but the complete, the total response rate, both PRs and CRs, was like 65%. And when you go back and look at the older trials of anastrazole alone, it was the same. So to me it was like 65% with anastrazole alone when you go back and look at the PEPI trials and stuff like that. And so the question is, do we see a role for these agents in early HER2-low disease? What do you think? I know the trials are ongoing right now, but any thoughts before we move on to testing?
Dr Komal Jhaveri: I think I agree with you. The first impression when we had the presentation of the TALENT trial was that the PCR and the RCB rates that were presented were not necessarily very impressive, and the responses that we saw were imaging-based responses, which necessarily don't translate into PCRs or RCBs, which is already low for ER-positive tumors. And so adding T-DXd does not necessarily increase the PCR rate so much higher. Having said that, the patient population, first, the numbers were smaller, but also it was not enriched for a very high-risk patient population either. These were not necessarily very high grade, very high nodal disease burden patients, and so we didn't know anything about their genomic profiling either. Were they low oncotypes, were they high oncotypes? Would it matter? Because if they're not going to benefit from aggressive chemotherapy with low oncotypes, I'm not sure if we're going to be able to identify a differential with the addition of T-DXd to hormone therapy in this group. So I feel like maybe the number of cycles needed to be optimized, maybe the patient population needed to be optimized to be able to understand that. Having said that, even if we did that, right now we have T-DXd that is approved against single-agent chemotherapy, so it's monotherapy compared to monotherapy, can we really replace T-DXd for a poly-chemotherapy regimen for our high-risk early-stage breast cancer patients? I don't know if we can, and we might need to really study it very well. But maybe one can envision, could we use T-DXd for an anthracycline-free regimen? Could we sequentially use T-DXd and, say, taxanes? And could that have an impact in those patients who definitely need chemotherapy in the neoadjuvant setting and would benefit from that? I think those are the questions that might still be unanswered and we need to still really tap into that potential before we can say yay or nay for sure in the early-stage setting.
Dr Adam Brufsky: Any other comments about where you think this is going to go in early-stage or not?
Dr Maryam Lustberg: And I think we need to gain additional comfort in terms of which patients may be most at risk for serious toxicity. I know there was one death reported in that trial, which may have been completely unrelated, but I think in this curative setting, I think there's going to be additional caution about some of these grade 5 events. So I think if we can better understand and better be able to re-stratify patients at risk for serious toxicities, I think that would be really critical before clinicians feel comfortable using these agents in that early-stage setting.
Dr Adam Brufsky: It would be helpful to know the mechanism of the toxicity. Again, just not knowing the mechanism of resistance. We have no idea what the mechanism is. Is it immune? Is it payload related? Is it antigen related? Is it all three together? We have no idea.
Dr Giancarlo Moscol: HER2 low is not a main driver, it's not an oncogenic driver for these patients, like HER2 3+, like overexpression. So that also, I agree that probably we need to get better at prognosticating and understanding which are the patients that are at the highest risk, similar to what we're doing with the CDK4-6 in the adjuvant setting. I will probably see more of a role on this in the adjuvant more than neoadjuvant and try to enrich for patients that having a natural poor prognosis like lymph node positivity, high-grade disease, in order to get the maximum response and limited toxicity on these patients.
Dr Adam Brufsky: Yeah, no, I agree with you.
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