Introduction

DR LOVE: I’m Neil Love from Research To Practice and welcome to Expert Second Opinion, as today we talk about the management of HER2-positive breast cancer in a session that was originally scheduled as a satellite to the ASCO Meeting.

We have a great faculty. Dr Erika Hamilton from Sarah Cannon Research Institute, Dr Joyce O’Shaughnessy from Texas Oncology and US Oncology in Dallas, and Dr Ian Krop from the Dana-Farber Cancer Institute.

Today we’re here to talk about HER2-positive breast cancer. And the reason we call it second opinion is we’ve got a bunch of cases from some of the colleagues of our faculty that we’re going to be presenting by video today, Dr Reshma Mahtani from the Sylvester Cancer Center here in Miami where we’re located at the University of Miami, Dr Ruth O’Regan, now with the University of Rochester, and Dr Ann Partridge, a colleague of Dr Krop’s at Dana-Farber. I met with them separately to pick out some cases and talk about what we should be covering with you all tonight. They want to challenge you with these cases.

I’ll also mention that I did separate Zoom sessions with each of these 3 faculty where they record a comprehensive discussions and presentations. And that will be posted along with this Roundtable discussion.

So we’re really here to make rounds with our faculty, really get a second opinion on some interesting cases.

Role of Immunotherapy in HER2-Positive Metastatic Breast Cancer (mBC)

DR LOVE: And I’m just going to jump right into the first topic which I know is a little bit unusual for breast cancer and HER2-positive breast cancer, but when I was talking to Dr Mahtani, I heard a case that really got my attention. I was like, I want to hear what you all have to say about this.

Case: A woman in her mid-50s with ER-positive, HER2-positive mBC enrolled on a clinical trial of nivolumab/ipilimumab — Reshma Mahtani, DO

DR LOVE: This is a 56-year-old woman, ER-positive/HER2-positive, metastatic disease. Heavily pretreated, running out of options, and was put on a protocol of ipi/nivo. Here’s Dr Mahtani.

DR MAHTANI: She came to me really, really very symptomatic, had a performance status of 2, had disease all over her chest wall as her major site of disease, skin nodules and really very symptomatic from all of this disease on her chest wall. And she participated on a clinical trial with ipi/nivo on protocol.

And after the first dose we actually thought that things were flaring or getting much worse. Her disease really became very angry all over her chest wall. And then after a couple more doses everything started to regress, and now she’s had a complete response. There is nothing on imaging, and it’s been going on now for 2 years.

DR LOVE: Wow.

DR MAHTANI: And she’s in a complete response.

DR LOVE: Wow. What a case. Unbelievable.

DR MAHTANI: Yeah, yeah. It was just amazing to see.

DR LOVE: That’s incredible.

DR MAHTANI: It was just an amazing response. I’m really interested to see in HER2-positive disease where we go with immunotherapy to see what the role is in select patients.

DR LOVE: So, Erika, of course we can’t practice anecdotal medicine, but when you hear cases like this, it just kind of gets your attention a little bit. Breast cancer doesn’t have much of a reputation for responding to IOs, but I don’t think we know that much about HER2-positive disease. HER2 patients get always get sort of pushed out of the trials, Erika. Any thoughts about this case and about the concept of IOs in HER2-positive disease, Erika?

DR HAMILTON: I mean the case is remarkable as well. I mean currently, we don’t have any approvals with immunotherapy in HER2-positive disease. Funny that you ask about this.

We just published an article in Clinical Breast Cancer about a little exploratory cohort where we combined atezolizumab with trastuzumab/pertuzumab or atezolizumab with T-DM1. We actually saw upregulation in PD-L1 and immune cells in the patients that received antibody drug conjugate with T-DM1. We know that, kind of biologically, HER2s are more similar to triple-negative’s than they are hormone receptor-positive, so it is the other subset of breast cancer that I would think potentially could get benefit from immunotherapy.

There are some trials ongoing — we did see a recent trial that had negative results. But I don’t think the jury is completely out on this yet. I think we’re going to see more exploration of immunotherapy in HER2-positive.

DR LOVE: So, Joyce, HER2 is not just an issue in breast cancer, it’s also an issue in gastroesophageal cancer, colorectal cancer, lung cancer. T-DXd, we’ll talk about that later. But interestingly, just in May, in gastroesophageal cancer, pembrolizumab plus trastuzumab plus chemo was approved as first-line therapy, HER2-positive gastric cancer. Now we know gastroesophageal cancer, it has approvals for IOs in both now adjuvant as well as metastatic disease. So this could be kind of 1+1. But this is the data that Dr Janjigian from Memorial presented at ASCO when you add pembro to the so-called TOGA regimen they’ve been using for the last 5 or 10 years, trastuzumab plus chemo. Any thoughts, Joyce, about the future of IOs in general in breast cancer and specifically in HER2-positive disease?

DR O'SHAUGHNESSY: Well, I think in triple-negative breast cancer we’re just kind of foaming at the bit waiting for some FDA approval of preoperative checkpoint inhibitors for Stage II/III disease because now we’ve seen 3 trials that look promising. We haven’t seen the data yet from the KEYNOTE 522, we just heard the press release that it hit its event-free survival endpoint. And then we saw really cool data at ASCO with preoperative durvalumab in the GeparNEUVO trial. And then IMpassion031 also was trending; it’s very small numbers. It was trending there as well for EFS.

So we have 3 lining up and we really, really need it because there’s like a 20% delta on path CR for the clinically node-positive patients, which, of course, do the worse. So I’m optimistic for the curative setting of TNBC.

For HER2-positive, like Erika said, there is definitely similarity there, to some extent, and particularly the ER-negative/HER2-positive patients do very well. They’re very chemotherapy sensitive as we see with the subset of TNBC. It was interesting to see from the ADAPT trial at ASCO with just preoperative weekly paclitaxel for 12 weeks, plus trastuzumab and pertuzumab, path CR in this ER-negative/HER2-positive, mostly T1, T2, 54% node-positive, path CR rate of 90%. Woo! Which is 12 weeks of preoperative therapy.

So, that tells you the immune system is very, very active. Because the way you get a path CR is your immune system gets in there and clears it out. But right now I’m only aware of data — that’s fascinating that Erika’s published

DR LOVE: Let me see if I can ask Ian what his thoughts are. There is actually a Phase III trial of CLEOPATRA plus or minus atezo, Ian. I don’t know the exact status of that. But it’s interesting how the HER2 patients they got cut out of the OlympiA trial. They weren’t in a lot of the CDK trials. And then docs in practice are trying to figure out what to do when they run out of options with patients with HER2-positive. Again, any thoughts, Ian?

DR KROP: So I think there is certainly interest, but as Joyce was kind of alluding to, so far, we haven’t seen any conclusive data to suggest that immunotherapy is beneficial. We have the single-arm study of trastuzumab plus a checkpoint inhibitor that showed a very low response rate. And then we had a randomized trial of T-DM1 plus or minus a checkpoint inhibitor which, also, was not a technically positive trial. There was a trend towards some benefit in the immune-activated subset of patients. But clearly not a homerun. But there is clearly interest.

There is the study that you just mentioned in first line that’s going on in the United States comparing the CLEOPATRA regimen plus or minus a checkpoint inhibitor. And we’ll have to wait to see the results of that.

Certainly, there’s preclinical data suggesting that immunotherapy could work especially with trastuzumab already having an immune effect. But we need to see some conclusive data. And in fact, at ESMO Plenary talk, there was a neoadjuvant study of ACTH-P with or without the checkpoint inhibitor and there was no improvement in path CR with the addition of the checkpoint inhibitor. So, zero evidence of benefit there.

So I think we’re still very much in a wait and see position right now in the HER2 space.

Management of HER2-Positive mBC

DR LOVE: So, let’s jump into more typical kinds of questions that come up in managing HER2-positive disease. And of course, spending a lot of time, particularly this past year, talking to general medical oncologists in practice, getting cases from them. Clearly, where most of the questions are coming right now is in metastatic disease, particularly second- and third-line therapy. So we have several cases that are going to get into that.

First, just to see where the audience stands on a couple of these questions in terms of metastatic disease, audience you’ve got a 65-year-old patient, ER-negative/HER2-positive metastatic disease to the bone and soft tissues. Gets first-line THP, second line T-DM1, but then has symptomatic disease progression. No brain mets. What is likely going to be your next systemic therapy?

And Erika, it looks like, of course there’s a split between T-DXd and HERCLIMB with tucatinib, but it looks like it’s two thirds T-DXd, one third tucatinib.

We’ll start with you Erika, in how you sort out this third-line therapy in this situation in general? And this situation particularly?

DR HAMILTON: I’ll be transparent that I’ve used both in the third line, both trastuzumab deruxtecan as well as capecitabine/trastuzumab/tucatinib. So, I don’t think one’s right and one’s wrong. I really make that decision based on the individual patient in front of me. Certainly brain mets would steer me towards tucatinib. Significant visceral disease or somewhere where I’m really needing a quick response, maybe trastuzumab deruxtecan.

Overall, I tend to kind of play by the book. We have a randomized trial that tucatinib improves overall survival. Do I think we’ll end up with that in trastuzumab deruxtecan? Yes. But I’d probably err on the side of — I’d probably do tucatinib for this patient. They have soft tissue and bone lesions, not visceral lesions. I’d probably think that.

DR LOVE: So we’ll take a look at the data later, but I just want to see where you’re at clinically. And here’s another scenario for you audience, same 65-year-old woman, again THP followed by T-DM1, but then she presents with a single brain met that’s resected.

So, what do you do? Do you keep the T-DM1 going? Do you switch to something else?

And Ian, the audience is about, again, two thirds/one third HERCLIMB versus continued T-DM1.

Any thoughts, Ian, about this situation? Theoretically, the old guideline, it seems old now — said if you only progress in the brain keep the same therapy going. But now we’ve got a lot more options. What do you think, Ian?

DR KROP: I think that’s exactly the point, is that the guideline from ASCO for this specific situation recommended continuing the systemic therapy and just treat the brain with local radiation. And I think that’s a very legitimate approach. And we actually have some interesting data from HER2CLIMB that did that with the tucatinib regimen and showed that patients can stay on this the same systemic therapy for another 7 months. And you can see similar types of benefit with T-DM1.

So I think for a patient like this, has got 1 lesion, treating with radiation and continuing T-DM1 is a very reasonable way to maximize your benefit from that systemic therapy and save the other ones for later.

DR LOVE: So, Joyce, before we go on to our next case, particularly in lung cancer where they have targeted therapy and osimertinib, and EGFR, etc. These patients, if they present with brain mets and they don’t have cerebral edema or brain symptoms, they’re going to treat them with osimertinib. Do you feel comfortable enough, for example, with HERCLIMB in a patient without CNS symptoms who maybe is going to require whole brain to try systemic therapy first? And have you done it?

DR O'SHAUGHNESSY: Yes, definitely. And I think that’s one of the things we learned from HER2CLIMB, because about a quarter of the patients had active brain mets who were on HER2CLIMB and they were allowed to come on without any therapy. And the response rate in the brain with the triplet was 47% and that’s in a pretty heavily pretreated group of patients. So, yes, I think that’s one of the really good things to come out of HER2CLIMB is that we can put off the radiation, both SRS, as well as whole brain, because even SRS is not without some morbidity And so, yes, I definitely do it.

Case: A woman in her early 30s with ER-positive, HER2-positive mBC — Ann Partridge, MD, MPH

DR LOVE: So, let’s go back to another case. And this is from Dr Partridge, of course well known for her research on younger women with breast cancer. She has a 30-year-old patient she’s been treating since 2012. And as you’ll hear, what we’re really going to focus on for her is her initial management because she was 21 at that time and did not want to receive intravenous therapy. That’s a whole other story we could get into. But interestingly, just to go along with the patient’s wishes, she actually started out with just hormonal therapy and that worked for 4 years. And then she had her on just trastuzumab and she got another year. Anyhow, here’s Dr Partridge commenting on the case.

DR PARTRIDGE: I have this boutique clinic that I see a lot of youngins. This patient is very interesting in that she was very much against more, rather than less treatment. And so, we were creative, and initially she very much did not want any anti-HER2 therapy because she didn’t want IV treatment. And so we opted to give her endocrine therapy alone and then, upon her first progression, we added on the trastuzumab, as well as treatment of her bones with the zoledronic acid.

And I would pose the question of, especially in light of recent data such as the ADAPT trial that was recently presented at ASCO, what do we think about doing early first-line endocrine therapy in ER-positive, HER2-positive breast cancer either alone or in tandem with anti-HER2 therapy such as trastuzumab or pertuzumab, or the combination of course.

DR LOVE: So, Erika, a few years ago we had this so-called PERTAIN study, which attempted to look at this issue of hormonal therapy plus anti-HER therapy without chemo. She’s actually bringing up the issue of hormonal therapy alone. Lots of patients are older, don’t want chemo. Maybe they have relative contraindications even to, say, paclitaxel. Any thoughts about this strategy, Erika, of hormonal therapy, either alone or just with anti-HER therapy?

DR HAMILTON: Yes, I think there’s no doubt that we don’t see a lot of these patients that ER-positive and HER2-positive that will benefit from endocrine therapy in combination with HER2 agents without the chemotherapy. I think we’ve been a little bit guilty of lumping all the HER2s in 1 bucket and not really separating those patients out of whether they have hormonal receptor-positive or hormone receptor-negative. We’re doing a better job of looking at that in trials. And I think we’re all pretty comfortable with doing so-called THP, dropping the chemo out and then putting the patient on endocrine therapy. But it’s less frequently that we just do that from upfront. But I think probably a very valid strategy for some but hasn’t really been looked at as much systematically across the board.

DR LOVE: Joyce, any thoughts? Is this a strategy you’ve ever used?

DR O'SHAUGHNESSY: I have from time to time. It kind of depends on the degree to which you think the estrogen receptor is highly functional. And so, of course, you’re going to look at the progesterone receptor, the grade, but the phenotype of the patient is very important as well. Because even with triple-positives, they can be Luminal A, and they can be more about ER than they are about HER2. They can, however, be Luminal B and highly aggressive. They can be HER2 enriched and really not about the estrogen receptor at all. So there’s a spectrum of biology. But if the ER is strongly positive, the PR is there, and the phenotype looks like its metastasized to sites that are ER-dependent, I think it’s very reasonable, along with HP.

Case: A woman in her early 70s with HER2-positive mBC — Dr Mahtani

DR LOVE: So, let’s go onto another case. This is a 72-year-old woman, a patient of Dr Mahtani. And we were talking about third-line therapy and HERCLIMB versus T-DXd. But this is a situation, and you talked about symptomatic patients and maybe in the interest in T-DXd, but suppose the symptoms are coming from the lung? And this patient had major problem with pleural effusions and was having dyspnea at that point. Was actually quite sick. And here’s Dr Mahtani talking about the case and what happened.

DR MAHTANI: She had extensive involvement with metastatic disease involving her lungs, bone, several lymph node sites, and at that point she was very symptomatic, with weight loss, shortness of breath with minimal exertion. She was on oxygen. There was a lot of drainage from the PleurX^TM catheter, and her ECOG performance status was 2 at best, bordering on 3.

We did get the cytology on the pleural fluid, but there wasn’t enough to test for HER2. So in the back of my mind I was wondering if we’re dealing with a HER2-low tumor, and I needed a response very quickly, so I decided to give her trastuzumab deruxtecan. I was a bit concerned regarding her pulmonary status and how I would pick up on any changes in her pulmonary status, given her baseline involvement.

So one of the questions that I would pose to the investigators is that in a patient like this who’s very symptomatic with her disease, and even on oxygen, would anyone feel uncomfortable about giving trastuzumab deruxtecan in that situation?

DR LOVE: Any follow-up?

DR MAHTAINI: Yeah, so I very cautiously gave her trastuzumab deruxtecan, and it was kind of a Lazarus effect, I would say. It was really, really impressive to see this woman came in in a wheelchair on oxygen, and after 2 cycles of therapy had a dramatic clinical improvement. She was able to come off oxygen. The PleurX started draining less. But despite her quick turnaround, then very quickly after 5 months she started to progress again. So at that point I made the decision to use the HER2CLIMB regimen.

Even though the patient hadn’t developed brain mets, I’m wondering how everyone is feeling about trying to sequence out these treatments and is anyone “saving” tucatinib until they do develop brain mets. Or at this point would everyone have decided to go with tucatinib?

DR LOVE: So, Ian, any comments about the case, particularly the decision to use T-DXd in the face of significant pulmonary involvement from the disease?

DR KROP: I think we’re no longer in the kind of one-size-fits-all approach for these third-line patients. I think Erika talked about it a little bit earlier, this is a patient who, for intents and purposes is in visceral crisis. I mean she’s already on oxygen. Her performance status if ailing. You need to get a response, or she’s not going to be able to tolerate another — she’s not going to be in a position to even get another line of therapy. So, for that situation, I think you want to use the agent with the perceived higher response rate and right now, albeit without randomized data, that, to me, looks like T-DXd or trastuzumab deruxtecan.

So I think that was a very reasonable approach. Of course, there is a risk of pneumonitis with trastuzumab deruxtecan. It’s not clear that it would be any higher in a patient who has an underlying malignancy in their lung. But I think here, the benefits far outweigh the risks and I think that was the right — I would have made the same choice for that patient, just as if a patient had substantial brain metastasis, I would always reach for the tucatinib-based regimen first as well. And then of course there’s everybody in between that we all have to figure out which of the 2 drugs we’re going to use before the other.

The bottom line is, they’re all going to get both drugs eventually; it’s just a matter of sequence.

Case: A woman in her late 50s with ER-negative, HER2-positive mBC — Ruth O’Regan, MD

DR LOVE: So, let’s go to another case. This is from Dr O’Regan, a 58-year-old woman, metastatic disease to the nodes and lungs. And as disease progression after getting upfront therapy with CLEOPATRA, then T-DM1, and then actually went on the HERCLIMB study and got tucatinib. Here’s Dr O’Regan talking about the case.

DR LOVE: So, Erika, a couple of questions there. First of all, now that we’re so sensitive to this issue of brain mets, are you screening people more? When you’re trying to decide, for example for third-line therapy even if they’re asymptomatic, are you screening these patients? Also, your experience in terms of tolerability, what are some of the issues that come up with HERCLIMB? This patient had some diarrhea.

DR HAMILTON: So the first question, am I truly doing asymptomatic screening? No I’m not. I have a very low threshold to scan these patients with new nausea, unsteadiness, headaches that are worsening. Anything like that I do. I think it’s a valid point now that we really have this fork in the road in third line of what are we going to pick? I mean should we maybe be doing that. I don’t think that’s our current practice pattern right now.

And as for tolerability, certainly we see a lot of the side effects that we typically see with capecitabine with the capecitabine/trastuzumab/tucatinib regimen. In my experience, I haven’t seen really worsened diarrhea than what I would expect with capecitabine. I noticed that Dr O’Regan mentioned that this lady was a little bit frail and had trouble tolerating therapy. So this is probably somebody that is really getting diarrhea with capecitabine.

DR LOVE: So, Ian, in terms of the capecitabine in the HERCLIMB regimen, it’s not uncommon to see if patients have already received capecitabine, maybe even immediately prior to like the NALA regimen, for example. How important do you think the capecitabine is to the HERCLIMB regimen, Ian? And what do you think about using just tucatinib and trastuzumab?

DR KROP: It’s a good question and actually, I haven’t been in that situation yet since the approval of tucatinib. There are data of tucatinib with trastuzumab. There are data with tucatinib with T-DM1. And we know of course, that lapatinib and trastuzumab is an active combination. So, I mean you certainly could do that. I’d actually be interested in hearing what my colleagues have done in that situation, would they reuse capecitabine, or would they try to use tucatinib without anything else? But we don’t have a right answer. I think nowadays we’re tending to use tucatinib prior to neratinib, so it doesn’t come up as much. But exactly what the right answer is in this situation is really kind of unclear.

DR LOVE: Joyce, you always have a few little pearls that I never think about. Any pearls about the HERCLIMB regimen and also any comments on capecitabine in it?

DR O'SHAUGHNESSY: Well, I’ve some patients not able to really take the capecitabine, 2 are coming to mind right now, and 1 is estrogen receptor-positive, so we get the tucatinib/trastuzumab going and add fulvestrant in, and she has done really very well. It’s kind of like the regimen, the triplet that’s being used in the SUMMIT trial for HER2 activated mutations. It was very well tolerated. She’s still going, and she’s got brain mets and other mets.

So, I think that a lot of us are reducing the dose of capecitabine. I think I agree with both Erika and Ian, that we’re seeing capecitabine toxicities and reducing the dose and then coming up as we can but trying to optimize the tucatinib dose at the 300 BID. But it does raise the question ER-positive breast cancer, is the breast cancer going to escape through the estrogen receptor? So I think it’s an interesting question. I’d like to see more data on ER blockade plus pan-HER blockade, like with tucatinib and trastuzumab. And I must say I think I probably am sneaking up on more brain MRIs at that third-line fork in the road, because we know by third line, gosh, we’re kind of pushing half of the patients and they had brain mets at that point if we take a look.

So, I’m starting to sneak up on that. I wouldn’t say I do it every time, but I’m sneaking up on that.

DR LOVE: So, Erika, Padma in the chat room has a patient on tucatinib who’s having LFT abnormalities and there’s no other explanation.

Can you talk about your thoughts about LFT abnormalities, Erika?

DR HAMILTON: Yes. So liver function test abnormalities, we can see both with capecitabine and tucatinib. And that’s definitely something that can come from the tucatinib. So that’s really the one side effect that I would consider reducing either the cape or the tucatinib or maybe even both. Most of the other side effects like nausea or diarrhea or fatigue, I would typically try to reduce the capecitabine first and leave the tucatinib alone. But yes, known LFT abnormalities with tucatinib.

DR LOVE: And, actually, Dr Mallidi says that when she held therapy the LFTs went back to normal. So, that’s interesting in terms of dose reduction also.

Case: A woman in her early 50s with ER-positive, HER2-positive mBC — Dr Partridge

DR LOVE: Let’s go to another case, this is again from Dr Partridge and this kind of gets into something we hear a lot about, not just hear but also, we were talking before about gastroesophageal cancer. They’re really into rebiopsying, doing liquid biopsies and looking at HER2 status, I think even more aggressively, maybe because of heterogeneity of the disease. In any event, Dr Partridge has this lady she’s been taking care of with metastatic disease since 2015. And as things have gone on, she’s starting to suspect that maybe this patient is not as HER2-posiitve as she kind of thought the patient was and was actually thinking about rebiopsy at this point, but also, the patient has received the HERCLIMB regimen is now progressing. So she’s trying to figure out what to do. Here’s Dr Partridge.

DR PARTRIDGE: When I think about this case I worry, especially given she had progression on T-DM1 in the past, and now she’s having clear progression on tucatinib, capecitabine and trastuzumab, I worry whether she still has HER2-driven cancer. And so this is a situation where I’d think about biopsying a person to make sure that we’ve got the right target that we’re targeting.

She actually now is becoming symptomatic from the cancer, and so we talked about getting a biopsy. And I said if we do get a biopsy and it shows you’re HER2-negative, then I won’t be able to give you the T-DXd (trastuzumab deruxtecan). And I know it can also work in HER2 low. And so, that’s why we did not biopsy her at this juncture. Maybe we should ask the audience, would you biopsy her at this juncture, and we can bring up that point.

DR LOVE: So, Ian, any thoughts about this case and this situation? I guess she was concerned she wouldn’t get approval to actually use the drug. Is that the treatment you’d be thinking about based on what you’ve heard so far?

DR KROP: No, I think this would be a natural time to use trastuzumab deruxtecan. She’s progressed on multiple other HER2 therapies.

In terms of the rebiopsy, I think more about in a patient who never responded to any HER2 therapy to make sure that we were really right in the first place. And this person, I don’t know durations of treatment for this particular patient. But really, if she had benefited from the other HER2 therapies, I don’t feel strongly that she needs to be rebiopsied. Because even that 1 biopsy comes back HER2-negative, I don’t typically throw out — I don’t typically never use another HER2 therapy again because of tumor heterogeneity and things like that.

So I think you can rebiopsy, but I don’t think it’s necessary, particularly in a patient who’s responded to their prior HER2 therapies.

DR LOVE: We’ll talk a little bit more about this as we move on, but Joyce, I want to show one of the slides that you have in your presentation, kind of starting to look a little more complicated than things were a couple of years ago. But can you talk about, and particularly the issue of choice of second-line therapy nowadays and how that is changing based on the presence of these 2 drugs. And also, how second-line therapy varies in your own mind? You have up there with brain mets or severe visceral disease, out to the side, Joyce.

DR O'SHAUGHNESSY: Yes, because the tucatinib triplet was studied in the second-line and greater setting and is labeled second-line or greater. So that’s Level I evidence, and it’s got a survival advantage. And curiously, the T-DM1, we don’t have Level I evidence after the taxane/trastuzumab/pertuzumab triplet. We certainly have nice survival advantage after taxane/trastuzumab, but not with pertuzumab. Nonetheless, we have good Phase II data. It works and certainly a reasonable choice, very well tolerated. But I do think that we have to realize that we could use the tucatinib triplet, particularly if the brain metastasis is the dominant site of disease and is a life-limiting site of disease. I think, though, the trastuzumab deruxtecan is third line and later, but I do think if we had a patient like we heard from Reshma, that patient who was oxygen dependent, et cetera, I think we do need the deruxtecan second line.

DR LOVE: So we have a question in the chat room, Erika, about margetuximab which is actually one of the things on Joyce’s slides beyond the fourth — I guess fourth-line therapy. In what situations, if any right now, Erika, are you using margetuximab?

DR HAMILTON: I mean I think margetuximab is a bit of a struggle. The trial was positive, but the magnitude of benefit was not great. I certainly wouldn’t be thinking about using margetuximab before tucatinib or trastuzumab deruxtecan, drugs that I think have shown a bigger benefit. I mean I think that would really be kind of a later-line patient where you’re using a new chemotherapy backbone and using margetuximab instead of trastuzumab.

The other question is, is that we had the CD16 allele, and so, questions around can we better predict those patients that do greater benefit, but right now it’s not linked to a companion diagnostic to predict those.

DR LOVE: So, Ian, Dr Partridge was talking about the issue of T-DXd in HER2-low patients, of course, the updated waterfall plot looks probably like the best waterfall plot we’ve seen in breast cancer and great PFS and OS. What do we know right now about HER2-low? And it looks like there are responses? Have you ever seen a response? Have you ever used it in that situation? Ian, where do you think things are heading in that regard?

DR KROP: We have this trial open at our institution. And so, we’ve used T-DXd, not only in this trial, but in the subsequent Phase III trial in HER2-low patients. I mean there were about 50 patients on this study and there was a clear response rate, particularly in the ER-positive/HER2-low patients. And it didn’t seem to matter whether you were IHC2+ or 1+. There’s still pretty robust response. And you can see the PFS was 11 months, that’s not trivial.

So, I’m very encouraged about this, particularly because HER2-low patients make up about 55% or 60% of all breast cancer. So, this is a big fraction of our patients for which right now we don’t have HER2-directed therapy that works, and so if the Phase III trial in HER2-low patients shows benefit, I think it’s a big deal because it basically creates a new subgroup of breast cancer.

DR LOVE: So, Joyce, of course the issue here, and what makes this such an intriguing and challenging situation, is the interstitial lung disease that’s seen, and of course a concern in all these other cancers, the GI people, the pulmonary people, etc. Any update on what we’ve learned about this, Joyce, and particularly whether or not attempting to pick it up early through imaging or even other functional tests is of value?

DR O'SHAUGHNESSY: I don’t think we have data that I’ve seen at least, that things like PFTs or even monitoring pulse ox, et cetera, has made a difference in terms of early detection. However, obviously, we want to have our antenna way up there for any dyspnea, any kind of cough, anything. Low threshold for that chest x-ray scan. I’m optimistic that with that and also now an algorithm, even with Grade 1, which is asymptomatic, just start some steroids — hold, start steroids. Grade 2 definitely start some good dose steroids and discontinue permanently.

I was curious about the fact that trastuzumab deruxtecan works in HER2 mutant non-small cell lung cancer.

That’s fascinating. And they only saw Grade 1-2 ILD, they didn’t see any high-grade ILD. So that’s very good. So, perhaps that’s an example of a trial that was done later, after the DESTINY-breast01, where people are learning.

So I’m hopeful, when we see these Phase III data, lots of Phase III data, that we’ll see just lower grade ILD.

DR LOVE: The weird thing about lung is that actually it seems to do better with the HER2 mutant and amplified. Ian, you had a thought?

DR KROP: Well, I was just going to say I think, obviously, now that we’re using a lot more of the trastuzumab deruxtecan in breast cancer and other cancers soon, the pneumonitis is something we all have to be aware of. And Joyce hit the nail on the head when she said I think that being aware of it is the biggest factor, not only just the providers but the patients need to know that if they have dyspnea, they need to let us know.

But there were data presented — looking at the incidence of pneumonitis or ILD before we started incorporating the new management guidelines into our trials and after. And if you look after, the rate of Grade 3 and higher ILD is substantially lower than it was prior to initiation of those guidelines, which supports this idea that if we act early, we can prevent it from progressing to more serious levels. That wasn’t a randomized intervention, but it’s hopeful that early intervention will be beneficial.

DR LOVE: So, Erika, as always, we learn a lot from press releases. And there was a press release about the so-called TULIP study, I like the name of it anyhow, Phase III trial looking at another antibody drug conjugate, Erika. Can you comment?

DR HAMILTON: I think antibody drug conjugates are something that we’re all excited about in the breast community, whether it’s HER2-positive or triple-negative. We’ve certainly seen several antibody drug conjugates there and even into hormone receptor-positive, in situations that HER2-low, sacituzumab, etc. So, I mean I’m very excited about this.

I think that antibody drug conjugates are attractive for patients. I kind of explain it to my patients it’s not giving naked chemo but giving high powered chemo directly to those cells that a trastuzumab, etc, would bind. And so, I mean not surprising that when we find a good target to deliver our payload that we’re getting good results there.

DR LOVE: So, Joyce, we’ve had a couple of questions about this presentation from ASCO looking at a question people have been asking a lot since T-DXd came out, which is does it work in the brain? Any thoughts about what they showed? It kind of looks like maybe it does.

DR O'SHAUGHNESSY: The thing about this though, was a little confounded I thought because patients had to have treated brain mets in order to get on the study. I think there was a decent interval though, it was months after they had finished their required treatment of the brain mets before they were allowed to matriculate onto study. But we know the radiation therapy works over a period of time. So, it was confounded. So I wasn’t quite sure how to interpret it.

Having said that, I have seen myself a dramatic response in the brain in a patient of mine, I got the MRIs to document it and her neurologic status went from wheelchair to walking with walkers. So this does have activity in the brain. I just wasn’t sure about this because of the confounding of the prior — immediately prior radiation before they entered trial.

Considerations in the Care of Patients with Localized HER2-Positive Breast Cancer

DR LOVE: So let’s talk a little bit about localized HER2-positive disease. A lot going on there as well. And we have a couple of cases that we want to get second opinions on from you. But first, let’s start out with the audience and say I’m kind of curious what neoadjuvant systemic therapy right now you would use in a 65-year-old woman with a 2.5-cm ER-negative, HER2-positive clinically node-negative tumor? And we’ll see what people would do in that situation.

Ian, do you want to comment on how you would generally, outside a clinical trial, what you would treat a patient like this with neoadjuvantly.

And interestingly, it looks like there’s a lot of heterogeneity in the audience.

But, Ian, any thoughts?

DR KROP: I think, this, a patient who’s kind of on the border between what you could safely treat with paclitaxel/trastuzumab or something more. I think the standard thing to do — quote “standard thing to do” would be to give her combination chemotherapy like TCHP. But I think we’re hoping, as a field, to start de-escalating these patients. Because we know that many of these patients with just a little bit of chemo, like 12 weeks of paclitaxel and trastuzumab and pertuzumab, will have a path CR and likely are going to do very well. In fact, Nadia Harbeck presented data at ASCO showing this particular patient population had. 90% path CR rate when treated with THP.

So I think the hope is that we can start using the response to neoadjuvant therapy as a way to de-escalate chemotherapy. And there is a national trial going on in the United States called the COMPASS trial that a patient like this could go on, get THP, if she has a path CR, she doesn’t need any more chemotherapy and she could just get antibodies outback. Which, I think, is the way eventually the field will go.

DR LOVE: So it looks like the 2 biggest answers are TCHP and TPH, but also paclitaxel and trastuzumab, TCH. Those 4 choices, I won’t say equal, but certainly a substantial number of people answering it.

How about this situation, audience? You have a patient who’s got neoadjuvant therapy with TCHP, and she’s had a path Cr. What likely therapy would you use in her post-op? And, also, I’m curious whether you would include neratinib, so we put that as part of the choices. Curious, in this patient who is ER-negative, whether or not that would be a consideration.

And it looks like by far the audience is saying trastuzumab/pertuzumab. Although, actually 17% of the audience say neratinib in spite of the ER-negativity.

Joyce, how you do think through this situation yourself in terms of the first year after surgery and then neratinib?

DR O'SHAUGHNESSY: Well, we have some data sets now that show that there can be a 10% to 15% risk of recurrence even with a path CR in any subtype of breast cancer. And she had nodes positive T2, but ER-negative disease, node-positive disease, T3 disease, are all risk for brain metastasis. And so, in the big picture, I’m not sure as a community we’re done trying to improve the outcome of these patients.

Having said that, I don’t think I have in hand right now treatment that I would give her beyond HP. HP I would. That is in the APHINITY trial. If we want to get the improvement with pertuzumab in PFS then we have to use a year of pertuzumab. And that’s the FDA label. If you give it preoperatively HP, use it adjuvantly as well. So that’s what I would do.

Unfortunately, I don’t think that neratinib right now, that we have data from the ExteNET study showing sort of a substantial improvement. I think there’s probably some improvement with neratinib in the ER-negative/HER2-positive, but not enough. And we don’t have any — we don’t really have data on the ER-negative for brain metastasis. We do with HER2-positive but not for ER-negative from the ExteNET.

So, I think that’s where, again, maybe the COMPASS trial will help us with T-DM1 plus tucatinib. Again, that’s in the patients with no path CR. But I do think we’re going to have to look at these patients who are and remain at high risk for brain metastasis, even though they have a path CR, and I think she is in that subtype basically.

Case: A woman in her mid-40s with 5-cm ER-positive, HER2-positive localized breast cancer — Dr Mahtani

DR LOVE: So Erika, we have the slides in there that show fascinatingly that you see less brain mets, as Joyce was referring to, in patients who get sort of the post-neoadjuvant neratinib. But here is a case of a patient who got neoadjuvant therapy, was ER-positive, where the question comes up about neratinib. Here’s Dr Mahtani posing this case.

DR MAHTANI: So my question, or my challenge in this situation was really that we know that even though patients that have a pCR usually that portends a good prognosis, we know that some patients who achieve a pCR still have a risk of relapse. And given that this patient presumably had N3 disease in the setting of a pCR, I would be curious to know if anyone would offer this patient extended adjuvant therapy with neratinib. Basically, are there patients that are at high risk of relapse such that even a pCR would not prompt the use of extended adjuvant therapy?

We actually haven’t made a decision yet, and I’m very interested to know what everyone would do in this situation.

DR LOVE: So, Erika, maybe you can help Dr Mahtani out by giving her a second opinion about this case. Again, the disease was pretty advanced when she presented, although she did have a path CR. How, in general, are you approaching the use of neratinib, Erika, both in ER-positive/ER-negative? And what are you thinking about in a case like this?

DR HAMILTON: I don’t use a ton of neratinib. I think that the magnitude of benefit for the average patient isn’t as high as I’d like it to be, but this is the type of patient that you have to think about it, right — very high risk to begin with, had a good prognosis by the fact that she had a good response, but you do worry about this patient ending up with brain mets or something like that.

So this is a patient that I would discuss it with them. Yes.

DR LOVE: And Nicholas in the chat room mentions the fact that in the ExteNET study, the patients didn’t get pertuzumab, so we always have to do a little working around trying to apply things. Also, I’m curious, Ian, what your experience is on the more recent mitigation strategies with neratinib trying to ameliorate the diarrhea. Dose escalation? Supportive medications? Any comments, Ian?

DR KROP: Well, again, I share Erika’s point about not using a lot of this anymore, partly because of what was brought up in the chat which is that the ExteNET data were in patients who did not receive pertuzumab or T-DM1, which a lot of our high-risk patients will have received both of those at this point. So we’re not absolutely sure that the benefit of neratinib still persists in this population. But I think many of us still reach for neratinib in the ER-positive patients who do have a lot of residual disease and are therefore at high risk.

In terms of mitigation, I think the control arm, there’s the CONTROL study – was a trial looking at multiple cohorts of different mitigation techniques. I mean I think the dose escalation seems the most promising in terms of reducing the risk of Grade 3 diarrhea and it works quite well. I mean presumably, it probably doesn’t have much impact on efficacy, since you’re only cutting the dose for a short time, but I think that’s the most promising for different techniques, as well as obviously, using loperamide.

DR LOVE: So, Joyce, in a way it reminds me a little bit of everolimus, how people were just not using that drug until we figured out how to prevent the mucositis. How do you think we’ve done in terms of neratinib? I hear a lot more cases now where people do well. Any thoughts about tolerance, now that we have better strategies?

DR O'SHAUGHNESSY: That’s certainly been my experience. I think the dose escalation is really important in not escalating if someone’s having any more than Grade 1 diarrhea. And I think people do really remarkably well with it and then you don’t overshoot the mark for the patients. And so, I think that’s made a huge difference. And I don’t think there’s as much neratinib use in the community as there should be. I’m a big neratinib fan because it’s non cross resistant in the metastatic setting with pertuzumab/trastuzumab and T-DM1. We know it’s got activity in the brain and that’s where we really need the help. And we also know that in ER-positive preclinically if you block the estrogen receptor and block pan-HER you get better effects than just blocking one and allowing the breast cancer to escape through the estrogen receptor.

So, anybody with residual disease, any nodes positive or any substantial disease in the breast after pre-operative therapy, if they’re ER-positive, I definitely want to talk to them about neratinib. But I’ve had a lot more success getting people through the year well with the escalation strategy.

DR LOVE: So, here are the data we’ve been talking about in terms of CNS disease. And you see over there on the right, .7 versus 2.1 at 5 years in terms of CNS mets. So, certainly something to consider.

Case: A woman in her early 50s with 4.5-mm ER-positive, HER2-positive breast cancer — Dr O’Regan

DR LOVE: Let’s do one more case.

So, 53-year-old woman. Interestingly, she had a bilateral DCIS, a lot of it. She had bilateral mastectomies. And lo and behold, they found a 4.5-mm focus of ER-positive/HER2-positive disease in the right breast. Here’s Dr O’Regan with what happened.

DR O’REGAN: She had a biopsy that showed DCIS. She ended up electing to have bilateral mastectomy, so they took sentinel lymph node out actually on both sides because she’s DCIS on both sides. And on, I think it was the right side, they found a 4.5 mm ER-positive, PR-negative, HER2-positive breast cancer. Obviously, the nodes were negative.

So the question with a lady like this is how would you manage her. Would you feel strongly about treating her with paclitaxel/trastuzumab? Would you give a patient like this T-DM1? Or what I actually did was I’m always skeptical when they’ve got DCIS. So actually this was IHC 3+, so I made them do FISH on the tumor, and it actually came back nonamplified. So it looks like they actually had measured the HER2 on the DCIS cells because DCIS is more commonly HER2 positive. And I think the pathologist really felt that was the case. What would you do in that case?

DR LOVE: So, Erika, would you like to provide a second opinion about what to do? And if you would treat this patient, what would you use?

DR HAMILTON: Yeah, I agree with Dr O’Regan. Typically, our threshold to treat HER2 is with chemotherapy and targeted HER2 therapy is 5 mm. This patient of course, skated in right under that. But I agree. I mean I think the HER2, the DCIS scenario is definitely a possibility there and especially with that patient being FISH-negative, I think that probably is the case, and I would side with what Dr O’Regan did as well.

DR LOVE: Ian, what about in patients with small node-negative tumors in terms of choice — if it’s clearly HER2-positive, choice of treatment in that situation. You have the ATEMPT choices. How do you go about making that decision?

DR KROP: So, the ATEMPT trial was this study looking at T-DM1 versus TH in Stage I HER2-positive breast cancers with the comparison being on toxicity, not efficacy, and showed that a year of T-DM1 led to very, very good outcomes, just a couple of distant recurrences out of the over 400 patients, or about 400 patients, though clearly, it’s an effective regimen. But, overall, it was not less toxic. A year of T-DM1 was not less toxic than the TH regimen, so we can’t claim that it’s an equally efficacious and less toxic regimen, but the toxicities are different.

So I think our take on the ATEMPT data was that the standard remains TH, but for select patients for whom the toxicities of paclitaxel could be problematic such as a patient who already has pre-existing neuropathy or is very averse to hair loss or other reasons for chemotherapy aversion, that using T-DM1 in those select patients is reasonable. But I think for most patients, TH is the standard for low-risk HER2-positive disease.

DR LOVE: So, Joyce, there are so many times in oncology that I’m surprised by how data gets applied. We had this great trial, the RELEVANCE trial in follicular lymphoma, where we showed we could treat without chemo with R2 regimen. Nobody is using it first line. They stuck with chemo. I thought for sure, once the ATEMPT data came out, people would start using T-DM1 and we’re not really seeing that. How do you sort through that decision, Joyce?

DR O'SHAUGHNESSY: I only use the T-DM1, as Ian said, if I can’t really use paclitaxel, otherwise I’ll use paclitaxel/trastuzumab for that very, very low-risk individual. But I think Dana-Farber is starting ATEMPT-2, 6 cycles of T-DM1 versus, again, the weekly paclitaxel/trastuzumab as a toxicity comparison. So, that will be nice. I just think the year of T-DM1 was a bit fatiguing, as we see in all of our patients who we have to give 10 months of T-DM1 to.

DR LOVE: So, speaking of de-escalation, Erika, at the ASCO meeting. We saw a really interesting study — particularly what I’ve been hearing from the Dana-Farber people about THP, and I hear lots of cases with people having problems with TCHP. So I’m curious, Erika, what you thought about this trial looking at THP, just 97 patients.

DR HAMILTON: Yes, it’s what Ian’s been talking about. It’s an attempt to figure out what size treatment each patient needs. And so, just giving THP here, you can see that residual cancer burden 0 here, pCR in 56% of patients, so really suggesting that for about half of patients, we may not need to give as much as we would standardly give. In that trial, those patients just go on to get antibodies, etc. And then patients that don’t have the response we’re looking for, then we give those patients more. But I think it’s probably likely that we are overtreating some of our HER2s. It’s not really one-size-fits all.

DR LOVE: So, Ian, what about this and also in metastatic disease, CLEOPATRA versus THP, how do you make that decision?

DR KROP: So, I mean the CLEOPATRA regimen essentially is THP. It’s docetaxel/trastuzumab/pertuzumab. And I think many of us aren’t thrilled about using docetaxel in the metastatic setting, so we tend to use — I tend to use paclitaxel in the metastatic setting. Was that what you were asking?

DR LOVE: Yes. But also in the neoadjuvant setting, the use of THP. Obviously, there’s a trial looking at that. Do you think it’s a reasonable thing to do outside of a trial?

DR KROP: Well, the one thing is we don’t have long-term outcome data, that just using this de-escalated amount of chemotherapy leads to the same very good outcomes that we see when patients get a path CR with more chemotherapy. So, I mean just for the record we have to say that we don’t have long-term outcome. And so, therefore, it feels a little awkward to say this should be our standard until we get the results of trials like COMPASS. But I think many of us are very optimistic that we will get rid of the extra chemotherapy, and some people are willing to start doing it already. I just want to make sure everybody is aware that we don’t have really definitive long-term data for this approach.