Introduction: Educating Non-Breast Cancer Specialty Oncologists About HER2-Targeted Therapies – ASCO Genitourinary Cancers Symposium 2024

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about the management of HER2-positive and triple-negative breast cancer following our recent program focused on ER-positive disease.

We have a great faculty today, Dr Ian Krop from the Yale Cancer Center in New Haven, Connecticut, and Dr Priyanka Sharma from the University of Kansas Cancer Center in Westwood, Kansas.   

As we do in all of our programs, if you have any questions or cases you’d like to share with us, just type them into the chat room and we'll talk about as many of these as we have time.

And as we always do, there’s a 1-minute pre- and postmeeting survey in the chat room for you to take. You’ll get a lot more out of the meeting.

We know a lot of people end up listening to these webinars. If you’re into audio programs, check out our Oncology Today podcast series, including a recent program with Drs Bardia and Tolaney.

We’re going to be starting up another Meet The Professor series with myelofibrosis this coming Thursday at this same time. And then next week, we’ll be continuing with chronic lymphocytic leukemia. Now a new BTK inhibitor available first-line. And then on the 8^th, gastroesophageal cancers. February 13^th, lymphoma. We’ll talk about the big Hodgkin study, what’s happening there. And then bladder cancer on February 22^nd. As we’ve been talking about the last month or 2, we’re reawakening our weekend-long General Medical Oncology Summit this March here in our hometown of Miami.

And we’re going to kick that off on Friday night with a very special session that I wanted to mention here tonight on ER-positive metastatic breast cancer, a topic we talk about all the time, but this is going to be a little bit different. And if you’re not coming to Miami, you can check it out online because we’re going to be interviewing a bunch of clinicians, hopefully medical oncologists and oncology nurses, who have breast cancer and see what their perspective is on some of the key decisions in breast cancer, and particularly this session. It’s just an experiment to see what their perspective is. I really will be curious to see how they respond. But we’re going to try to do that. And one of the reasons we’re bringing that up is we are asking you, the audience, to let us know if you know someone, any doctor or nurse, but particularly a medical oncologist or oncology nurse who has breast cancer, maybe somebody who has already gone public with it, would be willing to talk to us so we can bring that to this meeting. And we’re going to, as we go through this tonight, share a little bit about some of the things we’re thinking about related to that. Here are some of the other sessions that occur during that weekend. As you can see, we’re covering a lot of oncology, not all of it. I think we’re bringing in like 30 investigators here.

But tonight, we're talking about part of the breast cancer story, HER2-positive, triple-negative disease. As we do in all of these programs, I meet individually with the faculty prior to this meeting, so I met with both of the faculty last week. And we recorded 2 very in-depth presentations going through a lot of papers. We’re not going to go through all that tonight. Here are some of the papers that Ian covered on HER2-positive disease from this past year. And then, you can see how many there are. And then Priyanka, again, so many things going on in triple-negative breast cancer. We’re going to pick out from this group of papers some of the more interesting ones and get a little bit more into what the data showed, what the clinical implications were.

But first, I’ve got to tell you a little interesting story to get started which is that last week when we were recording these 2 presentations, actually I think it was a week ago, I was set to do the recording with Priyanka. But last Friday night, we did a program at the ASCO GU meeting on bladder cancer. And we had 5 modules and one of the modules and one of the topics, Priyanka, was HER2-positive disease. And what I did, as I do with a lot of these programs, I interviewed 2 very, very prominent national GU investigators. We went through GU now has an ADC and an IO first-line. Maybe that’s going to come to breast someday, who knows. But enfortumab vedotin and nectin ADC plus pembro first-line therapy. But they didn’t know too much about HER2-positive disease, HER2 testing. And yet, we’re seeing some data, particularly with T-DXd, the basket trial that was presented at ASCO, 40 patients but a pretty impressive waterfall plot and response rate. So our group, we were talking and we said, well why don’t we ask Priyanka and see if she has some things that we could play for them because maybe she will bring some of that to them. So that’s what we did. This is the symposium we had last Friday night. I wouldn’t doubt quite a few who are watching tonight might have watched it. It was a great program. And when we got to the HER2 section, Priyanka was making the comments.

I just want to show you. And, Ian, I’m curious what your thoughts are after you see this. I hadn’t even thought of that the day before when I was meeting with you. See what you think about how they responded to one of the comments she made about management of T-DXd side effects. Here’s what happened.

DR SHARMA: Nausea/vomiting is clearly an issue. Most patients need some sort of a delayed nausea regimen with this drug. And if you don’t, they’re quite miserable. If you’re very proactive, then they’re fine.

DR YU: Okay. Here are their questions for the faculty. What’s your approach to the prevention and management of T-DXd-associated nausea and vomiting? Dr Milowsky?

DR MILOWSKY: Yeah. So again, I mean I really don’t have experience so I’m going to do what Dr Sharma’s telling me to do. I think that it sounds like using agents that we would use for drugs like doxorubicin and cisplatin, so I think that it sounds like it’s fairly straightforward.

DR LOVE: Ian, any thoughts? This happens with a lot of agents, IOs. Initially, it was the melanoma people who learned about it, then the lung. By the time it got to your guys, they were very into it and used to it. PARP started with ovary, again, then came to you. And now in prostate. Any thoughts about this issue of educating specialty investigators, Ian?

DR KROP: Well I think doing what Dr Sharma tells us to do is always a good idea. But no, I think you’re right. This is going to become more and more common as our drugs are less tumor-specific and more antigen or molecular target-specific. They’re going to start crossing from one disease to another and we’re going to have to teach each other. I know that we were talking earlier that the breast community had to learn how to use IO agents from our lung and melanoma colleagues because they’ve had much more experience than we did once it got approved in triple-negative disease. So yeah, I think this is going to be the wave of the future and we’re going to need to figure out how to do that education.

DR LOVE: Priyanka, the one thing I couldn’t get, it was kind of hard to get through is the efficacy. You can see a waterfall plot. You can see response rate. But when you start talking to people and hearing stories, it kind of sinks in a little bit. When particularly a general medical oncologist even experiences it in one tumor and then they start thinking about it. Any thoughts?

DR SHARMA: It’s definitely one of those drugs where you have patients on, for those it works in, for a very, very long period of time without much of dose-limiting toxicity that requires you to stop it. You don’t run into peripheral neuropathy. PPE which we’ve dealt with, with capecitabine and some other drugs. So this is one of the drugs, besides ILD which would require you to stop it, there’s not much in terms of cumulative toxicity. And even the ILD actually dips after a year. That doesn’t mean you shouldn’t be vigilant. But if somebody has been on it for a year and are benefiting from it from the disease control status, then they can stay on it longer with no additive toxicity, at least that’s what my experience has been in the clinic.

DR LOVE: And it’s also possible that maybe we’ll learn something from these other specialties that we haven’t thought about. One thing, Ian, that I find really interesting. I keep bringing it back up to the GI people, particularly the upper GI. GI is not just GI. They have the upper. They have colon, biliary tract. And they’re just as siloed. But in terms of that, in terms of T-DXd, trying to bring up kind of how you’re going to monitor them in terms of ILD. Also, repeat HER2 testing. The upper GI people, if they repeat HER2 testing, somebody is HER2-positive and then later on becomes HER2-negative, they won’t use HER2 therapy. I don’t think I see you all doing that. I’m not sure who is right, incidentally.

DR KROP: Yeah. Well the biologies of the 2 different diseases are a little different. HER2 in gastric cancer tends to be a little bit more heterogenous and lower level, and that may explain why it changes from time to time. In breast cancer for the HER2 amplified cancers as opposed to HER2-low, these cancers are really driven by that HER2. And it’s pretty uncommon for them to lose expression, at least early on. Whether it happens after fourth, fifth, sixth lines of treatment, we have less data. But early on, they don’t tend to lose HER2 just because it’s such a driver of this cancer type.

DR LOVE: Another thing we find really controversial, Priyanka, is the screening for ILD. You all are way more sensitive to that, particularly as they just begin reading about it essentially. And the idea of doing, you know, we played the video of you saying that you all do CT, high-res CT every 9 weeks. And that is something to swallow for docs who are not really used to it. Any thoughts about vigilance in screening for ILD and whether or not other disciplines maybe don’t have the negative experiences or are as familiar with some of the negative consequences? Or maybe they overrate the risk too because the newer data seems to be a lot more encouraging. Any thoughts about how that will play out across disciplines, Priyanka?

DR SHARMA: So I think paying attention to what we need to do to keep our patients safe is important. I still tend to get the first scan at 6 weeks. And then it’s hard to do every 6 weeks, so I kind of split the difference and get it at 9 weeks. And I usually will restage if I’m doing the scans. And I haven’t had issues with insurance trying to fight it. Now if somebody has been on it for 2 years, would I stretch it to 12 weeks? Probably, keeping in mind that the patient has to be vigilant. And the best measure to manage ILD is early identification, right? So I think then the onus is on us to do the things at the right times just like we have to do a blood count before giving chemotherapy. We do it every week or every 3 weeks like we have to. This is just part of our management system. I don’t know if Ian does it differently, but I’ve been quite conservative and not laxed my scan intervals much yet beyond 9.

DR KROP: Yeah, I agree.

DR LOVE: I will say that as we talk to more and more people in breast, they give more and more of the same answers. I could pick out 5 other breast people who would have said almost the same thing that you did, screening and everything else. Because you’ve had enough time to kind of process it and settle in. All right, let’s talk about HER2-positive.

DR SHARMA: Maybe we’ve all met secretly and matched our answers so that it’s like a questioning session so that you won’t get any discrepancies. I’m just kidding.

HER2-Positive Breast Cancer — Dr Krop

DR LOVE: Right. All right. So we’re going to talk about HER2-positive disease and some of the things that came out this year. Maybe not quite as earthshattering as prior years, but a lot of important data. But I just saw a great case come into the chat room and I can’t resist it. Ian, this is from Lisa. A 34-year-old patient Stage III HER2-positive, ER-negative, path CR after TCHP, RT given. Two months later, headaches, symptomatic, visual issues, 3.5 cm mass in the occipital lobe. No other evidence of disease. Resection, SBRT. I’m not going to say what she plans to do. But what would you do, Ian?

DR KROP: Wow, that’s a tough case. It shouldn’t happen. Patients who have a pCR have generally very good outcomes. But we do see isolated brain recurrence in patients. It’s less common with pCR, but it still happens. What you do in this setting is completely without data. I think most of us would give, actually I would argue all of us would give some type of additional HER2 therapy. Which one you would do is where there’s the art of medicine. You could just continue with what you were originally going to do which is continue the trastuzumab and pertuzumab for a year. I think that would be the most standard thing to do. I might think about giving, this is a patient who you might think about giving some type of tucatinib-based regimen, but you would really be giving a course of a tucatinib-based regimen like T-DM1/tucatinib based on the data that we’ll talk about later or just give the capecitabine, trastuzumab — trastuzumab, capecitabine and tucatinib regimen from HER2CLIMB, doing that for a course. I wouldn’t do it indefinitely. I might do it for 6 cycles. You might think about neratinib, but she’s ER-negative and we don’t have data in the adjuvant setting for neratinib, positive data for neratinib in the adjuvant setting whereas we do in the metastatic setting, but it’s tough.

DR LOVE: So you comprehensively answered her questions. And yes, she is about to start HERCLIMB. And her question was, for how long? And you answered it. And I think one of the things we hear a lot from general oncologists is they feel reassured when you don’t know the right answer, that there is no right answer because they feel better about it. It was a great case. Thanks a lot, Lisa.

All right. Let’s talk about some of the papers that came out this year. And, Priyanka, of course one of the things that Ian reviewed was the follow-up on the APT trial. I guess that got started when Ian was at Dana-Farber. And then also the PHERGain trial, very interesting. So one of the things I was thinking about, and we were talking about this session we’re going to do with clinicians with cancer, and I’m curious how you see patients processing the decision about treatment in a patient who has got a small HER2-positive tumor, Priyanka, in terms of not so much what an oncologist would say about it because really I don’t know, but how you decide when to treat. When Ian spoke with me, I think he said 3 cm or maybe it was around the point at which he starts to treat.

DR KROP: 3 mm.

DR LOVE: 3 mm, I’m sorry. And he said that he usually uses TH other than people who have neuropathy or some reason not to give TH. Is that what you do or different?

DR SHARMA: Yes, I would concur. Tumors that are T1b and T1c are typically managed with the adjuvant APT type regimen with paclitaxel and trastuzumab. In some patients, I also kind of have a discussion about the duration of trastuzumab. Because one year may or may not be necessary. Now, we have a meta-analysis suggesting that 6 is probably as good as 12. So somebody with a smaller tumor, we also have that discussion. And tumors that start hitting 2 cm, even 1.5, between 1.5 and 2, if they’re ER-negative, a younger patient, I’m tending to have a discussion more for a preoperative regimen in those patients.

DR LOVE: And also, of course, we got into the issue of T-DM1 as an alternative. And also, maybe you can comment a little bit on this PHERGain study, Ian. I guess the thing that was so fascinating is they had people start out just with — without chemotherapy. And I think like 30% of them had a path CR just with anti-HER therapy. Any thoughts about this, Ian? And is this a strategy that you would consider using?

DR KROP: Yeah. So I think we’ve now seen in multiple trials that there are certainly a subset of HER2-positive cancers that are exquisitely sensitive to HER2-directed therapy. And those patients, as was seen in this trial, do very well even without giving any chemotherapy. So in this trial, which I think was an interesting and pretty bold study, they just treated with 2 cycles of trastuzumab and pertuzumab without any chemo. And if the patients had a response on a PET scan after 2 cycles, they continued to just get more of trastuzumab/pertuzumab. They got a total of 8 cycles. They went to surgery. As you said, 38% of those patients had a path CR. And those patients then continued without any chemotherapy. And what was found in this now longer-term follow-up of this trial was that those patients did very well. IDFS I think was about 98% in the patients who did not get any chemotherapy. And that was about overall 30% of the patients on the study were able to do very well without any chemotherapy. I think —

DR LOVE: I was going to say, have you ever done it outside of a trial?

DR KROP: So I haven’t done this. Using PET as a response is something that’s certainly investigational. I think outside of a trial, I haven’t — the de-escalation that we’ve done is either using the TH regimen we just talked about or T-DM1, both of which have very good outcomes if they have a path CR. That’s being tested in the COMPASS trial. There’s been other trials looking at T-DM1 for patients who — if I was averse to give, if I was worried about them having toxicity from chemotherapy, I think that would be, for me at least, an easier option than doing a more comfortable option and using just trastuzumab and pertuzumab since we don’t have a lot of data for that outside of a trial.

DR LOVE: Yeah, that’s what I was thinking about, people who refuse chemo or can’t get chemo or whatever. So, Priyanka, Karen Green who is one of our favorite oncologists, she specializes in breast, says since patients with Stage I HER2-positive breast have such a good prognosis with the APT regimen, what do you think about for premenopausal patients who are ER-positive? Do you give adjuvant tamoxifen or osi plus AI? Gets into the whole issue of hormonal management of HER2-positive disease which we’ve got a lot of questions about.

DR SHARMA: Yes. And if we go to the APT dataset, again, I think 65 or 70% of patients were postmenopausal. And the time that it was conducted in, I would think that among premenopausal women, the use of ovarian function suppression was low. So I tend to also be careful in selecting my patients for APT. So a 29-year-old with a 1.9 cm tumor, I will think a little harder about. That person, I’d probably want to give them benefit of neoadjuvant therapy approach and adjuvant TDM and other things. But a regular person that you’re comfortable taking through APT, I’m leaving them alone on tamoxifen and not really pushing the ovarian function suppression issue for majority of these women because I think that is what was represented in APT. Ovarian function suppression is also hard. It’s hard for 3 to 5 years for most women.

DR LOVE: So, Ian, Oleksandra who I believe is from outside the United States is asking about hormone therapy in HER2-positive disease. And we get a lot of questions. There are so many things going on now in metastatic ER-positive with SERDs and AKT, et cetera. And HER2 is kind of getting left out of that, at least for the moment. What about endocrine strategies in HER2-positive disease, Ian? CDK, there’s some data on from your former colleague, Dr Tolaney. Can we bring in the new hormonal strategies into HER2-positive disease?

DR KROP: Yeah. So, again, we have to distinguish between early-stage disease and metastatic disease. But you’re right, the preclinical data say that CDK4/6 inhibitors work very well in HER2-positive models. We have the data from monarcHER that Sara Tolaney presented showing the combination of abemaciclib, trastuzumab, and endocrine therapy was quite effective. It actually was better than chemotherapy and trastuzumab. So I think that does provide an option for triple-positive patients in the metastatic setting. That trial was not done in a way that would lead to FDA approval for that regimen, but it’s clearly an active regimen. It’s pretty well tolerated. And I think that, again, I certainly use that in the metastatic setting in patients. It would be great if we had dedicated trials of the new SERDs, of the PI3 kinase inhibitors, the AKT inhibitors in HER2-positive disease. But I’m not sure we’re ever going to get large trials, but there are some smaller studies. And these drugs are efficacious in HER2-positive disease.

DR LOVE: Let’s bring up a few other issues and then we’re going to move on to triple-negative disease. So, Priyanka, we’ve been talking about post-adjuvant neratinib for quite a while now. We saw a publication this year with some more follow-up from the ExteNET study, more from the CONTROL trial. Of course, diarrhea has been a big issue. And incidentally, I was also wondering, I wonder how medical oncologists if they were in this situation how they would process it. I wonder if maybe they would be affected by the experience they have with patients who get neratinib. I don’t know. It’d be interesting to kind of speculate. But getting back to the issue of lower-risk HER2-positive — I’m sorry, neratinib in the post-adjuvant setting. I’m curious whether or not, to what extent you’re using it, Priyanka. And how do you see people sorting out the risks and benefits? Does it fall into the typical oncology situation, the patients who want to do everything will try it versus the ones who are more concerned about toxicity? And what have you seen as the years have gone on in terms of your ability to control diarrhea?

DR SHARMA: I think delivering our most effective therapies neoadjuvantly really helps us tailor these drugs that come in later and have significant toxicity. So certainly for patients who have a pCR with our TCHP or ACTHP regimen, I don’t think any of us are escalating beyond the standard adjuvant finishing HP part. The patients who have residual disease are getting T-DM1, so the challenge with the neratinib data is it was studied in absence of T-DM1 and absence of pertuzumab. So it will fall after a person finishes a year of T-DM1. And the benefit was primarily seen in patients who have ER-positive disease.

So if you have a patient with hormone-positive breast cancer that has a large amount of residual disease after preoperative, good chemo, finishes a year of T-DM1 and are motivated to try something else, then I will pursue it with them. I have to say I have not been successful in pursuing many women to take this. By the time they finish a year of T-DM1, they’re almost 2 years from diagnosis and kind of exhausted from therapy. And if they have hormone-positive disease, for the person who has a lot of residual disease, yes, we’re offering them an AI, offering them ovarian function suppression. So you’ve added those agents and the toxicities associated with those. And those have proven efficacy. So I have not had great success in many women taking this up. For those that do, I do follow the prophylaxis and control type of slow escalation because that will make it more likely for an individual to tolerate and stay on it.

DR LOVE: I’m sure though that the fact that you presented this to the patients to consider is important because if they later relapse and they read about this strategy, well why didn’t you mention it to me? We saw actually in the last report in 2021, less brain mets, 0.7 versus 2.1 which was quite interesting.

DR SHARMA: And fortunately, we have the Alliance trial that’s ongoing right now that’s looking at T-DM1 versus TDM plus tucatinib, so we have that open.

DR LOVE: Right.

DR SHARMA: So a lot of patients that will fall into that very high-risk category are actually taking opportunity of that trial.

DR LOVE: That’s a good point. Incidentally, I meant to mention when we were talking before about CDK. You said that there’s an ongoing randomized study in HER2-positive looking at CDK, right? That’s coming out hopefully in the near future. Did I hear that right? CDK in HER2-positive metastatic disease. Ian, didn’t you tell me?

DR KROP: Yeah.

DR LOVE: Or no, you did, Priyanka.

DR SHARMA: Yes.

DR KROP: Well I think we both were talking about it, that it is an interesting idea. This PATINA trial is looking at patients who are in the metastatic setting.

DR LOVE: PATINA, right. Yeah.

DR KROP: Yeah, who are in the metastatic setting who are doing well on maintenance trastuzumab and pertuzumab after induction chemotherapy on the CLEOPATRA regimen are randomized to either endocrine therapy alone — I mean, endocrine therapy plus HP or endocrine therapy/HP plus palbociclib because there are certainly strong data that CDK4/6 inhibitors can be effective in HER2-positive disease. And the hope is that this will extend the disease free interval for these patients.

DR LOVE: So, Ian, neratinib is also an issue in terms of HER2 mutant disease. We were talking about HER2 outside of breast cancer. In non-small cell lung cancer, most of the patients are HER2 mutant and they give it first-line. They see great responses. Obviously, it’s not as common. If you remember, Dr LoRusso’s discussion of the HER2-low paper, she brought this up in terms that it does occur in breast cancer. And, Ian, you talked about this paper looking at a combination of neratinib, fulvestrant and trastuzumab on patients with HER2 mutant metastatic disease. Any comments on what they saw? And is this a strategy you use yourself in your practice?

DR KROP: Yeah. So it is not a common phenotype to have HER2 mutations. Again, we’re distinguishing HER2 mutations from HER2 amplification. But there’s about 3 to 5% of breast cancers, more commonly in lobular breast cancer, that have these HER2 mutations. And this basket trial called SUMMIT which has been looking at multiple different combinations has clearly demonstrated that neratinib as a single agent has activity. Neratinib plus fulvestrant has what looks like more activity with response rate of about 30%. And then this updated study now, as you mentioned, added trastuzumab to neratinib and fulvestrant showing almost a 40% response rate and pretty good PFS, about 8 months. The problem was it does look like you get even more diarrhea when you add trastuzumab to that. But I think, to your point, for patients who have a HER2 mutation, and that’s going to come up when you do sequencing, standard sequencing of patients’ metastatic disease, neratinib is clearly an active drug. And I have used it. I haven’t used it with trastuzumab, but I’ve used it neratinib plus fulvestrant in triple-positive — I’m sorry, in HER2-positive, ER-positive patients, and patients have done well on it. So it is within the NCCN guidelines as a possible option. And I think it’s worth thinking about for this subset.

DR LOVE: So I want to just finish out with HER2-positive metastatic disease and rather than showing a lot of slides, just kind of get your general reactions to this. So one thing there, Priyanka, at the bottom, you see the paper that Ian did looking at the age-specific pooled analysis of T-DXd showing that these patients I guess seem to respond as well. And surprisingly, Ian, maybe you can comment on this, they seem to tolerate dosage fairly well. I was telling you that we had a couple of cases of 90-year-olds presented who got T-DXd where they preemptively dose reduced. But I guess it looked like in your study, counting age 65 as elderly. They didn’t seem to have much difference. Anything you want to say about that? And then, I’ll ask Priyanka what her experience is.

DR KROP: Yeah, the data was pretty clear. We also had a subset of patients over the age of 75. And what we saw was that the outcomes were identical between patients under 65 and those 65 and older in terms of progression free survival and response rates. There were somewhat higher, about a 10% increase in Grade 3 or higher adverse events in the older patients, but that didn’t affect their overall outcomes. And I think the take home message, or at least my take home message, from that trial was that T-DXd in HER2-positive disease is a good option for patients regardless of age. And, again, I think this was a pretty extensive dataset and it was, I think, the results were pretty clear across all 3 studies.

DR LOVE: So I encourage you to check out the entire presentation with all the data in there, but just to pick out a couple other points. One was the issue of brain mets. And, Priyanka, we’ve had that issue out there for a while in HER2-positive disease. When tucatinib came out, there was a big switch towards using that in the second-line setting with people with brain mets. And then we started to see encouraging data coming out with T-DXd. So nowadays, if you present, I know if we present a case of somebody who has new brain mets but also new liver mets, T-DXd is definitely an option. What’s your take on CNS activity of a HERCLIMB-type approach versus T-DXd, Priyanka? Obviously, indirect.

DR SHARMA: Yes. In HER2CLIMB, the data comes from a randomized Phase III trial from a predefined subset. But having said that, what we see in terms of efficacy of T-DXd looks very robust too. So the choice between whether you’ll switch to T-DM1 — a T-DXd-based therapy or tucatinib-based therapy may be based on what else is progressing, the patient’s tolerance to previous things, their willingness to take 2 oral drugs in different schedules, which is what you have to do with HER2CLIMB, or not. So I prefer to have the discussion of a tucatinib-based regimen in that situation, but I’m totally not opposed to doing T-DXd either. So I think that agent also has efficacy although we don’t have randomized Phase III data, but what we see clearly shows pretty good efficacy.

DR LOVE: So Dilip in the chat room says lobular is most often HER2 mutant. Do we manage those differently? Dilip, don’t even get me started on lobular. That’s a whole other thing we’re going to get into soon. And the faculty knows about that.

All right. One final thing on HER2+, we’ve got to move on here. HER2CLIMB, I was kind of like, when I saw this come out, I was like what does that mean clinically? So, Ian, do you want to take — this is basically looking at adding tucatinib to T-DM1. You can see the patients with brain mets, the PFS is better. What’s the clinical meaning of this exactly, Ian?

DR KROP: Yeah, I think that’s really the open question. As you said, the data are clear. Adding tucatinib to T-DM1 improves PFS modestly. There is a little bit bigger benefit in the patients who have baseline CNS disease. But there’s absolutely no survival benefit and there is somewhat increased toxicity over T-DM1 by itself.

So how do you use it? I think the simplistic question is, do you use — as we’ve talked about, tucatinib is clearly a good drug. And the question is, do you use it as we have been along with trastuzumab and capecitabine in the HER2CLIMB-01 regimen? Or do you use it, now with these data, do you use it early, you know, with T-DM1? And I don’t think there’s a right answer. I’m a little bit underwhelmed by the activity here. So I probably am still thinking about using T-DM1 by itself and then using tucatinib with trastuzumab and capecitabine. But I think over the couple months we’ve had since these data came out, I’ve been talking to other oncologists and we’ve been talking about the idea of maybe you should use tucatinib in both combinations. Is it possible that tucatinib is going to have activity in both regimens sequentially? It’d be great if we had data. We have no data on sequencing tucatinib in more than 1 line of treatment. But that would certainly be a nice thing to have as an option for patients is to be able to use tucatinib in more than 1 line, but we don’t have that yet.

DR LOVE: So I encourage you to check out Ian’s presentation. There’s so much more we haven’t talked about. It’s really amazing after all these years. I was just flashing on it. It was 2005 when the adjuvant trastuzumab trials came out. And now, we’re in the middle of de-escalation and adding in new agents. It’s really amazing.

Triple-Negative Breast Cancer — Dr Sharma

DR LOVE: All right, triple-negative disease. And starting out, of course, with localized disease in the KEYNOTE-522 where we saw some updated data at ESMO. But also, the issue of alternative chemo regimens, one that Priyanka is looking at in a big randomized study. Also, a couple other papers that came out looking at atezolizumab in the neoadjuvant situation, the trial presented at ESMO, taxane/carbo with or without atezo. And then in the ALEXANDRA study which was basically a negative adjuvant trial. So first of all, talking about the 522 regimen, Priyanka. One of the things I was wondering about is, again, I was curious how a medical oncologist with triple-negative breast cancer, they’ve seen certainly the 522 regimen play out a lot. I don’t know if they’ve seen some of the alternatives, particularly your regimen, cis/gem/pembro. But we did see follow-up data. And I guess the one thing that people still ask, Priyanka, about this is whether or not the adjuvant, you know, whether or not adjuvant therapy is needed, particularly in the path CR situation. Any possibility that cell-free DNA might be a consideration? Any comments on the questions that are coming up nowadays with this regimen, Priyanka?

DR SHARMA: So I think the KEYNOTE update provides reassuring efficacy data for 5 years. But the design really prohibits us from knowing what the adjuvant phase adds. Fortunately, we have trials that are trying to address this question. There’s an ongoing Alliance trial led by Dr Sara Tolaney, COMPASS-pCR that is looking at the role of adjuvant pembro in patients who achieve pCR to neoadjuvant chemo plus pembro. It doesn’t dictate the type of chemo a person takes neoadjuvantly as long as it’s 6 cycles of some sort of good chemo. So that will provide the answer. We see that there is a small separation in the curves even in patients with pCR in KEYNOTE-522. But whether that is driven by the preoperative component of pembro or is the adjuvant pembro doing anything to it is unanswered from the design.

Historically, what we know is patients who achieve pCR do well, so that’s our trigger to do less. So it just feels counterintuitive to keep doing something that led to a complete pCR after the pCR has been achieved. Personally, and this may not be part of what fits the guidelines, if I have a patient with a small node-negative cancer that I’ve given preoperative chemoimmunotherapy to and they achieve a pCR, I’m not pushing the adjuvant pembro a lot. We have the COMPASS — the OPTIMIZE study open, so we’re offering that study that our patients. But if they have some hesitation, if they had a rash or any side effects from preoperative pembro, I’m finding an excuse to not give it in a node-negative small tumor. For people who have node-positive disease or clearly for those that have residual disease, we’re continuing it not knowing the extent of benefit for that agent.

DR LOVE: Could you compare the regimen that you have, that you’re looking at in the SCARLET trial with 522 in terms of what the patient goes through?

DR SHARMA: Yes. So the SCARLET, which is a randomized Phase III trial that’s comparing KEYNOTE-522 to a regimen we tested in a small Phase II study called NeoPACT. So NeoPACT was a 2-institution study conducted at KU and Baylor. And there, we evaluated 6 cycles of carbo/docetaxel with pembro. So if you think of TCHP, just remove the HP from it. It’s the same chemo backbone that we use for TCHP but adds pembro to it. So 6 cycles, so it’s 18 weeks of treatment. Duration-wise, it’s shorter than KEYNOTE-522 and it’s only 6 visits for treatment. The pCR rate was 58% with that regimen, 3-year EFS was about 85%. Completion rates were very high which is not surprising. We know that TCHP has high completion rates. So that’s an alternative that is a good one, especially for patients who clearly have contraindications for anthracyclines, have had prior cancer and have received anthracycline or have cardiac comorbidities or patients who want to avoid anthracyclines at no cost, a family member who had leukemia from it or something like that. And the carbo/docetaxel regimen by itself is endorsed in the NCCN guidelines as an alternative regimen, so you could combine that with pembro.

And this is the data from NeoTRIP which we saw updated at ESMO. And NeoTRIP also looked at a platinum/taxane regimen for 8 cycles with a different checkpoint inhibitor, atezolizumab which is a PD-L1 antibody. A little bit about the NeoTRIP. Even though it’s an early-stage trial, 90% of the patients had node-positive disease in this study so the risk level of these patients is quite high. It is possible that a modest proportion actually had metastatic disease to begin with. If you have the entire study population that has node-positive disease and about 40% have T4 disease, the chances that many would have metastatic disease is high. In this study, the addition of atezolizumab didn’t show any improvement in pCR or in long-term outcomes. We can all speculate why that was. Whether it’s the atezo itself which we’ve had some negative data. Whether it is the patient population. Whether it’s the chemotherapy backbone. Is it pure chance? Is it difference in biology between the 2 arms? It was a small 250-patient trial. It was not a registration trial by any means. So this stands out there.

Also, I would like to make a point that 8 cycles of carbo/paclitaxel, so 8 cycles of paclitaxel is pretty hard from the point of neuropathy. So I think 6 is the maximum we can push our taxanes in before we start running into troubles with peripheral neuropathy.

DR LOVE: So, Ian, actually, I had the pleasure of doing a video interview with your colleague, Dr Winer. And we were talking about this adjuvant trial of atezolizumab that was reported at San Antonio that was negative and why it was negative. But, of course, the issue that Priyanka just mentioned, does it matter that it was atezo, PD1, et cetera? But also, maybe it’s the idea of adjuvant versus neoadjuvant, happening in the neoantigens, et cetera. Any thoughts, Ian?

DR KROP: Yeah. Again, as Priyanka was talking about with the previous study, you can’t really say what you — you can speculate, but you don’t really know why this was a negative study. But I think that it certainly is possible that without the cancer there, the primary cancer in place to provide anagenic stimulation, that the checkpoint inhibitor is less effective than it is in the neoadjuvant setting with the tumor there and the chemotherapy causing neoantigen production. There are certainly models to suggest that might be the case. So I think it’s, to me, a much more interesting question of, do we need the checkpoint inhibitor in the adjuvant setting once you’ve given it in the neoadjuvant setting? Then, the converse like this. Because I don’t think at this point there’s any reason to think about just using it in the adjuvant setting.

DR LOVE: Ian, any thoughts about whether cell free DNA is going to come into the adjuvant setting and maybe help with some of these issues? Of course, it really is coming in fast in colorectal cancer in the adjuvant situation. Any thoughts about whether this is going to happen in breast cancer as well?

DR KROP: I hope so and I think it’s very likely. I think in some ways, the ctDNA has the promise of kind of being the holy grail in early-stage breast cancer and other diseases. Right now, we treat a whole lot of patients with adjuvant treatment and we know that many of them are already cured just with their surgery. If we had an ultra-sensitive ctDNA test that could detect those microscopic metastatic tumor cells very reliably, then we could know who really needs adjuvant treatment and who does not. We’re not there yet. I don’t think the sensitivity of our ctDNA assays is enough yet to say, to rule out patients who don’t need adjuvant treatment. It does seem that if you have ctDNA, it’s certainly a poor prognostic sign and probably you’ll need to increase your, you know, escalate treatment perhaps in those patients. But I definitely hope that in the upcoming few years when we have some definitive trials with ctDNA driving our treatment decisions that we’re going to be able to use a lot less treatment for a lot of patients and more treatment for other patients.

DR LOVE: So let’s talk just a bit about PARP inhibitors. We talked a little bit about this in our other breast Year in Review program. Priyanka, we saw this from Dr Robson, a follow-up on the OlympiAD trial. What I wanted to really get into there was, and you can see, it looks like that’s maintaining its benefit. You have this fabulous graphic here kind of outlining approaching recurrent — or Stage IV disease based on biomarkers. And the one that interested me the most that I was just curious, I’m going to ask Ian how he would handle it. I know it’s kind of hard to figure this, to see it. But the one that I was curious about is the patient who is hormone receptor-negative, so triple-negative disease in a patient who is BRCA germline, PD1-negative, and has gotten 522, the neoadjuvant/adjuvant regimen that we just talked about, and now has metastatic disease. That’s one of these little boxes that you can read if you spend an hour going through all this.

DR KROP: Yeah.

DR LOVE: Because I’ve been curious about that situation as well, particularly for BRCA germline. You can talk about LOH and other mutations. But I think that she has done here PARP inhibitor.

DR KROP: So you’re talking about patients who —

DR LOVE: Is that right, Priyanka?

DR SHARMA: Yeah.

DR LOVE: Right.

DR SHARMA: So this is NCCN guidelines and it’s first-line therapy for metastatic disease that is PD-L1-negative.

DR KROP: Yeah. So I think there —

DR LOVE: But BRCA-positive.

DR SHARMA: Exactly. Yes, in a BRCA carrier. Yes.

DR KROP: I think there, we have pretty clear data that using a PARP inhibitor is superior to chemotherapy, it tends to be better tolerated and has good outcomes. And so I think most breast oncologists are going to reach for a PARP inhibitor in that first-line setting. I think it gets a little bit more complicated in patients who have both a BRCA mutation and are PD-L1-positive.

DR LOVE: Right.

DR KROP: Therefore, in that situation, you have 2 good options. Do you use a checkpoint inhibitor or do you use a PARP inhibitor? I, and I think the guidelines are now supporting this, would tend to use immunotherapy first and a PARP inhibitor in the second-line just because immunotherapy has a survival advantage in that setting whereas the PARP inhibitor doesn’t yet have it. It just has a PFS benefit. So that’s where I think it gets a little complicated, but I feel pretty comfortable with that approach.

DR LOVE: Any thoughts about that situation, Priyanka? I wonder would you approach that differently if the patient had prior IO like a 522 or maybe you didn’t? Would you be less inclined to use an IO?

DR SHARMA: So if the recurrence happened within 6 months of finishing the adjuvant IO, I would worry about the efficacy of adjuvant IO. And 522 did allow a subgroup that was within 6 to 12 months — not 522, 355 trial. But, again, having no other options short of a clinical trial, I would still offer that patient IO with chemo and try to pick a chemo backbone that the tumor hasn’t seen before in the neoadjuvant/adjuvant setting. But a prior checkpoint exposure wouldn’t affect my decision for using a PARP inhibitor in this situation.

DR LOVE: Yeah, I was thinking that would affect your choice of using an IO later. But I guess, like you said, maybe it depends on how long after it happens. I don’t know.

DR SHARMA: Yeah.

DR LOVE: Let’s talk a little bit about ADCs. We could spend the whole hour talking about ADCs. I feel like we talk about that every day in so many different solid tumors. I was talking about bladder last week. They already have 2 ADCs approved in bladder and they have these 2 HER2s that are coming along including T-DXd. Anyhow. So we’ll talk about ADCs.

First, I guess we can talk about the ones that we already have available, T-DXd and sacituzumab. And, of course, the HER2-low angle here is what we’re looking at. And you talked — there was some data presented at ESMO from the Breast04 study and also a paper at ASCO looking at HER2-low status. So Priyanka reviewed the update on the ASCENT trial published in the European Journal of Cancer. But other than to just start out going through all the data, I just want to get a little bit about how you approach the issue of using, of treating patients who are HER2-low.

First, in terms of testing. Priyanka, you — and also, again, I’m curious how a medical oncologist as a patient would feel about if you had run out of options for metastatic disease participating in trials of some of the agents that we’re going to talk about. But we saw updated data from the DB04 trial. But also, this issue of repeat biopsies. Maybe what your take was from this paper. But more importantly, how you, Priyanka, approach the whole issue in a patient who starts out obviously HER2 0 is the challenge.

DR SHARMA: So patients with HER2 0, at this time in metastatic disease, all of us are biopsying some site of metastatic disease. And as long as it is an area where you’re not worried about too much effect of decalcification which can impact not just HER2 but ER/PR, I’m comfortable with that testing. So if on metastatic sample, it’s 1+ or 2+ with FISH/ISH-negative, that is a HER2-low tumor and I would deem the patient eligible for T-DXd.

Do I rebiopsy a patient every time their metastatic disease progresses? I am not doing that. I think the major challenge with HER2 discrepancies is not so much the, in my opinion, the number of biopsies that we do. It may depend on the sites, but it is just the technical issues with the assay itself. If you look at 1+, the concordance is like 19% between pathologists. So it’s like you can test the same sample 5 times and have reads that are both 0 and 1. Unfortunately, that’s what we have to choose patients, to select patients for. And then you can see it move in both directions, 0 to 1, 1 to 0.

So DESTINY allowed any primary or metastatic HER2-low for eligibility. I think about 30% of the patients had submitted primary samples. So we take all the samples that we have testing on. And if any of them have HER2 1+, in clinical practice, we use that as HER2-low definition and give the patient benefit of doubt with T-DXd.

Having said that, in terms of how I sequence SG and T-DXd for patients with triple-negative disease. SG with the ASCENT is Phase III data with survival benefit, a larger number of — and all triple-negative. So I am choosing SG over T-DXd when the line of therapies are matched in terms of the approval of the 2 agents. So looking at a second-line, a patient who has had 1 line of chemo or some other therapy, if it’s second-line, I’m choosing SG over T-DXd because that data comes from a large randomized Phase III trial. That doesn’t mean the patient isn’t going to get T-DXd later down the line.

This updated data was about quality-of-life and time to worsening of quality-of-life, SG versus chemotherapy of physician’s choice. And overall, it suggests that SG is more favorable in terms of quality-of-life and deterioration of quality-of-life compared to chemotherapy of physician’s choice, at least it’s not worse. So I think this supports the continued use of SG over treatment with chemotherapy of physician’s choice in patients who meet the criteria for SG.

DR LOVE: So, Ian, do you agree with that sequencing for hormone receptor-negative HER2-low? And what about hormone receptor-positive HER2-low? Of course, we’re not talking about ER-positive today, but just out of curiosity, HER2-low.

DR KROP: Yeah. So for the ER, I completely agree with Priyanka for the ER-neg — for the triple — well, ER-negative HER2-low patients. We have this wealth of data in ASCENT supporting that, and would use that typically in the second-line and then use T-DXd after that. In the ER-positive HER2-lows, we have the DB04 data which are so strong. And the sacituzumab data from TROPiCS-02 is in a later-line setting and I don’t think the data are quite as compelling. So I would tend to use T-DXd in the ER-positive HER2-low patients first and then consider using saci. And the opposite in triple-negative for exactly the reasons that Priyanka was saying.

DR LOVE: So let’s talk a little bit about new ADCs, and there are several. We’ve talked about this before. In the program we were talking about earlier with Dr Tolaney, we talked about the initial data that was presented at ESMO. But, Priyanka, I was mentioning that in bladder, first-line therapy is IO/ADC. Actually, better efficacy than cisplatin chemotherapy which it was compared against. That’s pretty interesting.

And I thought this was pretty interesting, also presented at ESMO, Dato-DXd which is the same payload, but different target, and an IO, durvalumab. Pretty interesting looking waterfall plot. Any thoughts? It’s first line.

DR SHARMA: Yeah, first-line. So clearly, quite robust activity in this cohort of BEGONIA. I’d just like to point out a few things. Only about 50% of these patients had any prior chemotherapy for early-stage disease. So that’s a little bit different than what we would normally think about our patient population, so to keep in mind that might be driving the response rate a little bit higher up. And in terms of the first-line Dato-DX response rates, we don’t have a wealth of data in TNBC. So how much the 2 are complementary to each other we have yet to see. So I think the randomized Phase III trials will answer that question for us and whether this is something that’s going to be effective regardless of PD-L1 or not. Just because we have an ADC on board instead of genetic chemotherapy, future trials will have to tell us.

DR LOVE: Yeah, it’s interesting also in terms of tolerability issues, Ian. Again, we brought this up when we talked about the ESMO data monotherapy trials. We’re starting to see some tolerability issues we haven’t seen, for example, with T-DXd. So stomatitis, for example, and I think ophthalmic issues also if I remember correctly. Any thoughts about that? And breast cancer, you know, the lung people were really perplexed about mucositis because you don’t see too much of that. But you all have a lot of experience with mucositis. Do the mucositis regimens for everolimus work for Dato?

DR KROP: It looks like it does. And I think that’s what we tend to use in the clinic and when we’re doing these trials. It does seem to help substantially. And for the most part, the stomatitis seems to be manageable with this drug. And it doesn’t have the same level of — it has much lower levels of ILD and it doesn’t have much hematologic toxicity and less nausea than T-DXd. And so I think from a tolerability standpoint for most patients, you can manage the stomatitis. And otherwise, it’s a pretty good drug. It’s a pretty tolerable drug for most patients.

DR LOVE: So, Priyanka, when you think about the idea of ADC plus IO, it’s kind of like chemo plus IO. And it makes a lot of sense if you think about lung cancer and others, breast cancer where chemo and IO go together. I remember when this regimen in bladder first came out. They only were using it in people who were not eligible for, older people. And I’m like I think that’s what I’d want. Where do you see ADC and IO heading in breast cancer, Priyanka? Do you see possibly in the future, we might be using it early on like in the first-line setting?

DR SHARMA: There are trials that are ongoing not just in first-line, but in curative setting as well. So I think this combination is rapidly moving up. And we’ve seen, at least in breast cancer, the efficacy of IO is higher the earlier you are in the disease course, the less other treatments the cancer has seen so that makes rational sense. The key question would be whether it would beat our polychemotherapy plus IO combinations in terms of efficacy and toxicity and finally, cost, right? So let’s not forget cost.

DR LOVE: So another ADC is patritumab deruxtecan, HER3 DXd. A different target, same payload. We can talk a lot about sequential ADCs. You change the payload or the target. But, Ian, bottom line is this seems to be an agent that — it’s also used outside of breast cancer. It has a lot of activity in lung. But it looks like it has activity in all 3 subtypes of breast cancer. I guess the issue is, as I think Mark Pegram at San Antonio put it, it’s a target. We lock chemotherapy onto it. If we can find something that has a target, we can use an ADC. Any thoughts about this agent? Also, tolerability issues, Ian.

DR KROP: Yeah. So as you said, in this Phase I study that we did a couple years ago, there was activity in all 3 subtypes. HER3 is overexpressed in all 3 subtypes. And these were heavily pretreated patients. And you saw response rates ranging from about 23% up to 43% in this population. From a tolerability standpoint, it has much of the same toxicity as T-DXd, but a little bit lower level I think for most things. So it has less ILD. It has a little bit less diarrhea — I mean, I’m sorry, a little less nausea and vomiting, less fatigue. It does have a little bit more thrombocytopenia. But otherwise, it’s pretty similar to T-DXd but just a little bit lower for most toxicities. So it’s a viable and active drug. It’s just a question of where you put it because we already have DXd ADCs being used in all 3 subtypes of breast cancer right now. But hopefully, patients whose cancer is progressing on a HER2 DXd or a Trop2 DXd drug may still respond to this because you’ve switched targets. But that’s what you were saying. As you said, we need to figure out how to sequence these ADCs.

DR LOVE: So we’ll skip talking about this B7-H4 ADC because we’re about to do a program, we’re going to spend like an hour and a half on these new things that target this new target that I’d never heard about. But I’ve really got to ask you about a case I saw in the chat room just to finish out here. I can’t resist it because it seems like it’s maybe going to help Daniel who has a 52-year-old lady, ER-positive, HER2-positive, node-positive, Stage III. Gets TCHP x 6. Breast surgery reveals disease in the breast, 4 positive nodes. Planning adjuvant TDM-1 and endocrine therapy. Wants to know what you think about the outcome here. And is there a consideration to use, he says, T-DXd instead of T-DM1? How about using neratinib in a case like this? Would you like to help him out, Priyanka?

DR SHARMA: This would certainly be the case that we talked about that neratinib after finishing a year of T-DM1 would definitely be something I would discuss. If they have access to the Alliance T-DM1 versus T-DM1 plus tucatinib study, I think that would be a very attractive option for this patient. Short of a clinical trial, I wouldn’t jump into T-DXd here. In the metastatic setting, it’s much more efficacious than T-DM1, but we need definitive data in curative setting.

DR LOVE: So final question to Ian. This 52-year-old woman, let’s say, is a medical oncologist and says I see all this data, would you please give me T-DXd and follow it up with neratinib? They’ll pay for it.

DR KROP: Yeah. And obviously, we all understand where that feeling is coming from. We obviously want to minimize recurrence at all costs. But we have no idea that T-DXd has any efficacy in that setting. We know that T-DM1 does. We just saw updated data from KATHERINE showing clear survival benefit. So I would strongly encourage that patient to stick with the known benefit. And as Priyanka said, this is a perfect case to add neratinib to after completing the T-DM1. And the data we have is that most patients, even high-risk HER2-positive patients, now do well. So that’s why I would encourage that rather than her doctor shopping to find someone who will give her T-DXd.

DR SHARMA: If I could add just one sentence here. I just want to say there’s many times we’ve seen one drug outperform another one in metastatic setting when we’re treating bulky disease, but the same doesn’t hold true when we’re treating micrometastatic disease in the adjuvant setting. So as Ian said, short of good trial data, we are hesitant in making that leap.

DR LOVE: And actually, the Florida Cancer Specialists are partnering with us on our weekend thing in March. And one of their docs, Dr K S Kumar, just as you were talking about the trial says, we have a trial at FCS of T-DXd versus T-DM1 in this situation. So I think reflecting from the community what you just said. When you go outside the normal bounds, it’s best to be on a trial.

So, Priyanka and Ian, thank you so much. I wish we had a couple more hours to talk about this, but at least we were able to kind of dip our feet in the water of this big, big pond.

Audience, thank you for attending. Come on back on Thursday. We’ll see if Dr Oh can straighten me out on the management of myelofibrosis. Be safe, stay well, and have a great weekend. Oh no, it’s only Tuesday. Sorry.

DR SHARMA: Have a good evening, everyone.

DR KROP: Yeah, thanks.

DR LOVE: Yeah.

DR SHARMA: Thank you.

DR LOVE: Take care.

DR SHARMA: Bye.

DR LOVE: Bye.