Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome to Video Consensus or Controversy, as tonight we talk about the management of breast cancer. We have a great faculty today: Dr Komal Jhaveri from Memorial Sloan Kettering Cancer Center, Dr Kevin Kalinsky from the Winship Cancer Institute of Emory University, Dr Ian Krop from the Yale Cancer Center in New Haven, Dr Joyce O’Shaughnessy from the Baylor University Medical Center, Dr Hope Rugo from the University of California San Francisco, and Professor Peter Schmid from the Barts Cancer Institute in London.

We also have 3 faculty members who are going to be appearing virtually today, which is why we call this Video Consensus or Controversy. I sat down in the last couple weeks and met individually with these 3 investigators for about an hour or so and chatted with them about taking care of breast cancer. We’re going to bring some of their comments into the meeting tonight: Dr Sara Hurvitz from the David Geffen School of Medicine at UCLA, Dr Sara Tolaney from the Dana-Farber Cancer Institute in Boston, and Dr Tiffany Traina from Memorial Sloan Kettering in New York.

So as we go through this program we’re going to show you a few of about 75 short form videos that came out of these conversations that we’re going to put together to — we’re trying to develop a new platform. Have you heard of TikTok? We want to do TicTonc. So we’ll see whether we can come up with something.

But tonight we’re going to do what we’ve been doing really the last 3 years during the pandemic, which is integrating preproduced video into live events, both webinars, as well as live meetings. And actually we used this format here Friday night for the first time with lung cancer. So you all are the second part of the — the second patient on the Phase I study of this approach to CME.

Here’s where we’re heading tonight. We have a lot to talk about, but we’re going to try to really focus on taking care of patients and clinical implications, and what everybody wants to know from investigators is what do they do in common clinical scenarios. We’re going to start out talking about HER2-positive disease, just move on. We’ll try to incorporate some of the exciting things that have happened here at this meeting.

Management of CNS-only disease progression in patients with HER2-positive metastatic breast cancer

DR LOVE: So I’m going to start out, and Komal, I’d like you to react to this first comment that is made by your colleague, Dr Traina.

Let’s talk about a patient who has metastatic HER2-positive disease who gets CLEOPATRA first line, and let’s just say they get T-DXd second line, and then while on T-DXd, having a partial response, they develop a brain met, and it’s taken out.

DR TRAINA: Okay.

DR LOVE: Systemic disease still under control.

DR TRAINA: That was my next question for you. So this is an interesting area because if we look to what has been the guidance from NCCN and really breast cancer experts, with systemic control if the brain metastasis has been addressed, whether by surgery or radiation, we’ve been inclined to keep that same systemic therapy going and stretch that.

The challenge and benefit is that we have the data from HER2CLIMB with tucatinib that suggested a significant improvement in outcomes, including survival, for patients who had brain mets, both treated stable or even untreated brain mets. So in that setting I struggle sometimes with wondering whether it’s worth the change of therapy to tucatinib plus capecitabine and trastuzumab.

DR LOVE: So Komal, and then we could also bring up a situation where a patient was going to require whole-brain radiation or stereotactic radiation. We asked her about a scenario where a brain met was taken out. This is actually — we’re going to be showing these through the night. This is — so we took the questions we asked these 3 docs and put it into a survey, and then we asked the faculty. Our way of doing consensus is we ask people how they — what they do. If they all do the same thing we call it a consensus. So how do you think about this general situation, Komal?

DR JHAVERI: I think I agree with it. I think the guidelines that we currently have, and they’re published in the JCO, suggest that if you’ve addressed the issue at hand, and in this case it was CNS recurrence, and the systemic disease was under control, I think we can pull more mileage with a drug that is otherwise working overall for the tumor disease burden because you’ve locally managed the brain metastasis. So I would continue the therapy and watch them closely.

DR LOVE: Ian, agree, disagree, or in between? Again, would it matter if the patient needed whole brain?

DR KROP: Yeah, no. I was going to point that out. So I agree in this case with a single brain met definitely continue the T-DXd as was said. We have data saying that that buys you additional time on average on that drug, but if they have whole brain — I mean if they need — if they have multiple lesions, they need whole brain, we really are trying to delay the use of whole brain as long as possible. These patients are living a long time, and they really can get into trouble with the cognitive effects, of late effects from whole brain. So if they needed whole brain I would switch to tucatinib.

Synergy between tucatinib and HER2-targeted antibody-drug conjugates

DR LOVE: So here’s the next — we’ll get a little translational here, Joyce. I heard something recently that I hadn’t heard before, and I wanted to see if anybody else heard about it, so I asked Sara Hurvitz.

So I’m curious where you see tucatinib heading in the future. I always kind of visualize it well we’re adding brain protection. And then somebody brought up the issue that it’s thought that tucatinib upregulates HER2 and that maybe there’s synergy between tucatinib and ADCs.

DR HURVITZ: There is some evidence preclinically that tucatinib upregulates expression of HER2 which may make a tumor more amenable to therapy with the targeted therapy that requires high expression of HER2. This may be most important for drugs like T-DM1 where high levels of expression of HER2 are required for benefit from T-DM1.

And by the way, T-DXd is also being combined with tucatinib in at least 1 clinical trial, possibly 2.

A big question will be, especially in the palliative setting, how tolerable is it? How safe is it on the liver in terms of GI toxicity? So a lot of questions will have to be addressed.

DR LOVE: So Joyce, I’ve never heard that. Is it true also with lapatinib and other TKIs?

DR O'SHAUGHNESSY: Yeah. There’s data from Neil Spector showing the same thing, that lapatinib actually slowed down the cytoplasmic membrane turnover. That’s how it worked. It upregulated HER2. You can see the cell would want to do that if you’re hitting the TKI end of it. It upregulates it, and it can then lead to better efficacy preclinically for antibody-based therapy. The best responses I ever saw back in the old days was lapatinib/cape, patients who benefitted then given sequentially T-DM1, not necessarily together. And that’s why I always will give T-DM1 after tucatinib. I won’t use T-DM1 right after T-DXd. I’m going to put tucatinib in there for multiple reasons, but that’s one of them.

DR LOVE: So yeah, Saturday night at our prostate cancer meeting we showed a video where one of the investigators said, “Back in the old days, in 2019.” Whoa. Yeah. That’s the way it is, right? That is the way it is.

Management of trastuzumab deruxtecan–related adverse events

DR LOVE: All right. So another issue. Peter, we actually did a program recently at the ONS (Oncology Nursing Society) Congress on antibody-drug conjugates, and we had lung cancer people, GI people, and breast people all on the same stage, and we were kind of comparing notes. Of course now even beyond that T-DXd is going, but certainly in those 3 you’re seeing a lot of use, approvals, et cetera. And it was interesting to compare notes on how people deal with tolerability.

So that was the next question we had for our virtual faculty, related to T-DX tolerance.

What grade of ILD would you permanently discontinue T-DXd for and what grade would you rechallenge?

DR TOLANEY: Yeah. So right now, our guidance is that if you have Grade 2 or higher ILD, so in essence if you have any symptoms, you must permanently discontinue T-DXd. You're only able to rechallenge if someone has Grade 1 or asymptomatic ILD. And in that case, you can rechallenge with the same dose if the radiology looks completely resolved, the scan is improved in less than or equal to 28 days, but if it goes beyond 28 days to make your scan look better, then you have to dose modify. But really, you can't give the drug again if they have symptomatic ILD which is tough for patients.

DR LOVE: So I'm curious what you say to your patients who are about to begin T-DXd in terms of likelihood of getting chemotherapy-like side effects and what you say to them to expect.

DR TOLANEY: I do tell them it is chemotherapy.

T-DXd causes nausea, it can cause neutropenia. In a small number of patients, it causes hair loss. So it is chemotherapy.

DR LOVE: Can you talk a little bit about what we know about T-DXd and the heart?

DR HURVITZ: Yeah, so it's trastuzumab. So trastuzumab is associated with risk of cardiomyopathy. In the absence of anthracycline pretreatment or concurrent treatment, that risk is quite low. But in DESTINY-Breast04 where you're now treating a group of patients who have HER2 negative, a lot of these patients were pretreated, I assume with anthracyclines, and we are seeing a little higher rate of cardiomyopathy.

In my patients who've had anthracycline pre-exposure and are going on T-DXd, I usually involve a cardio-oncologist to see them at least once a year and to help me.

DR LOVE: So and actually Sara brought that point up in the editorial she did on the HER2-low paper because the HER2-low patients may have gotten anthracyclines, which is not very likely with HER2-positive breast cancer.

So Peter, you were the only one who was maybe not so clear about whether or not if they had some symptoms. The lung people, incidentally, they’re like — they’re so used to having people short of breath they’re like well, we’ll maybe wait another line and then restart it. Anyhow, what are your thoughts, Peter?

PROF SCHMID: Yeah. It’s great being the outlier. I think it comes down to how we define symptomatic ILD, and if you ask, practically every patient who comes through my door has a little bit of shortness of breath, as well as a little bit of cough, whether that’s ILD or not. And so it comes down to whether you associate those symptoms with the changes seen in the lung, or whether you say that’s just part of their overall disease situation.

Now if you clearly have a patient who has symptomatic ILD, where the ILD leads to cough or shortness of breath, then I would be cautious. But if you have a patient who’s just — has metastatic disease, a little bit short of breath, and you’re not convinced this is driven by ILD, and there is mild change in the scan, I don’t think it is unreasonable to do this, although this is against guidelines.

DR LOVE: So Kevin, any thoughts? And also, again, your experience with T-DXd in terms of chemotherapy side effects. And do you think differently about the heart in somebody who’s, again, HER2 low and has had an anthracycline going on T-DXd?

DR KALINSKY: Yeah. I mean I’m a bit of a rule follower, and so I think also I was thinking back to the old days, a couple of years ago, when we saw the original data that Funda Meric-Bernstam had presented with the HER2 — when we saw the Phase I data, and we saw deaths, and I think we’ve learned a lot in terms of management of trastuzumab deruxtecan.

So I also think — the thing that I — the challenge that I really face, I think, is how frequently to be scanning these patients. In the clinical trials they were scanned every 6 weeks or so, and so part of that is also to see whether or not we can detect asymptomatic or Grade 1 and potentially give steroids to mitigate the early development of ILD. So I think that’s something that clinically I think remains a bit of a struggle, also because we can see the ILD develop a little bit later. It’s not necessarily something that happens early on.

And in terms of side effects that we see, I think the ones that were mentioned, including nausea, we really optimize antiemetics from the beginning, the potential for alopecia, fatigue, and then monitoring cardiac function.

DR LOVE: So just to come back to Peter. Again, do you image the chest in people on T-DXd, assuming they don’t have disease that you need to look at? Are you going to add imaging every couple months?

PROF SCHMID: We image our patients quite frequently anyway, every 2 to 3 months, depending on the clinical situation. And I don’t think we need to screen much more often. So if you scan your patients every 2 to 3 months, from my perspective that’s enough.

Patient selection for and practical implementation of postadjuvant neratinib

DR LOVE: All right. So 1 more question before Ian kind of reviews some of the data. And Hope, I’m going to ask you to comment. Here’s the — I’m sorry, here’s the faculty thoughts. Again, I think everybody agrees about the chemo side effects. But the other issue I wanted to bring up here in this HER2 section is one that’s been out there for a while, but just want to see where people stand, post-adjuvant neratinib.

DR HURVITZ: I'm really restricting my use of neratinib to those patients who have hormone receptor co-expression given that ExteNET study showing that the benefit really did seem to be restricted to those patients and really high-risk patients, so lymph node-positive disease.

But I do like the fact that there is some evidence that it protects the brain. And so in a very high-risk patient population I think it's appropriate to discuss with patients.

DR LOVE: And when you do use neratinib what’s your starting dose and how do you approach dose escalation?

DR HURVITZ: I follow the way that we did dose escalation in the control trial. So a week at 120 and then a week at like 160, I think is the next one up, and then going to the full dose at week 3.

If patients are struggling with diarrhea or other GI side effects in those first few weeks, I will lengthen the time during escalation so maybe over 3 to 4 weeks, but it just really does seem to help patients to start slow.

DR LOVE: Hope, your thoughts.

DR RUGO: I think we all follow very much that same course. I use neratinib only in patients who have hormone receptor-positive disease, although it was approved, and you can see that that was what my answer was, was essentially what Sara said. And there’s also the randomized COMPASS RD trial, which is COMPASSHER2 RD, which is looking at T-DM1 a la KATHERINE with or without tucatinib. So if a patient was already on tucatinib on the COMPASS trial then we wouldn’t give them neratinib after that year.

But I think that giving tucatinib is an interesting question. The KATHERINE trial didn’t show any difference in the development of brain mets, which sat around 5%. There was no reduction. So the idea with giving an oral TKI in somebody who has a really high risk is maybe you can prevent or at least reduce that percentage. And for patients who have a lot of disease left at the time after neoadjuvant therapy with ER-positive, HER2-positive disease we know the risk goes out much longer than the ER-negative group. So adding in neratinib after a year of T-DM1 seems quite reasonable, and we all use this dose escalation approach. But again, a lot of patients need to go back down again, so you don’t really have to push hard. You could escalate over 4 weeks. You just want to make sure people are ready to go up to the next dose.

DR LOVE: It was a pretty hazard rate there in ER-positive patients. I think it was like 40% reduction, 0.6.

DR RUGO: If you chip away at things this is a good way to reduce risk. You’ve got 4 positive nodes, high-risk disease, you want to keep reducing risk.

Faculty presentation: Dr Krop

DR LOVE: All right, Ian. Let’s take a look. We’re doing a little tasting menu of the data. We could probably spend the next 2 hours talking about the data behind what we just talked about, but let’s just pick up a few highlights.

DR KROP: Yeah. So this is a fast-moving field, so we’ll go fast. So it’s hard to believe, but just 10 years ago we had very limited options for HER2-positive metastatic breast cancer. We gave trastuzumab and pertuzumab in the first line, and then trastuzumab or lapatinib in the second and later lines.

The problem was those later-line therapies weren’t very effective, so we needed new options. Fortunately we now have them, particularly antibody-drug conjugates, and we now know from the DESTINY-Breast03 trial, which compared T-DXd against T-DM1 to see what was the better second-line option, that clearly T-DXd was more effective in terms of progression-free and overall survival. And reassuringly the rate of ILD was about 15%, but there were no Grade 4 or 5 events, suggesting that we’re learning how to manage this adverse event better.

DESTINY-Breast02 also looked at T-DXd in a later-line population against chemotherapy and HER2 therapy. Again, improvements in progression-free and overall survival, but the magnitude of the benefit here is less than we see when we use this drug in the second line, so I think even though it works later line the drug should be — T-DXd should be used in second line in most patients.

Today at the conference we presented data on using T-DXd in older patients, and you can see across all 3 of the DESTINY trials that the efficacy in patients 65 and older was essentially identical to patients younger than 65 in terms of progression-free and overall survival, which was very reassuring and encouraging.

There are more Grade 3 or higher adverse events in the older patient population, but not dramatically so, and rates of ILD were somewhat higher in the older population, but it was all low grade events. The rate of Grade 4 and 5 ILD was very low in both younger and older patients and essentially identical.

We also have multiple tyrosine kinase inhibitors. Tucatinib is a HER2-specific TKI which was looked at in the HER2CLIMB study, adding tucatinib to trastuzumab and capecitabine. And we saw very clear benefit in terms of benefit of tucatinib causing improved PFS and overall survival, with a general manageable safety profile, with diarrhea and hand-foot syndrome being the most common adverse events.

Neratinib is a very potent pan-HER kinase inhibitor. This was looked at in NALA comparing neratinib plus cape versus lapatinib plus cape, and again improvements in progression-free survival with neratinib, but in this study there was no improvement in overall survival.

And as we were just talking about, diarrhea is a problem with neratinib, 24% Grade 3 in this trial despite prophylactic loperamide, but fortunately a lot of effort was spent trying to improve on diarrhea control, and as you heard from several of us the dose escalation approach seems to work quite well, starting with 120 and then gradually moving up to full dose. Very improved tolerability and much less drug discontinuation when using this approach.

Now there’s a lot of interest in trying to improve management of brain metastases with HER2-positive disease because it is unfortunately so common. We are making progress these days. The HER2CLIMB trial did show substantial benefit with the addition of tucatinib in patients with progressive brain mets, about a 50% improvement in survival in this patient population, and also roughly 50% intracranial response with the addition of neratinib — I’m sorry, with tucatinib.

Neratinib and capecitabine also has efficacy in the brain in a Phase II trial. There was also about a 50% response in the brain with this kinase inhibitor.

And more recently we’re seeing evidence that antibody-drug conjugates like trastuzumab deruxtecan also can have activity in the brain. In DB-03 patients with stable brain mets there was about a 60% intracranial response with the use of T-DXd, and now we’re seeing small studies, both retrospective and prospective, in patients with progressive brain mets showing about a 50-60-70% objective response in patients with progressive brain mets, again albeit small numbers.

So how do you put all of this together? So again, we’re still using the trastuzumab/pertuzumab chemotherapy regimen for first line. After that I think it makes sense to pay attention to whether patients have brain metastases. If they don’t have brain metastases, or stable brain mets, then certainly trastuzumab deruxtecan should be the standard of care for the vast majority of patients because of its very durable efficacy. And then you would use tucatinib or T-DM1 in later lines.

For patients with progressive brain mets I used to recommend using tucatinib solely because of the data from HER2CLIMB. But now that we’re seeing I think fairly compelling data suggesting efficacy of T-DXd in this patient population I think you could argue to use either one, and I would decide which one to use based on patient preference but also whether brain metastases or extracranial disease is the patient’s bigger problem because the response rate of T-DXd is so much higher than tucatinib outside the brain. And then of course you would use the other drugs after that.

So lastly I just want to briefly touch on early-stage disease. Not a lot has changed recently, but — I’ll skip this — but we do get a lot of questions about neratinib, and we’ve just talked about it a little bit, so this will be review.

But we have this ExteNET trial that looked at patients who received a year of neratinib after they completed their year of trastuzumab-based adjuvant chemotherapy. And as you heard, what that showed was that in the hormone receptor-positive, HER2-positive patients, but not the hormone receptor-negative, HER2-positive patients, there was substantial benefit to the addition of neratinib. It was most pronounced in those patients that were high risk, as defined by residual disease after neoadjuvant therapy. And you can see absolute benefit in terms of iDFS of over 7% and a benefit in terms of overall survival as well. And as also you heard, there also seemed to be an apparent benefit in terms of reducing the risk of CNS recurrence in those patients who received neratinib.

So how do you use this in the clinic? Well, again, there’s clear benefit, both relatively and absolute, in the triple-positive, high-risk patients, but you have to balance that against the toxicity, which again is diarrhea, is something that we have to pay attention to with neratinib. And I want to remind you that the ExteNET study was done a relatively long time ago so none of the patients on that trial received pertuzumab or T-DM1, which is of course what all of our high-risk patients are going to be receiving these days. So we don’t know whether you can extrapolate that benefit of neratinib from ExteNET into the current era where we’re using T-DM1 and pertuzumab very frequently.

So who should receive neratinib? Again, I completely agree with my colleagues that it is a very reasonable option for patients who are hormone receptor positive, HER2 positive and are high risk, and I define that as positive nodes after neoadjuvant therapy or patients who don’t get neoadjuvant therapy, multiple positive nodes at baseline.

So I will stop there with 10 seconds to spare.

DR LOVE: Awesome. So yeah, I was just flashing on that program we did with GI, lung, and breast, and Zev Wainberg from UCLA, who works with Sara Hurvitz, was telling us about a patient he had with gastric cancer, had a brain met, and somehow he was able to get the patient HERCLIMB even though it’s never been looked at in gastric cancer, and the patient responded. So interesting. We learn from what you all have done.

Ovarian function suppression to preserve fertility and prevent premature ovarian insufficiency; interrupting adjuvant hormonal therapy to attempt pregnancy

DR LOVE: I think this ASCO’s going to be called the ER-positive ASCO. I mean a lot of good stuff. Kevin, your session was like amazing, I think. We’ll talk about some of the things that happened. Again, we could spend the whole time on that.

But we’re going to start out. We’re going to talk a little bit about early ER-positive disease, so much going on. Just to begin, again, Komal, I’ll ask you to respond to what your colleagues had to say about the use of ovarian suppression and the POSITIVE strategy.

I’m curious about whether or not you use ovarian suppression/ablation to protect the ovaries of your patients. Patients, for example, either who wish to have childbearing or just don’t want to go into premature menopause.

DR TRAINA: Yeah. We’ve seen some great data, albeit that was largely in a hormone receptor-negative patient population, for using ovarian suppression for fertility preservation and preserving ovarian function. And yes, I think it’s critically important that we have the conversations about fertility preservation with our premenopausal patients of childbearing potential. And I do offer ovarian suppression to them concurrent with their chemotherapy, whether it is neoadjuvant or adjuvant therapy, and whether it’s hormone receptor-negative, -positive, or HER2-positive.

DR LOVE: What about the so-called POSITIVE approach to interrupting adjuvant hormonal therapy to allow women the opportunity to attempt pregnancy. Is that a strategy that you’ve been doing?

DR TOLANEY: I think the POSITIVE data was really very informative because in essence, it told us that you can hold endocrine therapy in these predominantly lower-risk patients, so most of them were Stage I and II patients.

So I usually do like to wait at least 18 months as was done in POSITIVE. I don't have quite as much comfort level in a high-risk patient because we don't have data on them.

DR LOVE: So Komal, any thoughts about that? It’s interesting. Again, last night we were talking about lymphomas. Ann LaCasce from Dana-Farber is here. We were talking about using LHRH agonists in patients about to be treated for diffuse large B-cell. We had a young patient who wanted to maintain fertility.

So Komal, any thoughts about (A) using ovarian suppression during chemo and also the POSITIVE strategy?

DR JHAVERI: Yeah, no. I think I completely agree with both Sara and Tiffany, and exactly what I do in my practice as well. I think our young woman, we definitely have data now. Initially, as Tiffany was pointing out from the POEMS study, which predominantly looked at the HR-negative patient population, but we certainly have this conversation with all our childbearing potential patients who we are treating with therapy.

Fortunately at our site we can easily refer them to our fertility preservation specialist, so we have that conversation, we plug them in with an appointment to have that conversation, have the egg retrieval of the embryo retrieval, whatever they prefer to do with them, and that’s when we initiate their treatment. And I certainly consider doing ovarian suppression to protect the ovaries during their chemotherapy as well. We use a different dose while we’re doing that with the chemotherapy, which is distinct from the therapeutic dose that we use for treatment, but I think I use that approach regardless of subtype.

DR LOVE: Joyce, you had a thought?

DR O'SHAUGHNESSY: I totally agree. I think the TEXT data reassured us that you can give LHRH agonist along with chemotherapy and not have an adverse effect on the effectiveness. We weren’t really sure of that for a long time, which is why some of the original POEMS trial was done in ER-negative breast cancer. But the TEXT data, the results look very, very good, every bit as good as SOFT, which gave the LHRH agonist afterwards. So I’m very comfortable in women who want to preserve fertility or who are low enough risk that they can have 5 years of an LHRH agonist and then go on with some ovarian function afterwards.

DR LOVE: So Kevin, I think I’m going to have to go back and watch that video again 2 or 3 times of that session you had there. There’s stuff there — the ovarian presentation by Richard Gray, the discussions that went on. I was trying to follow all the new trials that are out there.

Selection of patients for adjuvant tamoxifen monotherapy

DR LOVE: But I have a pretty straightforward question I think is pretty practical, which is who do you give tamoxifen to alone. And we started to do some surveying on this earlier this year as part of a project, and it was kind of interesting because there was a lot of discussion about that — or there was discussion about that in your session. But it’s kind of interesting what happens when you put that question out because we discovered something very practical that came out.

Here’s my 39-second summary of who should not get an LHRH agonist in the adjuvant setting and get tamoxifen monotherapy. Here’s the faculty.

What are the patients where you consider tamoxifen alone as adjuvant therapy in a premenopausal woman?

DR TOLANEY: Usually, in someone who has a low recurrence score, so definitely under 11, I'm usually pretty comfortable, and in a node-negative with a low recurrence score, then we're thinking tamoxifen alone.

DR TRAINA: I can imagine premenopausal women, teeny, tiny tumor, node negative, low-risk Oncotype, I would still be comfortable giving those women tamoxifen alone.

DR HURVITZ: Node negative, low recurrence score, small tumor.

DR LOVE: And that’s what we saw. You don’t necessarily see that in the guidelines, but when we started asking people all of a sudden recurrence score came in. Does that jive with your approach, Kevin?

DR KALINSKY: It does. It does. It does jive.

DR LOVE: And of course you have the tumor size. We asked the faculty, as you heard them verbalize it. I’m curious, Hope, any thoughts about this? To me it’s kind of hard to read the guidelines and try to figure this out. I’m not saying it’s simple, but what struck me was the involvement of the recurrence score in the decision. Again, is that the way you look at it?

DR RUGO: I do look at it that way, and I agree with the comments that have been made. I think when you’re talking about a 30-year-old patient I feel a little bit different, because I don’t know, the size of the tumor, and what we’ve seen so far is that ovarian function suppression seems to make a bigger difference if you’re younger and your ovaries are making a lot of estrogen.

So in that patient that came up I would think that maybe I would use some — I’m not going to commit them to 5 years of ovarian function suppression if they have a little, tiny tumor, but this could be 2 cm, node negative. Even with a low recurrence score I would probably optimize the endocrine therapy with ovarian function suppression with either an AI or tamoxifen at least for a few years because I think it really makes a difference. There’s something different about these cancers. We saw in one of the presentations on Friday afternoon that even if you had luminal A disease the young women had worse outcome with these tumors.

DR LOVE: So Kevin, if I understand this correctly, and believe it or not we were talking about this Saturday night here in our prostate session, there’s something going on in prostate cancer that’s a lot like this model. I won’t get into it, just to let you know what’s happening.

But Kevin, I guess you could say that we know that if you add ovarian suppression to tamoxifen you’re going to get a little bit more of a hazard rate. You’re going to bring that down a little bit. But I guess the thinking is the absolute benefit is not worth the side effects/complications, and so you can bring it to the patient as a possibility, particularly a younger patient. Again, is that the way you think it through?

DR KALINSKY: Yeah. So I have a few thoughts. So (1) it comes down to what’s the risk/benefit ratio. And when we think about ovarian function suppression for our patients it’s not a strategy that all patients can tolerate, and there are some longer-term side effects, as well, cardiovascular health, bone density, going through menopause. There are some patients who really can’t tolerate this. And so if I had a patient who was young and had — was node negative, small tumor, good genomic assay, I do think it’s reasonable.

I also think that the point that Hope made is a very important one, and those were data that were also presented during the session. There were 2 things. So (1) the luminal A patients, those very young patients, despite them having luminal A tumors, which we think of these as being endocrine sensitive tumors, those patients did worse. And we also saw that there was a higher rate of luminal B tumors for those very young women compared to the older patients. And I think when Hope made the comment about a 30-year-old patient I do think about for very young women that their tumors, the biology I think is a little different.

Utility of genomic assays in the neoadjuvant setting; management of node-positive disease in postmenopausal patients with low-risk Recurrence Scores^®

DR LOVE: So Ian, I’d like you to respond to this next question. One of the things — I included the questions on the videos because it’s always fascinating to me to watch people’s faces as I ask their question. You don’t see this on our audio programs, but you can kind of see the wheels turning.

So here’s my RxPONDER question, and we’ll see how Ian’s approach compares here.

Any situations where you use the 21-gene recurrence score in the neoadjuvant setting?

DR TOLANEY: Yeah, so we've actually started doing this a lot now and one case is certainly, if they have a locally advanced cancer and you do need to downstage it for them to be able to get breast conservation, then I want to get a genomic assay so I know what drugs I should be giving to downstage. Do they need endocrine therapy to shrink it or do they need chemo to shrink it?

DR LOVE: If you have a postmenopausal patient with a low recurrence score, how many nodes can be positive for you to be comfortable not giving chemo, 1 to 3? Or do you go beyond that?

DR TOLANEY: Good question. I will say that currently, our data is really for up to 3 positive nodes. Once you hit 4 or more, we don't have data to say we can omit chemo.

But I will say, I do wonder if it's the right thing because biologically speaking, does it matter how many nodes you have to say if your cancer is going to derive benefit from chemotherapy? We just don't have data here and knowing risk is so high, we generally just give the chemotherapy to those patients.

DR LOVE: So Ian, neoadjuvant use of genomic factors outside a trial. Of course some great trials looking at it. And how many nodes?

DR KROP: Yeah. So again, obviously we use Oncotype for 2 things. It’s prognostic, but it’s also predictive. It tells you, and I think this is the most important thing, it tells you how sensitive the cancer is to chemotherapy. So I think it’s a great tool to use to decide whether you’re going to give neoadjuvant endocrine therapy or neoadjuvant chemotherapy for a postmenopausal patient because we know based on the adjuvant data, we also have neoadjuvant data that says that that is going to tell us, at least to some extent, how well chemotherapy is going to work versus endocrine therapy. So I use it just like Sara does for that purpose.

In terms of the nodal cutoff, obviously Sara’s correct that the RxPONDER study was up to 3 positive nodes, but there’s nothing magic about that. That was arbitrary in the trial.

So if I have a postmenopausal woman who’s 68 or 70 — in their 70s and has 5 or 6 positive nodes with an Oncotype of 6, I’m going to have a discussion with her saying that I think the benefits of chemotherapy are going to very small, and I would be comfortable, if she was, to proceed with maximal endocrine therapy with abemaciclib in that patient and forgo chemo.

DR LOVE: I feel like in almost every meeting this weekend the issue of involving patients in a decision comes up because it’s just you have to do it when you’re not really sure of the answer.

Selection between abemaciclib and ribociclib in the adjuvant setting

DR LOVE: All right. Here we go. So this was before they saw the data, but I think they assumed what they were going to see there, and I think — I’m not sure there were any huge surprises, although I was surprised that they lowered the dose there in NATALEE. That was very interesting. I want to ask you about that. But I guess there are going to be patients, assuming that ribo’s approved, who theoretically could receive either. So I was curious what the preference of the faculty would be.

How you’re going to decide between ribo and abemaciclib in patients who are eligible for both?

DR TRAINA: Ribociclib does have some GI tox. We need to monitor for LFTs. We need to be sensitive to QTc prolongation and drug/drug interactions, so that may be a factor in and of itself if this is a patient who has other comorbidities and is on a lot of other medications.

On the flip side, abemaciclib has this really challenging diarrhea. You also have a duration of therapy difference there, right, with ribociclib in NATALEE being 3 years of CDK4/6 inhibition versus 2 years with abemaciclib.

DR LOVE: What's your estimate of the likelihood that somebody will finish 2 years of adjuvant abema?

DR TOLANEY: So we know at least in monarchE that about 27% of people discontinued abema prior to getting to 2 years of therapy. But that was also at a time when people didn't know how to manage abema, right? There were a lot of discontinuations that happened in that trial without any dose modification.

In real-world practice, we're not actually discontinuing abema very often because we know how to manage it and we know how to dose modify it and that works really well.

DR LOVE: I assume the main issue is diarrhea?

DR HURVITZ: Yes and just a rumbly gut. They can control the diarrhea, but it's unpredictable. So going to a Pilates class or going to tea with friends or being at work, it can just be very inconvenient and unpredictable to have the diarrhea. So even if it's only once a day, it can be very disruptive to one's life.

DR LOVE: I think that was another theme that I saw in that session there about dose reduction as a way to keep people on therapy, just the way Sara explained it. Probably the same thing’s going to happen with ribo in NATALEE. In the trial they weren’t maybe as tuned into it as they will be now in the next year or 2.

Anyhow, it was interesting though, when we asked the faculty, we presented this situation, which if ribo's approved this would be included, whether the faculty had any preference to the agent, for example Grade 3, 3 cm, 1 positive node. Kevin, you say that you’d be okay with either one. A number of people said abema. We’ll ask Joyce why she made that answer. But what are your thoughts, Kevin?

DR KALINSKY: I think now that we’ve seen the data I feel like — and we’ll talk about this, just in terms of the median follow-up that we have right now in NATALEE, I think one of the important topics is just we’ve seen other studies like PENELOPE-B where there was an improvement when patients were on palbociclib, for instance, on adjuvant palbociclib, but when they got past that year those curves got closer together.

And so I think that we have now 4-year invasive disease-free survival data with abemaciclib. It’s clear that once they discontinue when they hit that 2-year point that they’re still having this benefit. The hazard ratio remains the same, actually slightly improved. So I think given that we have those long-term follow-up data I would now change my answer to say abemaciclib in this context.

DR LOVE: So Joyce, any thoughts in terms of — and I guess another thing, yesterday we had a session on ovarian cancer, and it’s very interesting that the primary maintenance trial with niraparib used 3 years, and the olaparib used 2 years. And people stick with the study, and they were like that’s a whole year of extra therapy.

Anyhow, how are you processing things now that you’ve seen the NATALEE data?

DR O'SHAUGHNESSY: For high-risk patients like this, Grade 3 disease, node-positive, I am going to stick with abemaciclib because of the longer follow-up, as Kevin said, and the delta and the continuing pulling apart of those curves even though everybody’s done with therapy. They’re 2 years off, and that’s very reassuring. These patients are at risk for shorter-term recurrence.

On the other hand, node-negative patients who are higher risk, who fit the criteria for NATALEE, of course I’d be comfortable with ribociclib because abemaciclib is not indicated there.

I think there’s an intermediate risk group that I have equipoise on, actually, which would be like Cohort 2, for example, of monarchE, which is 1 to 3 nodes, Grade 1 or 2, T1 or 2, and a Ki-67 above 20%. That’s a lower-risk population. You can see that in the events.

And then also in Cohort 1 of monarchE there are patients that were Grade 1 or 2, T3, 1 to 3 nodes positive. That’s more indolent biology, more ER-driven biology. I have equipoise right now on that, but higher-risk individuals I would go with abemaciclib.

Potential utility of circulating tumor DNA assessment in breast cancer

DR LOVE: So Hope, before you comment can you take a look at 1 video here? Because you actually asked the question in the discussion session there about this topic. So I’d like you to comment on what Joyce said and then also comment on Sara.

Have you or would you order a circulating DNA assay like Signatera in a patient with breast cancer?

DR TOLANEY: So I actually haven't. But I've seen a lot of second opinions of patients who come in with their tests. So there are definitely people who are doing it.

I think it's a really interesting assay and I do think the data is quite robust to suggest if you have detectable ctDNA that you are at high-risk of recurrence. My problem is, one, I don't know what to do with that. Is it modifiable in any way with additional therapies? And two, how confident am I in a negative assay? Because I do think there are a lot of people who just, the test isn't sensitive enough to pick up positivity with this particular assay. So the assays are getting better and better. And there are trials being designed to see if we can intervene for positivity. But at this point in time, I just think the assay aren't perfect and I don't know what to do in terms of intervention in a positive assay so I have not been routinely getting it.

DR LOVE: So I joke with our webinar audience that I always wait to see how long it’s going to be before somebody asks about circulating DNA, regardless of tumor type. Of course they’re all over it with GI, particularly colon, but everything they’re asking about it. We did a survey of 75 oncologists, and for the GI session the thing they wanted to know most about, even though there’s very little data, was, again, circulating DNA.

And thoughts about, again, this issue of choice of CDK, and where do you see — I mean it was a really cool thing with the PENELOPE study. It looks like this is — maybe Sara’s answer might change after she saw that session. Any thoughts, Hope?

DR RUGO: So yeah. Just to start with the CDK inhibitor. I think the NATALEE data is early, and the data wasn’t separated out perfectly with the Stage II, node-negative versus higher stage.

So in a high-risk patient like the one we talked about I would generally start with abemaciclib, but there are patients who have colitis, they have various issues, and they’re just not going to tolerate abemaciclib. So having another option that you feel likely is going to be effective and has positive data is encouraging, which is why I said I would use either one in the right setting, even though you might still with this early data choose abemaciclib first. I’ve had people really — some people have a hard time with abemaciclib. But people finish their 2 years, so I think they will.

For the ctDNA, I have to say I feel like in part it’s like a marketing issue because I’ve had patient’s complementary doctors, they’re plastic surgeons, everybody’s getting a ctDNA. And I had a patient be told we’ll determine if you need trastuzumab again in the adjuvant setting, after she finished a year of TP, after she had a pCR, we’re going to do every-6-month measurements to see if you need to go back on HER2-targeted therapy.

And so these are big issues. An older woman was told that she could do ctDNA assay to decide if she should get adjuvant chemotherapy for a triple-negative breast cancer. So I think we’re having a lot of trouble with it, and I really agree completely with what Sara said, and I don’t think any of our opinions changed based on the data presented here. It’s clearly prognostic, but we don’t know what to do with the information yet, and so we could actually be putting patients at risk by giving them therapy that’s toxic and isn’t going to help them.

DR LOVE: Final comment from Peter. This is a cool thing presented at San Antonio in patients getting neoadjuvant therapy also. Again, it seems like a great time to look at that. Peter, you say that you have used this strategy. In what kind of situation?

PROF SCHMID: So I think it’s standard of care in the metastatic setting, but I think in early breast cancer the utility hasn’t been shown. We know the technical ability is there for those assays to detect subclinical recurrence and detect a recurrence at an earlier stage, but we don’t know what the clinical implications are. Can we prevent the clinical manifestation of those recurrences or not? So would at the moment only use those assays in the metastatic setting to guide or treatments but not in early disease setting.

DR LOVE: I mean only — I mean not everybody does it, so it’s kind of interesting that you are doing it.

Faculty presentation: Dr Kalinsky

DR LOVE: All right, Kevin, let’s take a look at the data.

DR KALINSKY: Great. So as Neil mentioned, there’s a lot that’s going on in ER positive the early-stage setting. So we talked about the RxPONDER study, 1 to 3 positive nodes, the randomization was for those patients who were 0 to 25 where they were randomized to receive chemo versus not. All patients received endocrine therapy. I will say there was a discussion about whether or not we should include the 4 to 9 nodes involved, but there wasn’t sufficient information from S8814, so we decided that we weren’t really powered to look at this. But I’ll also say the OPTIMA study, which is looking at PAM50, is including N2 disease, and that’s an ongoing study.

So what did we see from RxPONDER? Postmenopausal women in that category, 0 to 25, had no chemotherapy benefit when we look at different outcomes. On the other hand, and these were updated analyses that we reported at San Antonio about a year and a half ago, where we saw for invasive disease-free survival, as well as distant relapse-free survival that we’re seeing this absolute benefit.

One of the major limitations of this study, but this also applies to the other genomic assay randomized trials, as well, is the rate of OFS, of ovarian function suppression, in premenopausal women is low and remained low over time. You can see in red are the patients who were randomized to endocrine therapy alone. It’s looking in the last 6 months. And you can see that that rate remained in the mid-teens throughout the duration when patients were taking their endocrine therapy.

There’s been a study that has been designed that should be hopefully opening soon which is looking at premenopausal patients with high-risk, node-negative disease, or the RxPONDER population that we just described, where patients are randomized, called the OFFSET trial, where patients are randomized to ovarian function suppression plus aromatase inhibition for 5 years with or without chemotherapy. And this is a really important study that should be opening at our centers soon.

These are some data that Irene Kang in Los Angeles presented at San Antonio last year in terms of RxPONDER, and what you’re looking at here is we looked at cognition scores. And what I’m showing you here are the premenopausal women, and in blue are the patients who were randomized to receive chemo followed by endocrine therapy versus red, endocrine therapy alone. And what I’m demonstrating to you is even 3 years out we hear from our patients oh, I have chemo brain, I just don’t feel like I have the same cognitive function. It is real, and that can be persistent for some patients, which just further highlights the importance of giving chemotherapy when we should be giving chemotherapy.

Also these are some data from TAILORx, and I’m really just demonstrating that for the population when we think about these scores it’s not just the score by itself, it is also the incorporation of the clinical features that help inform and individualize what — a patient’s risk and help us decide what kind of individualized treatment we should be considering.

So Joyce had mentioned the SOFT/TEXT trial. I’m just going to show a few slides. These are pivotal studies which look at the question of ovarian function suppression and its utility in patients who are premenopausal. When we look at the group of patients who did not receive chemotherapy, and we have this 12-year follow-up, the patients who were not high enough risk to receive chemotherapy, these patients did quite well, number 1. And then also really didn’t seem to be benefitting from the addition of ovarian function suppression.

And this is different than what we see for the patients who received prior chemotherapy, where we are seeing this delta in benefit from giving ovarian function suppression. Again, with this subtype of breast cancer we can see late recurrences, which is why it’s important for us to have these data that are after 5 years.

So I also just wanted to mention the ASTRRA study. These are data that were presented — they were published in JCO and then presented at last year’s ASCO, which is a study that looked in patients in Asia who were less or equal to 45 years of age. Patients received ovarian function suppression for 2 years, and the randomization was tamoxifen versus tamoxifen plus goserelin.

This is just a slide that demonstrates the differences between the 2 trials, and ultimately we saw that even with 2 years of ovarian function suppression, again with tamoxifen as the endocrine therapy, there was this improvement in disease-free survival.

So one of the comments that we’ve been talking about is what about giving ovarian function suppression during chemotherapy for fertility. And so these are some data that have been published by Dr Lambertini and colleagues, where you see that for even 12 years or so of follow-up, including in the hormone receptor-positive, HER2-negative population, that it seemed to be safe, and there was not an increased risk of ultimately having a recurrence.

So we talked about monarchE. Again, this did not include patients with node-negative disease, only node-positive disease. And there were 2 cohorts, including high risk based on clinical pathologic features or high risk based upon Ki-67. Patients could take AI or tamoxifen with or without abemaciclib, and it was a 1:1 randomization.

And these are data that were presented and updated at San Antonio last year, where we can see that Ki-67 is prognostic. Patients with high Ki-67 do worse, but it’s not predictive of abemaciclib benefit, and as we know Ki-67 is no longer incorporated into the label for utilization of adjuvant abemaciclib.

NATALEE, we talked a little bit about this. I just want to highlight a few points just for the sake of time. So we mentioned this included node-negative patients, but patients would have had to have some high-risk features. Those are described here. If it was Grade 2 or if it was Grade — you had to have a high genomic score, for instance, or other — high Ki-67. It could be Grade 3. And it also included that N1 population.

I’ll also say in terms of the endocrine therapy this was not tamoxifen, right? All the patients had an aromatase inhibitor, and that’s because when we looked in the MONALEESA-7 study there was some QT prolongation with tamoxifen. I just wanted to make that point.

I just wanted to highlight here in this slide that in terms of how long patients have been in follow-up, this is median follow-up of 34 months. But if you look near the bottom of the slide, in terms of the patients who are still ongoing, that are 2 plus — who are continuing the ribociclib treatment, the majority — and also only 20% of patients completed their 3 years of ribociclib. We are seeing this delta in terms of an improvement in invasive disease-free survival. The median follow-up for iDFS was 27 months. And as Hope had already mentioned, this is looking at the overall population.

If we look at the hazard ratios that are seen here, I just want to draw your attention to the bottom of the slide, that bottom box, which is looking at the node-negative population, which is about 800 or so patients. The vast majority are N1 to N3. The hazard ratios are similar. But again, the N0 population is small, and that confidence interval is wide. And this is also the importance of additional follow-up for events.

And then I just want to complete the story by just talking about the context of BRCA mutations. We have PARP inhibition that is approved for patients with BRCA mutations in the metastatic setting for patients who have high-risk HER2-negative disease, whether it’s triple-negative or hormone receptor-positive, HER2-negative disease. We saw the results of the OlympiA study comparing olaparib versus placebo.

I just want to highlight that box that showed hormone receptor-positive, HER2-negative disease and what was required in order to go into that study. It's a higher-risk population than what we might have seen in the triple-negative group.

And these are the data where we see this improvement in invasive disease-free survival. That splaying of the curve happens early and then is persistent, and this is practice changing. These data that I’m showing you here were published in Annals of Oncology with the median follow-up of 3 1/2 years.

And then this is the overall survival data, which are important, where we’re already seeing this numeric improvement in overall survival.

DR LOVE: So we’ve got a couple of questions from the audience that I need a very creative faculty member for. Joyce O’Shaughnessy, I think these have your name on it.

So KS has a patient with a 2-cm DCIS that’s been taken out by lumpectomy, but there’s a tiny ADC “7-8 cells”, and it was HER2 positive. What would you do?

And then Allison wants to know what would you do with a triple-positive patient, so HER2, ER, with a lot of residual disease in terms of abema.

DR O'SHAUGHNESSY: So the first question is 7 or 8 cells in 1 node? There was a node?

DR LOVE: No, in the breast.

DR O'SHAUGHNESSY: Oh, in the breast.

DR LOVE: In the breast there’s a tiny HER2-positive IDC.

DR O'SHAUGHNESSY: No. So that’s micromet — that’s microinvasion, so that’s basically the same prognosis as just DCIS, so we just treat that patient —

DR LOVE: And you see a lot of HER2 positivity in DCIS too.

DR O'SHAUGHNESSY: You do, and I would treat that patient, if she’s younger and interested, with tamoxifen, if she’s young, and with anastrozole if she’s older, and radiation therapy.

And —

DR LOVE: Abema in HER2-positive.

DR O'SHAUGHNESSY: No data, so I would not do it. We’ve got lots of very important — in the metastatic setting we have monarcHER, that’s with fulvestrant, trastuzumab, and abemaciclib, but nothing in the adjuvant setting, so we just stick with our HER2 algorithm.

DR LOVE: I saw the whole row going like this. Hope?

DR RUGO: The 1 caveat to that microinvasion is if you see somebody with DCIS and has like 15 foci of microinvasion. We all treat those patients since I’ve done my cyber tumor boards on those patients.

DR LOVE: Awesome.

DR RUGO: And the abema, I have a patient who’s been on for 3 years, who progressed after 2 years on T-DM1, and is 15 years out from de novo metastatic disease to liver. She’s on abema/fulvestrant that she already progressed on, and trastuzumab. So it’s pretty amazing.

Preference of CDK4/6 inhibitor in the metastatic setting

DR LOVE: All right, Komal, you’re going to go through the data, but let’s listen to your colleagues talk about metastatic disease, ER positive, HER2 negative, and choice of CDK.

How about metastatic ER-positive, HER2-negative disease? Any preference on choice of CDK premenopausal/postmenopausal?

DR TRAINA: Yeah. So we’ve now seen several studies showing overall survival advantage to ribociclib in the first-line setting. Certainly in the premenopausal population we saw that first. But we’ve also seen that now in the postmenopausal patients.

DR HURVITZ: In the metastatic setting I prefer ribo. I think they're both excellent drugs and maybe abemaciclib has even better efficacy. We don't know until there's a head-to-head trial comparing ribo and abema just because it's, it's more potent inhibitor across a wider array of cyclin-dependent kinases. However, I think that ribo is better tolerated from a patient perspective in terms of GI side effects. They're less aware they're on it day to day.

DR LOVE: So Komal, any thoughts about that? I’ve been hearing a lot of people talk about the survival benefit, which you do see with ribo as a particular reason to use it. How are you approaching choice of CDK?

DR JHAVERI: I think I agree with my colleagues. I think if you had asked me this question before last ASCO my answer would have been perhaps different because my practice was to utilize the first kid on the block, which was palbociclib; very well tolerated, very easily monitorable, very easy tolerability profile.

I think the question now in our heads is why not ribo when you have consistent overall survival benefit across every Phase III study regardless of the menopausal status rather than questioning why palbo. And so I think right now for my new starts I am favoring ribociclib unless there is really no reason to consider an alternative CDK4/6 inhibitor, for example ethnic neutropenia, if I’m really worried about it with abemaciclib. We see slightly lower incidence of that. On the other hand, if there was a preference for abemaciclib after a discussion we could discuss whether their comorbidities include inflammatory bowel disease when you would prefer drugs like palbociclib or ribociclib. For my new starts right now ribociclib.

Sequencing of trastuzumab deruxtecan in ER-positive, HER2-low metastatic breast cancer

DR LOVE: All right. Let’s talk about the use of T-DXd in HER2 low, hormone receptor positive, and I’ll ask Ian to respond to this.

What about HER2 low, hormone receptor-positive?

DR HURVITZ: I will exhaust the endocrine therapy options first, and then I will usually give capecitabine and then go on to T-DXd, keeping in mind that I think capecitabine allows patients to have a really good quality of life and sometimes prolonged progression-free survival. I'm not eager to get them in the chemo infusion room and to give them the side effects that are associated with T-DXd earlier, unless we see evidence that it's better in the first-line chemo setting, but I think those patient-reported outcomes are going to be quite important for us to look at in those studies.

DR LOVE: So again, Ian, any thoughts about this? If the patient’s very, very symptomatic and really needs a response? If they’re younger, in good condition does it make any difference? Are you generally using capecitabine first?

When you talk about exhausting hormone therapy nowadays that can be an interesting journey with all the options out there. But Ian, how are you thinking through hormone receptor-positive, HER2-low?

DR KROP: You’re right. It’s an interesting journey, but that’s a good thing that we have all of these options for patients. I agree with every point Sara made, that we still want to exhaust our endocrine therapy. We’re still paying attention to quality of life in the metastatic setting. We have no data to say that using T-DXd earlier is going to improve their quality of life or their survival. But of course we do have a pending trial that’s going to look at the earlier line of therapy, and if that shows a huge survival advantage then obviously we’ll all switch. So I agree with what Sara was saying.

To your point, Neil, if you had a patient who was in clear visceral crisis and had blown through their adjuvant chemotherapy, yeah, I guess I might think about using T-DXd there. But I still don’t know that’s going to do any better than capecitabine in that position, and I certainly haven’t ever done it in clinic.

DR LOVE: So Hope, I was going to ask you before when we asked the faculty about which agent first. When we said postmenopausal you said you didn’t have a preference, so maybe you could elaborate on that. But what I really want to know is what do you think the first-line trial of T-DXd is going to show versus CLEOPATRA. But particularly the thing I want to know is do you think pertuzumab is going to add to it.

DR RUGO: That’s a great question. So I think we could ask all of us, and we would say the same, the trial would be positive for T-DXd. I mean there’s no way you’re going to have that result in the second-line setting and not see a dramatic positive outcome in the first-line setting.

I think back to MARIANNE, and my guess is pertuzumab will not add to T-DXd. And also, if you have a drug that’s like a slam dunk it’s hard to add much to that. And so that’s where I don’t think the pertuzumab will be of benefit. And I do think that it’s likely to increase toxicity. I think it was an important question to ask, but I think we will start using T-DXd in the first-line setting after we see those data.

DR LOVE: Peter, any thoughts? And also, do you see a future for T-DXd in the neoadjuvant setting?

PROF SCHMID: So I think in the metastatic setting it will also be down to the quality of life because we obviously — I think we all expect to see a PFS benefit, but we don’t know. If you look at the SONIA trial today, Neil, of positive disease, where whether you give CDK4/6 either as first line or second line, if you look at PFS2 it actually doesn’t make a difference. And something very similar could happen in the HER2-positive arena, that if you give T-DXd first line or second line ultimately the time from beginning to the end of your second-line therapy could be very similar, but with possibly an inferior quality of life of patients who start on T-DXd first compared to TPH. So it comes down to how we look at those trial data.

In the neoadjuvant setting, again, I’m more intrigued about using T-DXd in the post-neoadjuvant setting, and I think that’s where we expect the strength. If you look at the dramatic response rates compared to T-DM1 it’s almost inconceivable that T-DXd is not superior to T-DM1 in the post-neoadjuvant setting in patients with residual disease.

Do we need that drug in the neoadjuvant setting? That’s a difficult question to answer. I think we need to wait for the data. But I think we have a great standard of care at the moment with TPH plus/minus AC there, and then stratify patients with residual disease into more treatment or less treatment. And so I’m slightly reluctant to change that paradigm unless we see a strong benefit from giving T-DXd prior to surgery.

DR LOVE: In that post-neoadjuvant setting, Peter, what do you think we’re going to see in terms of the brain? It was brought up earlier that in the KATHERINE study there wasn’t a decrease in brain. What do you think you’ll see with T-DXd? Do you think that maybe at some point we’re going to do T-DXd plus tucatinib the way it’s being studied with T-DM1 plus tucatinib?

PROF SCHMID: Well, it is a clear challenge. The brain is somehow a sanctuary for cancer cells, and especially when at an early timepoint the blood-brain barrier is still intact. We all know that at the later stage it isn’t. That’s why we see benefit with T-DXd in advanced disease when patients have established brain mets. But can you really prevent brain metastasis with an antibody-drug conjugate? I think that’s less clear. And if we see a substantially increased percentage of patients with brain mets coming out of their treatment regimen we may have to think about combination with TKIs.

DR LOVE: I just want to come back to 1 other thing that we were talking about before and was commented on in the video, which is the issue of abema side effects. And I’m curious, Kevin, how you — and Sara was referring to the fact that we’ve learned a lot about dose reduction. Can you talk about like when you start somebody on abema, let’s say adjuvant abema, what are some of the things you’re doing pre-emptively? What are you saying to the patient? And then when do you do dose reduction? How much dose reduction? Do you bring the dose back up?

DR KALINSKY: Yeah. So we know from the neoMONARCH study that giving prophylactic meds like loperamide were not helpful. We were seeing a higher rate of things like constipation.

I will say one of the things that we learned in the session at ASCO from Erika Hamilton’s data is, and this was one of the questions that was discussed, is we saw that for the patients who had a lower dose that they still seemed to — like if they had a lower dose intensity that they still seemed to have the same level of benefit. And that was reassuring because I certainly have some patients that I’m worried about, and I feel like well, if I start them at the 150 twice a day, and they do not tolerate, they’re not going to take it at all, then they’re done. So there are certain circumstances that I have started at a lower dose and then escalate up.

But I do think that it’s critical, as you mentioned, to set expectations so that there are no surprises, including the gastrointestinal issues.

The other thing that I also bring up is that slight increased risk of alopecia that we can see, which in any setting, but including the…setting is something that is important, as patients are taking this for years.

DR LOVE: Yeah. The comment was made, which I thought was really interesting, about using E or electronic means to try to remind people to report symptoms. Interesting. Also maybe more involvement with the nurses. We just came back from the Oncology Nursing Society, and adherence, I mean that’s their thing, so I think maybe more education in nurses.

Faculty presentation: Dr Jhaveri

DR LOVE: Komal, let’s talk about some of the amazing things that are going on. Finally we’ve got stuff to talk about in ER-positive mets, new treatments. We’ve been waiting for a while, but now it’s here.

DR JHAVERI: Absolutely. So as you said, it’s a very ER meeting.

So I think we know at this point about CDK4/6 inhibitors. We’ve been talking about it a whole lot. We’ve seen consistent progression-free survival benefits, both in the first line, shown on the left of your table, and in the second-line setting, on your right, regardless of menopausal status. So you have MONALEESA-7 for pre- and perimenopausal women.

What has been interesting has been the overall survival benefit that has been reported out. All MONALEESA programs. We’ve seen a numerical trend in the right direction in the MONARCH-3 study already that has been updated by Matt Goetz. We did see negative overall survival in the PALOMA-2 trial, hence the conversation about choice of CDK4/6.

I think we were also discussing about young women and aggressive tumor biology. And so this was a very interesting question in the RIGHT Choice trial looking at should we be giving chemotherapy to these young women or is CDK4/6 inhibitor still appropriate. But not only that, this was also targeting people with more symptomatic visceral metastases. So this is visceral crisis, and the definition is in the eligibility criteria here.

And these women were then randomized to receiving ribociclib with letrozole and ovarian suppression or anastrozole and ovarian suppression with ribociclib compared to physician choice doublet chemotherapy, primary endpoint being PFS. And what we really reassuringly saw again is that giving a CDK4/6 inhibitor is appropriate even in this setting.

So this was a nice data set to really complement what we already know from overall survival in MONALEESA-7. So really you can give CDK4/6 inhibitors to these women.

They also showed data for time to treatment failure. You see almost doubling with ribociclib and the endocrine arm compared to combined chemotherapy here, even for time to treatment failure. No real difference in time to onset of treatment responses between the 2. And very interestingly the dose reduction requirements, or the toxicity data, also were favoring the CDK4/6 inhibitor arm.

So here again talking about toxicity. All grade treatment-related toxicities were lower in the ribociclib arm compared to the combination chemotherapy arm. No new safety signals that were determined in this study, as well, with ribociclib.

This was a very interesting trial that was actually presented today, the SONIA study, and I think the question here was should we be initiating every single patient in the first-line setting with a CDK4/6 inhibitor. Can we give it in the second-line setting? So patients were randomized to AI/CDK4/6, got fulvestrant at the backend, or started with AI alone and got fulvestrant/CDK4/6 at the backend.

Primary endpoint was really PFS2, shown here as PFS1. Again, patients who got CDK4/6 in the first-line and second-line setting the median PFS1 here was 24.7 in first line, 16 months in the second line. No difference in overall survival between the 2 data. And the whole conclusion from this data set was it doesn’t matter when you actually start a CDK4/6 inhibitor, when you do. But I think we can talk a little bit more about whether that’s really appropriate in this day and age with all the overall survival data that we have, and newer combination drugs and drugs that we use in the second line setting. Here it was only fulvestrant, so we’ll talk a little bit more about that.

PALMIRA was an interesting study looking at should we be rechallenging patients with continuation of the same CDK4/6 inhibitor if they progressed on a prior CDK4/6 inhibitor. So these patients started with AI/CDK4/6 inhibition, or in this case fulvestrant or letrozole with palbociclib or got single-agent endocrine therapy along. It was 2:1 randomization. And what you see is when you’re continuing this you don’t necessarily see a difference by continuing palbociclib in this patient population compared to single-agent endocrine therapy.

This is similar to what we saw with the PACE trial as well, where continuation of palbociclib and just switching out the endocrine partner to fulvestrant did not make a difference. And in contrast Dr Kalinsky presented data on MAINTAIN, which actually showed when you switch both the endocrine therapy partner and the CDK4/6, in that case to ribociclib, there was a statistically significant difference seen.

We also have data for the EMERALD trial. This is a novel agent, elacestrant, an oral SERD which is now approved for patients with ESR1 mutations that are harbored in tumors. So this was a study looking at ER-positive tumors that would have received no more than 2 lines of endocrine therapy, had to have received a CDK4/6 inhibitor. One line of chemotherapy was permitted. Patients were randomized to elacestrant alone versus physician choice endocrine therapy. Coprimary endpoints of PFS for all comers and PFS in mutant ESR1 tumors as well.

These are the data on your left for PFS in all patients, on your right with those tumors harboring ESR1 mutations. And really what you see is that the progression-free rate at 6 months and 12 months both favor elacestrant compared to physician choice endocrine therapy. And they in fact showed interesting analysis, when looking at fulvestrant, which was 70% of the physician choice endocrine therapy arm, and again similar results were noted.

But the signal in ESR1 mutation was more pronounced, doubling of PFS from really 1.9 months to 3.8, and that’s where this drug is now currently approved for patients whose tumors harbor ESR1 mutations.

Interesting exploratory analyses was presented at San Antonio by Virginia Kaklamani from this study trying to identify who might be that patient who might most benefit with the single-agent approach. And here we looked at duration of CDK4/6 inhibitor in the first-line setting, and for those patients who stayed on a first-line CDK4/6 inhibitor beyond the 12-month timepoint you see single-agent elacestrant gives you 8.6 months if you also harbor an ESR1 mutation. So very interesting data there as well.

With respect to safety, I think it’s reassuring to see that most AEs were Grade 1 or 2. Very low-grade nausea that was common in both treatment arms, and no severe toxicities that were seen with elacestrant use.

What about PARP inhibitors? So I think when we have germline BRCA mutations in hormone receptor positive, about 4-5%, we have data from both the OlympiAD trial and the EMBRACA studies for olaparib and talazoparib respectively where we’ve seen a statistically significant improvement in progression-free survival, which his really our standard of care in the metastatic setting.

And beyond that we’re now trying to address if we can expand this label even further in those patients whose tumors have somatic BRCA mutations or germline PALB2 mutations as well. So this is the TBCRC 048 trial. Nadine Tung has already published that in the JCO. We’re further expanding these cohorts, Cohort 1 looking at germline mutations, including germline PALB2. You see 80% response rates in the study presented thus far, and somatic BRCA1 or 2 mutations in Cohort 2, where we also saw 50% overall response rates. So really with more data hopefully we can get approval for olaparib in this setting as well.

When patients are now progressing with endocrine — tumors are progressing with endocrine-based regimens and are more endocrine refractory we have antibody-drug conjugates. This is the DESTINY 04 trial which randomized patients to T-DXd versus physician choice.

This was patients who have had at least 1 line of chemo in the metastatic setting, no more than 2, and the primary endpoint was PFS here. 60% were HER2 1+, so these are HER2-low tumors. 40% were HER2 2+ that are FISH not amplified. Predominantly HR positive, which is the natural prevalence of this HER2-low entity.

These patients had 2 prior lines of endocrine therapy, and 70% had prior CDK4/6 inhibitor. And you see a doubling of PFS from 5.4 months to 10 months in the HR-positive group, shown on your left. Same results, with all patients shown on your right. Again, median 1 prior line of chemo 70%, prior CDK4/6. We again saw unprecedented overall survival benefit, improvement from 18 months to 24 months, favoring T-DXd here.

With respect to ILD, we do see an ILD signal. I think this is not showing up really appropriately here. There was 12% incidence of any grade ILD. Fortunately, the incidence of ILD is something that we are now being aware of and taking treatment interventions soon enough so that we can try and keep a close eye on that. But the FDA has approved this, and this is our current standard of care for HER2-low patients.

We have data for TROP2 ADCs with sacituzumab govitecan, which is an antibody-drug conjugate. Again, similar payload, topoisomerase I. And here from initial Phase I studies with good response rate. We designed the TROP2 — the TROPiCS-02 study, which looked at heavily pretreated patients where patients were randomized to sacituzumab versus physician choice chemo. These are progression-free survival benefits.

98% had prior CDK4/6, median 3 prior lines of chemo, so really pretreated patients. And while there was modest benefit from 4 months to 5.5 months favoring sacituzumab, which was statistically significant, we see that at landmark analyses 3 times more patients were progression free at the 12-month timepoint compared to the standard of care arm.

With overall survival now with interim analyses that Hope Rugo presented actually we see a 3-month improvement, statistically significant, favoring sacituzumab even in this pretreated patient population, making this a very attractive option for our patients who are heavily pretreated.

DR LOVE: So a couple of follow-up questions before we go to the next topic. Ian, this is like a memory thing if you can remember all 3 of these things. Any current role for abema monotherapy, tolerability of elacestrant in your own hands, and what about CDK after CDK if they had prior adjuvant a couple years ago?

There you go. Let’s start out —

DR KROP: It’s been a long conference.

DR LOVE: Too many things going on in your head.

DR KROP: So single-agent abema, there are data to say that it’s active. I just don’t — I can’t think of a situation where I wouldn’t include an endocrine therapy. I don’t see there’s any downside to adding endocrine therapy, so I don’t — I can’t remember ever using single agent.

DR LOVE: We were talking about abema in prostate. Now it’s being studied in prostate, incidentally. They’re super interested in it. All of these things you’re trying they’re trying in prostate too, even capi. Sorry, please continue.

Tolerability of elacestrant.

DR KROP: Yeah. I actually haven’t used it yet in my clinic. As was said, based on the data that’s been published it looks reasonable well tolerated. Whether it’s better tolerated than fulvestrant I don’t think anything is better tolerated than fulvestrant. Other than the soreness from giving the injection it’s a remarkably well tolerated drug. But it certainly seems like it’s a drug that we’ll be able to use without a problem in the clinic.

DR LOVE: So what about CDK after CDK if somebody had it adjuvantly a couple years ago and it was stopped?

DR KROP: Yeah. I mean we don’t have a lot of data there, but I think just as we were talking about with the patients who get adjuvant T-DM1. And we all, I think, are using just kind of common sense until we have data, and if it’s been a reasonable amount of time since they had their adjuvant treatment I think knowing the overall benefits of CDK4/6 inhibitors I would reuse it in the metastatic setting.

DR LOVE: So Joyce, we were talking a lot about PARP inhibitors the other night with prostate cancer. They just got a new approval moving olaparib up even earlier. But one of the issues there is — Komal was talking about in terms of what kind of somatic mutation. So we know in ovary, and it looks like the same thing in prostate, that somatic BRCA patients respond as well as germline BRCA, but yet when you’re looking in the adjuvant setting you don’t have NGS. So are you sending it?

DR O'SHAUGHNESSY: No, not in the adjuvant setting, just germline BRCA1 or 2 in the germline setting. However, I’ve polled some of my colleagues, my expert colleagues, about germline PALB2 for a high-risk individual in the adjuvant setting. I haven’t done it yet, but my colleagues have been doing it, so I’m probably going to go ahead and do that for the next time.

DR LOVE: Yeah. The prostate people call PALB2 BRCA3.

DR O'SHAUGHNESSY: Right, right.

Selection of therapy for ER-positive metastatic breast cancer progressing on a CDK4/6 inhibitor; future role of capivasertib

DR LOVE: All right. Let’s go on because we want to hear about the new therapies and what to do about that. So here’s some thoughts from the faculty.

So second-line endocrine therapy after a CDK inhibitor. It seems like PI3 status and ESR1 status are going to be 2 things you want to know. Given those 2 variables which ways do you go? And also would that change if capi were available?

DR TRAINA: Right. Oh my gosh. So great. This is something I’ve been thinking about quite a bit because the space is getting really crowded.

You’re absolutely right. I reflexively need to know PI3 kinase status and ESR1.

For those patients who have a PI3-kinase wild type and ESR1 mutation we have data from the elacestrant EMERALD trial that compared the oral SERD to standard of care single-agent endocrine therapy. We know elacestrant was superior in that setting.

For patients who have a PI3-kinase mutation and are ESR1 wild type I would fall back on our data from SOLAR-1 for fulvestrant with alpelisib, using the PI3-kinase inhibitor in those that have the biomarker.

And then in patients who have both alterations, PI3-kinase mutation, ESR1 mutation, we have 2 different options here at least.

DR TRAINA: And you mentioned finally that we see capivasertib on the horizon. We see exciting data from the AKT inhibitor, and we’ll need to see whether that indication is linked to a biomarker or if it will be to the overall intention to treat population.

I think that the easiest place to introduce it would be in those patients that lack a biomarker altogether so far, PI3-kinase wild type and ESR1 wild type.

DR LOVE: So first of all, anybody here use elacestrant? So Joyce, what’s your experience in terms of tolerability?

DR O'SHAUGHNESSY: So far, so good. What’s nice is that the nausea can be mitigated with taking it with food. So that’s important. Secondly, there’s no drug/drug interaction with your proton pump inhibitor. A lot of people have dyspepsia, so that they can take their PPI, and that will help GI as well. So far, so good.

DR LOVE: So Peter, let’s get back to second-line therapy after CDK. First of all, again, I’m going to bring up do you want to see NGS.

PROF SCHMID: I think NGS is helpful because you ultimately — you have patients on combination endocrine therapy, and you want to know which part of that treatment is possibly failing. And if you see an ESR1 mutation emerging that suggests that the endocrine backbone isn’t doing its job. So that would be a possible scenario where you just switch the endocrine backbone. The data are not conclusive at this point in time, but clearly we know that SERD compounds are superior to aromatase inhibitors in patients with ESR1 mutations.

On the other hand, we have targeted drugs in the PI3K-AKT pathway, and finding or identifying a PIK3CA mutation at that stage I think is also helpful in defining what we do as a second-line treatment strategy. So I think this is the timepoint when you want to do NGS, but ideally from circulating DNA because a lot of these mutations are acquired, subclonal, and best identified from blood rather than from tumor.

DR LOVE: I was thinking also about looking for HRR mutations that you can treat with a PARP inhibitor. Again, you’re not going to see it up front, but do you want to look — you can look for it in metastatic disease.

PROF SCHMID: Absolutely. I mean in terms of obviously BRCA1/BRCA2 somatic mutations the data are a little bit less strong or less clear what we do with somatic mutations at this point, but it’s certainly one of those few indications where we can select the targeted therapy based on NGS. Also HER2 mutations we see in about up to 6% of patients, and there are good data there. Small studies, but with neratinib, for example, that you have single-agent activity in patients with HER2 mutations.

DR LOVE: So Komal, also obviously T-DXd in HER2 mutations, that’s why it’s being given right now, and approved in lung cancer, and “you don’t see it that much in breast cancer”, but if you do will you give T-DXd?

DR JHAVERI: So I’m a little biased. I’ve been an investigator for the SUMMIT trial where we evaluated neratinib with trastuzumab and fulvestrant in HER2 mutant tumors, where we have data that we’ve already shown. It’s now NCCN Category 2B, so I would do that first.

There was a clinical trial that enrolled T-DXd that allowed HER2 mutant solid tumors, and that has a breast cancer cohort. I eagerly await that data. I should see why not if lung cancer had it.

We spoke about HER2 mutations not being that common, but if you think about lobular cancers our data from Memorial Sloan Kettering from our inhouse NGS assay shows the prevalence is 15% in lobular metastatic tumors, so it’s not that trivial. We see it quite often in those tumors, and that’s where we want to think about this. And I’m thinking more about sequentially using them, hopefully, because I’m sure that once we use this it’s not going to work forever, whether I use neratinib as an approach, whether I use T-DXd as an approach. And I’m hoping with more data hopefully I can offer both of these options for these patients.

DR LOVE: Yeah, the lung people, they’re using T-DXd first line. They’re not waiting for any randomization. They see a 50% response rate. They’re bringing it in first line because of their other experience with targeted therapy.

DR JHAVERI: I would be happy to use that as well. I would try neratinib first just because we have more data and it’s NCCN Category 2B at this point.

DR LOVE: Good point. All right, Hope, can you take a shot at trying — your answer to the question I was asking Tiffany, which is kind of like what’s your algorithm and how is it guided by PIK3 and elacestrant.

DR RUGO: Yeah. I think now it’s an interesting question, and a lot of us — I will have to say the caveat is a lot of us have clinical trials so they fit — patients will fit into specific categories in our clinical trials. If the patient has an ESR1 mutation, eligible for the ELEVATE trial, which is looking at elacestrant with a number of different targeted agents. And one of the nice things about that trial also is that elacestrant is being given with alpelisib, so if you have both mutations you can give the drugs together.

DR LOVE: Wow.

DR RUGO: So the trial’s just getting started. It started enrolling just a few months ago. So I think that that’s going to be helpful because we need to know how the oral SERDs perform in combination with our targeted agents. And that’s what, I think, Komal was referring to in this SONIA trial, is that now our second-line options are more combinations with targeted agents.

So I use very much a similar algorithm to what Tiffany mentioned. I think I have a patient on elacestrant as a single agent who doesn’t want to go on a trial, doesn’t tolerate things, had an ESR1 mutation. We’ve used a fair bit of alpelisib, we were part of the investigators of everolimus, and I’ve given CDK after CDK, but I switch. And we even did it before MAINTAIN a little bit because — probably shouldn’t have, but I think that’s — this seems to be generally the approach that people are using.

And what I’ve heard a lot at this meeting is that there is maybe a patient category who get fulvestrant as a single agent in the second-line setting. That would be SONIA like, so then you could wait the CDK4/6 until the second-line setting.

But for most of this situation we’re not really comfortable giving fulvestrant alone. We want to give it with something.

DR LOVE: So what about capi, Hope? How’s that going to fit in your algorithm?

DR RUGO: What about —

DR LOVE: Capivasertib, yeah.

DR RUGO: I’m like what did he say? Sorry. Capivasertib. Well — so as you know, CAPItello-291 showed an improvement in progression-free survival that did go across subsets. I think it’s taught us something, and I’ll show that in a moment, but it says a little bit more about how prior treatment with CDK4/6 inhibitors, as did SONIA, affects your response to next-line therapy.

So we saw survival benefit with the MONALEESA trial in the first-line setting, 2 trials, but we’re still seeing these kind of crummy responses to single-agent endocrine therapy in the second-line setting. Adding capivasertib improved outcomes, the toxicity is manageable, and more manageable in terms of the risk of hyperglycemia for sure than alpelisib. So we’re hopeful that that will get regulatory approval.

The other thing about capivasertib is that there’s some data that it may work for all comers, although I think we’d all like to see the ctDNA data that will come not until next year. So this I think may be a very attractive option for us as we’re looking for further improvements, but the real key is could we give capi/cami.

DR LOVE: Capi/cami.

DR RUGO: So camizestrant being —

DR LOVE: That’s another SERD.

DR RUGO: — the oral SERD from the same company, so that’s a big interest, and a combination that’s being studied.

DR LOVE: So Kevin, it looks like there’s kind of a consensus here, although when I talk to general oncologists alpelisib is still a pretty big challenge for them. Could you see capi being used here instead of alpelisib, Kevin?

DR KALINSKY: I could. In this circumstance I could. I think that in terms of the tolerability of capi we’re still seeing diarrhea. It’s about 70%. You can see hyperglycemia as well. I just think we are having a difficult experience with being able to — for patients to tolerate alpelisib.

So I will also just say there are other PI3K specific inhibitors that are in investigation, Phase III trials, but then I also would keep your eyes on PI3K mutant specific inhibitors like H1047R mutations, where you’re not hitting wild type, so then the hope is that you won’t have the same toxicity profile and will have more exact targeting of the agent. And those are — some of that was reported here at ASCO.

DR LOVE: Ian, any pearls of advice to oncologists trying to use alpelisib? What do you typically see? What do you talk to the patient about ahead of time? And how do these people do in your hands?

DR KROP: So I mean in many patients it can be difficult, and I tell them that there are a decent number of potential adverse events associated with it. I think premedicating with antihistamines helps with the rash, and Hope has done a lot of nice work looking at that. And dealing with the hyperglycemia, having to have discussions about managing that. So again, there’s a decent number of adverse events that really can make it difficult for patients. Even when you are able to treat the rash and the hyperglycemia anorexia can be a really troubling thing for many patients, especially older patients that make it hard to stay on a drug for a long time.

DR LOVE: I see a lot of head-nodding here, again, from the faculty.

Hope, let’s talk about some data.

Faculty presentation: Dr Rugo

DR RUGO: Okay, great. So I’m going to talk about novel investigational strategies. And as we’ve been talking about it, I think that resistance to endocrine therapy and CDK4/6 inhibitors combined is now a big unmet need, and I think that’s what really led some to this — what we just saw in the SONIA trial. We really need to understand what resistances do to try and counter it. And you can see some of these pathways listed here are where the agents are, and you can see CDK4, CDK6. There’s AKT, PI3-kinase, RAS there’s agents for, ERBB2, FGFR1, et cetera.

But let’s talk about some of the agents that we have a little bit of data with, and it’s obviously not comprehensive. So AKT, inhibiting AKT, we’ve been talking about, AKT pathway activation seems to be associated with resistance to endocrine therapy and can occur in patients who are progressing on CDK4/6 inhibitors. They do have a — although they benefit from CDK4/6 inhibitors they have a shorter PFS overall.

Capivasertib is a potent selective inhibitor of AKT, and then the Phase II FAKTION trial showed an improvement in progression-free and overall survival that on further analysis appeared to be limited to patients who had alterations in this AKT pathway.

So CAPItello-291 is a Phase III randomized trial looking at capivasertib or placebo with fulvestrant in patients who’d previously been treated with up to 2 lines of prior endocrine therapy, they could have had 1 line of chemotherapy, and they were allowed to have or not CDK4/6 inhibitors.

You can see the demographics there. About 70% had a prior CDK4/6 inhibitor, a little under 20% prior chemotherapy, and about 70% had visceral metastases. Most patients were treated in the second-line setting.

What you can see here is the altered population. Here about 40% of patients had an alteration. Lower in PIK3CA than we’ve seen in other trials, but combined with AKT1 and PTEN it was about 40%. And then about 60% of patients had unknown status so they were included in the non-altered population.

So the dual primary endpoint was PFS overall and in the AKT pathway altered population. And you can see that this was statistically significant for capivasertib in both the overall population and in the 40% who had AKT pathway alteration, with hazard ratios that were relatively similar, 0.6, and then improving to 0.5 with the altered population.

At ESMO BC Nick Turner presented on behalf of Mafalda Oliveira the subgroups by PFS, and you can see that in all of the subgroups evaluated prior CDK4/6 inhibitor or not, chemo, liver mets at baseline, and in the overall and AKT pathway altered population the capivasertib was better than placebo with fulvestrant.

Now one of the interesting things that we did learn from this data is that if you look at the patients who had liver mets, and they got fulvestrant, their PFS was 1.9 months. So that’s really crummy, and with prior chemotherapy 2.1 months. Even in prior CDK4/6 inhibitors it was only 2.6 months. So we are being able to now select out patients who don’t benefit from our current therapies.

In terms of safety analysis, we presented this data here at ASCO in a poster, and you can see just looking at the discontinuation rates on the right-hand side of the slide you can see they were very low, hyperglycemia 0.3%. The rate of hyperglycemia Grade 3 was only 2% in this trial, and the patients who had hyperglycemia that was more significant had diabetes. Rash 4.5% and diarrhea 2%. And Kevin mentioned the diarrhea rate is 72%, 9% Grade 3, 38% rash. And so it may be that we can really help by improving our supportive care and using non-sedative antihistamines for the rash. And of course we know how to manage diarrhea, and we can dose reduce as well. The on/off nature of capivasertib makes the safety profile a little bit easier to manage, 4 days on, 3 days off.

So we’re waiting to see what the regulatory agencies say about the CAPItello-291 data. In the New England Journal paper, which was published just last week, we had done an early look at the overall survival at the request of the regulatory agency, and this shows a trend towards an improvement in overall survival. Obviously we need mature data. That won’t be until next year.

There are a number of different studies going on trying. Triplets are very popular now to be studied with the oral SERDs, as well as with agents like capivasertib, adding a CDK4/6 inhibitor and endocrine therapy in CAPItello-292. There’s also an ipatasertib study with a similar design. And inavolisib is being studied in a triplet as well.

There are new PIK3CA inhibitors, as Kevin mentioned, both ones that are not mutation specific like inavolisib and RLY-2608, and then these mutant specific, H1047, and all of these appear to be more glucose sparing. LOX783 and a drug from a company called Scorpion, and then there are many others.

So this just shows you the RELAY data that was shown at AACR, where there was a lot of clinical benefit. It wasn’t received well, mainly because they thought they would have great response rates, and they didn’t. But in combination with fulvestrant in a heavily pretreated population you can see that some patients had very long duration of clinical benefit. And they didn’t see hyperglycemia, so 18%, but 0% Grade 3. So we’ll see where that drug goes.

There are many new oral endocrine therapies. Of course we now have elacestrant approved, but there are additional oral SERDs, SERMs, SARMs that work against androgen, SERCAs, PROTACs, and CERANs, so lots of different agents. And I won’t go through them, because I don’t have time, all the mechanisms of action here, but there’s a very nice slide that’s in your handout, so you can look at some of this.

So SERENA is a trial that looked at camizestrant plus fulvestrant, and you can see that camizestrant was studied in 2 arms, 75 and 150 mg. They’re going forward with the 75 mg. But you can see that it was better than fulvestrant, which is in the red arm in this randomized Phase II trial.

There were some imbalances in liver mets in ESR1 mutations because it wasn’t stratified. It was a Phase II trial. So it’s really hypothesis generating to tell us that camizestrant appears to be an effective SERD, and it’s being studied in a number of different settings.

They did look at prior CDK4/6 inhibitors versus not, and it didn’t appear to be effective, but in patients who had no prior CDK4/6 inhibitors less of a benefit. Also in those patients who had ESR1 wild type we didn’t see a benefit as well. Again, hypothesis generating, and more information is really needed. Patients who didn’t have liver metastases also seemed to have a really big benefit from capivasertib — from, sorry, camizestrant, although it was different between the 2 different doses.

Low rate of discontinuation. Fairly well tolerated, with a weird side effect called photopsia, which is flashing lights. It doesn’t seem to bother patients much. There’s some sinus bradycardia, as well, that’s being studied. So there are Phase III trials ongoing.

Imlunestrant that Komal has presented data on. Here’s the Phase Ia/b trial. Also remarkable responses you can see in the little, tiny waterfalls plots there. And then ARV 471, a PROTAC ER degrader, also has remarkable efficacy and is very well tolerated.

So there are a number of Phase III SERD trials. I just showed you the metastatic breast cancer trials, although ARV-417 will be in a Phase III trial too. I think the most different trial is SERENA-6 that’s using ESR1 mutations being discovered in plasma in order to change therapy rather than imaging evidence of progressing.

There are CDK inhibitors in clinical development, some presented here, CDK2 and 4. Very interesting data here, and combination studies that are being done as well. Samuraciclib is a CDK7 inhibitor that we saw data from at San Antonio in 2021. It has efficacy, but it also has toxicity. Diarrhea, as you can see, and nausea and vomiting. In my experience in combination it does have significant GI toxicities.

There are other very interesting investigational endocrine agents, the selective androgen receptor modulator enobosarm, where there was efficacy in patients who had AR-positive, hormone receptor positive, resistant disease. The Phase III ARTEST trial is going on in these patients who need to screen for AR positivity.

The SERM lasofoxifene, very well tolerated. Interesting data on lasofoxifene compared to fulvestrant. It looked a little bit better, and very well tolerated. And then in the phase — there’s a tiny little trial looking at lasofoxifene and abemaciclib, very well tolerated, and a PFS of 14 months.

So there’s the ELAINE III trial that will open this year looking at fulvestrant or lasofoxifene with abemaciclib in 400 patients.

And there’s a little bit of data in alisertib. We’ll see where that goes. It has some toxicities, neutropenia primarily.

Now what about antibody-drug conjugates? We have a new novel TROP2 ADC, datopotamab deruxtecan, called dato-DXd, where there was very nice data presented by Meric-Bernstam at San Antonio. As you can see, the overall response rate is 27%, but clinical benefit rate 44%; very nice progression-free survival.

This drug causes stomatitis, alopecia, and has a very low rate, if any, of pneumonitis. Those patients also had COVID, so it’s unclear. TROPION-Breast01 in the second- and third-line setting has completed accrual, and we expect to see data later this year. So you may see a novel TROP2 ADC with Phase III data in 2023.

And then there are sequencing studies going on that are planned. TBCRC 064 will look at T-DXd and dato-DXd in sequence. And then there’s a registry sequencing study that will also open later this year that will look at sequencing of trastuzumab deruxtecan and sacituzumab in hormone receptor-positive and triple-negative disease.

Patritumab deruxtecan. Data presented by Ian Krop at ASCO last year showed very nice responses irregardless of HER3 expression, as you can see on the right-hand side of the slide, and then there’s an investigator-initiated trial looking at patritumab deruxtecan in hormone receptor positive and triple-negative disease. And that data was presented this afternoon by Erika Hamilton showing nice response rates. And I’ll just take you so you can see the waterfall plot, the spaghetti curves. But if you look just at that little box that looks at overall response you can see in 29 patients with HR-positive disease a response rate of 41%, lower in triple-negative breast cancer. It doesn’t look quite as good, but it was irrespective of HER3 expression.

This drug was well tolerated in this study. A lot of thrombocytopenia in the heavily pretreated group. In this group less heavily pretreated, less thrombocytopenia, which was encouraging, but some nausea, fatigue, et cetera, alopecia.

So very exciting data, I think, with these new agents. And I’ll hand it over to you.

DR LOVE: So just a couple thoughts. Dato, Friday night, the lung people are like this is going to be second-line therapy in non-small cell probably very soon. Patritumab they use in people who get osimertinib, the EGFR blocker, when they progress. For some reason it works.

Another thing I want to ask you about is the PROTACs. Again, I heard that from the prostate people. Are PROTACs like fulvestrant?

DR RUGO: So they actually work quite differently. They block ubiquitination of the estrogen receptor.

DR LOVE: But they get rid of the receptor though, right?

DR RUGO: So they get rid of the receptor by blocking this pathway, ubiquitin. So it’s very cool. It’s a different mechanism than all of the other agents we have. It seems to be very well tolerated. It doesn’t cause the kind of odd like photopsia type things. And it works in a percentage of patients. I mean I have a patient on a Phase I study.

She already progressed on T-DXd, capecitabine, CDK4/6 inhibitor, fulvestrant, AI, and she has been on ARV-471 for a year with resolution of her liver mets. So some of these drugs may really be big homeruns. We’ll see. I mean that’s an N of 1.

DR LOVE: So forgive me if you talked about this, but what about the CDK that targets just CDK4?

DR RUGO: So I had 1 slide on that, with CDK4. There are actually several companies that have developed agents that target CDK4. It appears to be a mechanism of overcoming some of the resistance that’s created by CDK6 with an odd protein, INK4. I learned all about this from Komal on Friday because she discussed those abstracts, and so listen to her discussion on Saturday. And they do seem to have efficacy, and CDK4 in particular has less neutropenia.

DR LOVE: Right.

DR RUGO: So I think it will be really interesting. They are struggling a little bit about where to put the drug, right? It’s a big field now. But maybe in combination with a CDK2 inhibitor, maybe in combination with a CDK4/6 inhibitor you would add CDK4. It’s hard to know yet, but we’ll see a lot of this coming up in the future.

DR LOVE: I’m bringing up a lot of these things because I know there are a lot of people live and on Zoom who follow us through the whole weekend, and there are things that I’ve said, “Oh, I’m going to ask the breast people about.”

I was going to ask you all in the faculty room, but I forgot, but I’m going to ask you now anyhow. So Joyce, we were talking in the bladder session this morning about a HER2 bispecific called zanidatamab. Have you ever heard about that? Is it being looked at in breast? And the other thing is, let me see — oh no, that was in upper GI and biliary. This morning in bladder we were talking about a drug called disitamab vedotin, which actually has the antibodies called hertuzumab, HER-tuzumab. I thought that was kind of cool.

Anyhow, do you know anything about disitamab in breast, anti-HER, and zanidatamab, a bispecific that hits HER2 in 2 places?

DR O'SHAUGHNESSY: Yeah. That’s a biparatopic. It binds to HER2 in 2 separate places, 2 different epitopes, and the ZW25 is just a naked antibody, and ZW49, zani, I think is the ADC with the payload.

DR LOVE: No. It’s an antibody.

DR O'SHAUGHNESSY: This is the antibody.

DR LOVE: Bispecific, yeah.

DR O'SHAUGHNESSY: It looks —

DR LOVE: But not like those CD3 immune bispecifics.

DR O'SHAUGHNESSY: No.

DR LOVE: I think about amivantamab. It’s not hitting the immune thing.

Komal, were you shaking your head? Do you know something about disitamab?

DR JHAVERI: Yeah. So I think both zanidatamab — the ZW25, is the biparatopic antibody. We also have ZW49 which combines the ZW25 antibody portion, but it has like a payload the way we have ADCs. It’s a bispecific ADC, and we presented the data at ESMO last year in a cohort for solid tumors that had breast cancer patients as well. So these were HER2 expressing tumors. And the 1 side effect that has shouted out from that program is keratitis. It’s low grade, but that’s what we see as a signal in terms of ocular toxicity with that molecule.

Disitamab vedotin is a vedotin-based payload. We’ve seen some activity with both HER2 positive and HER2 low. In fact, there’s a registrational Phase III trial in HER2-low metastatic breast cancer that’s currently ongoing. So similar to what we have with T-DXd and DESTINY-04, a similar study design in HER2 low with that molecular that’s currently ongoing. It’s a vedotin-based payload.

Management of localized TNBC; selection of patients for adjuvant olaparib

DR LOVE: I don’t know about you, but my brain’s getting ready to explode here. But okay, let’s keep going and talk about triple-negative disease, and here are some thoughts about localized triple-negative disease, also the issue of adjuvant PARP.

DR TRAINA: For a tumor that is 2 cm or greater or with positive lymph nodes, I would absolutely recommend neoadjuvant therapy and following KEYNOTE-522.

DR LOVE: And how do you approach postoperatively management?

DR TRAINA: For those who have residual disease and lack a germline BRCA mutation I tend to incorporate capecitabine for 6 months.

For those with a germline BRCA mutation, instead of capecitabine I would be inclined to add adjuvant olaparib for 1 year overlapping with completing pembrolizumab.

DR LOVE: I want to flip over to adjuvant olaparib and also ask you, in your experience, what's the likelihood that somebody get through a year of that?

DR TOLANEY: For me, it's very doable because I can deal with the lab abnormalities with a little dose modification for the most part. And the nausea is usually very early on and ondansetron works great and then it usually fades.

And I've never had someone discontinue it early from treatment.

DR LOVE: And right now, what's your criteria to consider adjuvant olaparib?

DR TOLANEY: That's a good question. In a triple-negative patient, I think it's a little more straightforward because it's, if you give preop therapy and they have residual disease, you're going to give olaparib. If they have a Stage II cancer in the adjuvant setting.

I think the ER-positive population is where I struggle a little bit because the criteria in the adjuvant setting where you had to have 4 or more nodes. And that's just really high risk.

And so truthfully, I would think about it even in the patients with fewer nodes, so 1 to 3 positive nodes and have a high genomic assay, a high-grade cancer.

DR LOVE: So a lot to talk about there. Peter, what about localized triple negative; Tiffany’s thoughts about when and how to apply 522?

PROF SCHMID: I think it’s a standard of care for patients with Stage II and Stage III disease, that’s very clear. I think the only modifications we can consider is does everyone need in the future 6 months of neoadjuvant therapy. What about early responders? Can we possibly cut the chemotherapy slightly shorter? And then obviously we have work to do post-surgery in patients with path CR to define how much benefit comes from the adjuvant pembro and in patients with residual disease probably introducing ADCs there to improve the outcome.

So that’s very clear. Stage I disease is probably an area where we need to put a bit of focus on there, and is there a role, for example, for shorter chemotherapy possibly with immune therapy. Is there a role for ADCs with chemotherapy combinations? Those studies are just starting at this point in time.

DR LOVE: Any trials or thoughts of looking at cell-free DNA in people with path CRs?

PROF SCHMID: So I think these are concepts that are at the moment being developed. And again, if you think about Stage II/Stage III disease, if you wanted to de-escalate let’s say halfway through, after carbo/pacle and pembro you have a complete imaging response, imaging response is probably not reliable enough to select patients for reduction in therapy. And if this could be combined with a sensitive cfDNA assay I think that’s an interesting research question.

DR LOVE: So Kevin, any thoughts, again, about the comments about adjuvant olaparib, particularly the bar that we’ve set? This came up a number of times this weekend. To do a trial you put higher-risk patients because you get more events, you get the answer quicker, but does that mean that those are the only people you’re going to treat once you establish the principle, and the question of do you really need to have 4 nodes to think about, you have BRCA germline, to be given olaparib?

DR KALINSKY: Yeah. I really agree with Sara’s sentiments. I think that, as you mentioned, this was really because we were trying to define a very high-risk population and there’d be more events. And so I think that if I could get it paid for then I would think about if a patient had a BRCA mutation think about exposure to adjuvant olaparib. I also — I’m glad Joyce brought up the point about the context of PALB2 mutations, germline PALB2 mutations. I do not suspect that we’ll see an adjuvant study in breast that’s asking the same question that we saw in OlympiA with BRCA mutations. And if I could get that covered, as well, I would do the same thing.

DR LOVE: And it’s kind of interesting. Just seeing that comment, again, from Sara about her perception that it’s so easy to get through olaparib, and then I reflect back on when we talk about it in ovary and how much — we hear about a lot of issues, and I wonder if it’s because they’ve had major surgery in their belly prior to getting it. It makes a big difference compared to breast.

Komal, you had a thought?

DR JHAVERI: Yeah, no. I was talking to Mark Robson about this because we all get that same sentiment when we have young patients and want to offer them the right therapies. I think 1 of the thought processes behind choosing this very high-risk patient population was to mitigate the risk for MDS or AML that we potentially suspect with the PARP inhibitors.

And so when the study was being designed I think one of ideas was should we try to focus it on the very high-risk patient population just because of that risk. And fortunately at least the risk that has emerged out from the data set that we have from the OlympiA study does not seem to have a very high rate of MDS or AML from PARP inhibitors, and that gave us some comfort. So I think I agree that if I can get that covered by the insurance I’d be willing to offer it beyond more than 4 positive nodes or residual disease with a CPS+EG score of 3 or higher, which is very complicated to get to.

PARP inhibitor tolerability

DR LOVE: So I want to hear a little bit more about what happens when you put people on PARP inhibitors whether in the adjuvant or metastatic setting. Here’s some thoughts from the faculty.

What has been your experience using PARP inhibitors in general in terms of tolerability/toxicity?

DR TRAINA: We saw a high degree of anemia in the clinical trials, although in my practice I haven’t observed that I’m happy to say. Certainly some low-grade upper GI, nausea, which we can make sure we educate our patients about and provide antiemetics for. And I would say fatigue is probably the other adverse event, which is tough to tease out in these women who likely have just completed adjuvant or neoadjuvant chemotherapy may have entered into menopause as a result of therapy and then are also getting the PARP inhibitor. It’s difficult to tease out what’s the cause of that fatigue, but it is a common adverse event that I hear.

DR LOVE: Do you use pre-emptive GI meds or you just see how they do?

DR TRAINA: I make sure that they have a prescription in hand, a bottle in the house. I feel a lot better with them being prepared just in case, but I don’t necessarily have them prophylaxing.

DR LOVE: If you're going to use adjuvant olaparib, do you bring up to the patient the potential for MDS and AML?

DR HURVITZ: It just hasn't been reported really in breast cancer. So I do now mention that there is this theoretical concern and may have been seen in other tumor types, but we really haven't observed it with breast.

DR LOVE: So Hope, I’m curious about what you say to your fellows about using PARP inhibitors, both practical issues in terms of symptoms, also long-term issues like AML/MDS.

DR RUGO: Well, in the OlympiA trial patients didn’t — there wasn’t an increased risk over the population, so I think some of it may have to do with the fact that we’re not giving leukemogenic — so much in the way of leukemogenic drugs, and I think you may be able to enhance that effect more if you were giving a lot of etoposide, for example.

But in terms of side effects, I’ve seen like enormously variable side effects. Some women do fine. Some women get headaches or nausea or fatigue. These are the different kinds of things.

Recently I haven’t seen as much anemia as we saw in the metastatic setting, I think mainly because we were treating people later in the course of their treatment. But anemia was reported in a number of patients, a few who needed transfusions in the OlympiA trial, so it’s definitely something you really need to watch out for. But if patients don’t get anemia early they don’t get it late. So it’s an effect that either happens or doesn’t.

So we talk about that. We talk about it with the patients also. I’ve dose reduced a few patients who needed dose reductions because of nausea. I use a lot of olanzapine for patients, low-dose olanzapine, and generally I haven’t had anybody discontinue at all for toxicity.

DR LOVE: It’s interesting, in ovary in the first report that came out the MDS rate was — in the trial that was reported was like 8%, and everybody’s like 8%. But it was very late, they’d had a ton of chemo. And the control arm had 4%.

DR RUGO: Yeah.

DR LOVE: And then when they started using it early they didn’t see it, just the way you’re not seeing it. So maybe it’s the chemo prior to that time that’s maybe interacting that. In any event, it looks like most of you at least bring it up. People go on the internet, and they’re going to read about it, but it’s maybe worth bringing up to head off any anxiety.

So Joyce, let’s talk a little bit about how you think through localized triple negative and particularly what the data is behind it.

Faculty presentation: Dr O’Shaughnessy

DR O'SHAUGHNESSY: Sure. Okay. So we have Peter here, and I’ll tell you all about his data here, the KEYNOTE-522 that’s been updated now. I totally agree this is the standard of care as it was in KEYNOTE-522 for Stage II/III patients. Preoperative carboplatin either AUC of 5 every — yeah, AUC 5 — is it 5 — yeah — every 3 weeks, yes, or 1.5 weekly with paclitaxel followed by AC or EC with either placebo or pembrolizumab every 3 weeks, 200 mg, and then surgery, and then finishing up placebo or pembrolizumab for 6 months, with the coprimary endpoints of path CR and event-free survival.

And at the interim analysis 1, which was the primary endpoint for path CR, there was a 14% improvement in path CR. You see that number there, about 65%. That’s a very good path CR, and it’s regardless of PD-L1 status. Better prognosis with PD-L1 positive patients, but we don’t have to look for PD-L1 in the early-stage setting because pembrolizumab works differentially whether you’re PD-L1-positive or -negative.

And then what really led to FDA approval and the standard of care was this 7.7% absolute improvement in event-free survival at 3 years, with a hazard rate of 0.63, which is highly statistically significantly positive.

Patients who got a path CR from — more got path CR with the addition of pembrolizumab, but if you got a path CR you did very, very well regardless. And there’s good news and bad news in the no path CR. The good news is that there’s a substantial improvement in event-free survival even if you don’t get a path CR with the pembrolizumab, but the bad news is we still have one third of patients recurring at 3 years. We have to do a lot, lot better for those patients.

So we have to tell our patients about the 15% chance of permanent hypothyroidism, a very small, 1% of permanent adrenal insufficiency, 1% risk of hypophysitis, and then the more reversible colitis, hepatitis, and pneumonitis, and I always throw in the very rare permanent insulin-dependent diabetes as well. So we do need — there were deaths of pneumonitis and encephalitis, autoimmune encephalitis, on this trial. So we have to be very well aware of that and discuss that with patients.

So not everybody can take doxorubicin, and this is the NeoPACT trial from Priyanka Sharma, presented at ASCO last year. And some of our patients have had 2 primaries or they just are not candidates for doxorubicin. And this was 6 cycles of carboplatin AUC of 6, docetaxel 75, and pembrolizumab preoperatively, surgery, and then no adjuvant therapy afterwards because KEYNOTE-522 wasn’t standard at that time, Stage I to III, and 16% of patients had ER/PR-low disease, 10% or less.

And the primary endpoint was pathologic complete response, which you can see down at the bottom under primary endpoint, I have a mouse, right here, 58% path CR rate. And be careful here — whoops — on the node negative/node positive. It looks kind of low on node positive, but these patients had to be biopsy-positive, node-positive, unlike KEYNOTE-522, which was clinical node-positive.

And the 2-year event-free survival rate in patients with a path CR and without a path CR are tracking very, very well as to where KEYNOTE-522 was at this time. So cross-trial comparison, small trial, 115 patients, but it looks encouraging that the path CR rate is in the same ballpark, and the 2-year event-free survival data are in the same ballpark as KEYNOTE-522. And I’ll tell you the follow-up on that here in a second.

So at ESMO Breast there was an update on the IMpassion031 trial with preoperative atezolizumab, the anti-PD-L1 antibody, in Stage II/III TNBC patients. Now this was nab-paclitaxel 125 per meter followed by dose-dense AC with placebo or atezolizumab then surgery then finishing up the year of atezolizumab. 333 patients with path CR. Primary endpoint in intent-to-treat and PD-L1-positive population. And a nice delta on path CR you’ll see in all comers over on the left, and again regardless of PD-L1 status.

And the new data at ESMO breast was a numerical improvement in event-free survival, not statistically significant. This is a small trial but looks encouraging here. So this is encouraging but not practice changing. Unfortunately, with atezolizumab in the adjuvant setting there was a press release, the Data Monitoring Safety Committee basically said it was futile with regard to invasive disease-free survival in IMpassion030, 2,300 Stage II/III TNBC patients, half node negative, half node positive, paclitaxel followed by AC with atezolizumab or not, and then atezo afterwards, and that was futile, unfortunately, in the adjuvant setting. So we don’t want to be using this in the adjuvant setting.

But we await the results of the NSABP B59, the GeparDouze trial, which is a parallel study to KEYNOTE-522, 1,520 patients, Stage II/III patients, paclitaxel/carboplatin, and here the carbo’s every 3 weeks, not the choice that we had in 522, followed by AC or EC with placebo or with atezolizumab, and then surgery, and then finishing up the year. So this will be a very important trial that we await the data for.

So I’m focusing on triple-negative breast cancer. Who should be tested for BRCA1 mutations? The NCCN Guidelines say TNBC histology, so that makes it easy for us to test all of our TNBC patients. I won’t belabor this because we just heard this from, I think it was Komal, but this is the — focusing on the TNBC population, as was said, no path CR is all you need if you’re a germline BRCA1 or 2 or Stage II disease, 300 mg BID versus placebo for 1 year, invasive disease-free survival. Most of the patients, 80%, were triple negative. Most were BRCA1. Most were premenopausal.

And the data we saw, an 8.8% absolute improvement in invasive disease-free survival, and the hazard of 0.58, very, very good. And then a 3.4% absolute improvement in overall survival. Unusual to see overall survival so early in the course of disease, so this is very encouraging here with this hazard rate of 0.68.

We just talked about the toxicity, and indeed 5.8% of patients did need a transfusion with the olaparib, and it was any grade 23%, 8.7% Grade 3. Here is the nausea here. Totally agree, it really does tachyphylax and go away. And about 10% of patients discontinued due to an AE, 25% had a dose reduction.

And here are the data we were just discussing. No increase at all in MDS/AML over what was seen in the placebo group, and these patients had had prior chemotherapy. So that was very, very encouraging.

And so we just talked about this, but I totally agree, Stage II/III patients, that’s the KEYNOTE-522, and I’d do the same that Tiffany mentioned, add the capecitabine or the olaparib if patients are not a path CR, T1a/T1b, surgery first, then chemotherapy, either the NeoSTOP regimen of docetaxel/carboplatin for 4 to 6 cycles or possibly Tc.

I think, as Peter said, we have a little bit more work to do in the Stage I patients. Do we do an AC-T preoperatively, a taxane/platinum, et cetera? And I tend to try to go with a taxane/platinum, the docetaxel/carboplatin, NeoSTOP and see if I can de-escalate therapy if patients do very, very well, knowing they could always get AC in the adjuvant setting.

Upcoming is the SCARLET trial from SWOG where the KEYNOTE-522 regimen will be compared to the NeoPACT regimen with the docetaxel, carboplatin, and pembrolizumab trying to de-escalate that chemotherapy in Stage II/III patients. And then the OptimICE trial from Alliance for patients who do get a path CR with the KEYNOTE-522 regimen randomized to stop the pembrolizumab at surgery or to continue for the standard year.

And then thankfully there are some trials going on to do better than capecitabine for patients who have residual disease. In the ASCENT-05 patients — trial patients will get 8 cycles of sacituzumab if they have residual disease with triple-negative breast cancer or they’ll get pembrolizumab with or without capecitabine, physician’s choice, with iDFS.

And then we have the TROPION-Breast03, again, for patients with triple-negative breast cancer, residual disease. It is the pembrolizumab. If they got pembro preoperatively with capecitabine or pembro along or capecitabine alone, if they didn’t get pembro preoperatively with the datopotamab and durvalumab versus datopotamab alone, the other TROP2-directed topo I isomerase antibody. Very, very promising.

So in summary, preoperative chemotherapy/pembrolizumab is standard of care for Stage II/III. There are some very high-risk patients that we should give a short course of chemotherapy/pembrolizumab to. I don’t think we know yet. It’s not standard. The SCARLET trial, very, very interesting to try to de-escalate the chemotherapy. So important that we are bringing these very powerful topo I inhibitor antibodies into the adjuvant setting, and we sure need novel biologic understanding and therapeutic strategies for RCB 2/3 patients who don’t have a great response with our current therapies.

DR LOVE: You getting all this, Gary? Gary Steinecker. We’ve been in this room for like the last 15 years, and he always has a box seat and just sits here the whole weekend.

So Joyce, we hear about reversion mutations in people who progress on PARP inhibitors. Do you know anything about that?

DR O'SHAUGHNESSY: Yes, you do see them commonly, unfortunately. It seems to be a real mechanism of resistance, and of course that’s been very well described in ovarian cancer. You see it in the metastatic setting, and they sometimes on the ctDNA test that we send they will call out that there’s a reversion mutation.

DR LOVE: So Kevin, first of all, we were working with your colleague Ticiana Leal Friday night. She is giving tomorrow a presentation that the lung people are like holding their breath on, Phase III second-line therapy of tumor-treating fields for lung cancer. Positive survival. We don’t know what the hazard rate is. Everybody’s just holding their breath.

But anyhow, I want to get back — I was thinking — I got triggered when I saw Joyce talking about carbo — of the biggest question I’m being asked all weekend, like what do you do if you can’t access it? What’s going on there at Emory? Can you get carbo? Sarah Cannon ran out of carbo the other day. It’s not just the community. I see everybody shaking their head. Like what do you do for neoadjuvant therapy in HER2 if you don’t have carbo?

DR KALINSKY: Yeah. So we are just now — we are now facing this issue. We were secluded from it for just a bit, but some of my community colleagues have already not been able to get any carbo. So what I would say in the context of triple-negative breast cancer we’ve talked about maybe doing something that’s similar to the I-SPY regimen where patients receive paclitaxel/pembro and then went on to get AC. In I-SPY that rate was similar to what we — because there’s this question of whether we fully escalate it now, and our patients really need to get all of the therapies that we’re giving in the neoadjuvant setting.

In this particular context I would do something a little bit different than what happened with I-SPY, meaning I would continue the pembro along with the AC, along with what was done in KEYNOTE-522.

I will also say in terms of HER2-positive breast cancer we’ve dropped the dose of the carbo just a little bit, and we’ll see if that helps with the shortage. For colleagues who do not have any access to carboplatin we’ve talked about things like giving paclitaxel/trastuzumab/pertuzumab or giving docetaxel/trastuzumab/pertuzumab. There’s an ongoing study that’s looking at neoadjuvant THP that’s being run within the NCTN as we speak, so it feels like right now there’s some equipoise just in terms of asking the question.

So while we’re facing this platinum shortage those are some ways that we’ve talked about mitigating some of that.

DR LOVE: So Hope, yeah. This came up this morning with bladder, and cis also is an issue, cisplatin. So any thoughts?

DR RUGO: And actually hydrocortisone, or IV hydrocortisone is gone, right? There’s none. And it’s really interesting what’s actually creating this. It has something to do with production not meeting FDA guidance, and then these are generics, and so people are just making the money to redo things. But it’s hoped that the cisplatin shortage will be over very soon, and carboplatin will come after.

But in the meantime ASCO has endorsed the GYN Society’s guidelines for alternative approaches to lack of platinum salts. I’m on this little advisory group where we’re creating. And then part of the advisory group are creating loose guidelines for all of the different diseases where platinum is used, and breast cancer will I think come out in the next week. And the same, right? You said THP, now trastuzumab, pertuzumab, and a taxane for patients who have HER2-positive disease.

And for triple-negative disease, where it’s a really big issue because we’ve seen improvement in overall survival with the addition of platinum to neoadjuvant therapy, we actually don’t know how much platinum adds if you also are getting pembrolizumab. So in that situation you might not give the pembro — not give the carbo, but you would have some rescue strategy. And we didn’t feel comfortable substituting cisplatin as a routine because of the really permanent and long toxicities, and we don’t even know what dose to use. But it’s a big issue.

DR LOVE: Komal, any thoughts?

DR JHAVERI: I would be okay with using AC-THP in my high-risk patients. I don’t think we shy away completely from that. I know we are all trying to have more and more data, and we’re trying to shy away from anthracyclines whenever possible because we have a body of data. But I think for the high-risk patients I’m very comfortable offering them AC-THP, especially when we don’t have carboplatin available.

DR RUGO: And you shouldn’t give an AUC of 6 right now. I think that’s a really important point. Like giving AUC of 5 or 4 is a better approach.

DR LOVE: Yeah. We were talking about the BCG with non-muscle invasive, and like they’re not using maintenance so they have more to use up front. I mean that’s been out there for a while though.

Selection of therapy for triple-negative metastatic breast cancer; sequencing of trastuzumab deruxtecan in ER-negative, HER2-low disease

DR LOVE: All right. Let’s talk about triple-negative metastatic disease. Peter, you’re going to go through some of the data. Here’s some thoughts about an important issue, the use of T-DXd in ER-negative, HER2-low disease.

Let’s talk about PD-1 levels and BRCA in the metastatic setting. How do you determine first-line therapy?

DR TRAINA: So you raise a really great point, that those 2 biomarkers are critical to start to strategize a first-line approach.

So in the setting of germline wild type, PD-L1 positive, we have KEYNOTE-355 that established pembrolizumab with first-line chemotherapy.

For the patient who has a germline BRCA mutation and absence of PD-L1, or PD-L1 negative, then my inclination is to lead with a PARP inhibitor. We have either olaparib or talazoparib in that setting.

DR LOVE: What about second-line therapy?

DR TRAINA: We need to be precise about HER2 status and look for those patients who have HER2-low breast cancer, 1+ or 2+, FISH nonamplified.

I would tend to think about sacituzumab or T-DXd if HER2 low, often leading with sacituzumab and then following with T-DXd.

DR LOVE: Are there really people who are HER2 0 that you will not give T-DXd to?

DR HURVITZ: No and you know what, Neil, if you look back in a patient's chart and path reports, because usually they have like the core biopsy, the breast sample, and a couple of tumor samples along the way, chances are you're going to see a 1+ in there.

It's rare that you have a patient whose IHC has always been 0. The concordance among pathologists for 0 and 1+ is really low, like 75% of the time they don't agree. So you could even send it for a path's second opinion and yes, we do see from the DAISY trial that about a third of patients with HER2 0 respond to T-DXd. So if we're in a bad situation, I wouldn't be against giving T-DXd.

DR LOVE: So Ian, any thoughts about that? Even if you’re HER2 0 I think you can still have some HER2 there, right? So like is there a situation where you wouldn’t try T-DXd?

DR KROP: Yeah. I mean I think in general for the triple-negative metastatic patients I tend to use sacituzumab first. Of course we don’t have data on that type of sequence of ADCs, but again, I think if you’re running out of other options using T-DXd after saci is very reasonable, and certainly I’ve done it. And there are now some studies, as Hope pointed out, that are starting to try to look at sequential ADCs. I think this issue of HER2-low testing in both triple negative and ER positive is just a mess.

I mean the bottom line is the test isn’t designed to separate zeros to ones. And as was shown in a very nice data set that was presented today at the conference, if you keep repeating your test you’re going to hit, just by I think, really random chance, you’re going to get a 1. So it’s almost like why bother, just treat everybody like was talked about. I haven’t done that yet. I’m still waiting for that 1, but I think the data are starting to become more and more clear that it’s not really worthwhile, and we need a better test.

DR LOVE: So Peter, I’m curious about your approach. First of all, which comes first, sacituzumab or T-DXd with HER2 low? And any thoughts also about — I mean of course we ask this of everybody, better predictors of benefit from IOs, from immunotherapy, going beyond PD-1 and TMB anything out there that looks exciting to you?

PROF SCHMID: I think first of all it’s super exciting that we have now ADCs coming into TNBC that drive a really high response rate. This is, for me, the number 1 thing that excites me about the ADCs, responses in the range of 30% or higher. That was unheard of in a second/third-line setting in TNBC.

How we sequence those drugs, that’s something we can work out in the future. And I think at the moment we have slightly more data for sacituzumab, so it’s probably — most people probably feel that’s the drug we use a little bit earlier compared to the 58 patients we treated with T-DXd. But both drugs are highly effective.

I’m intrigued by the possible combination with IO drugs, and we’ve got data in the slide set. If you think about first-line setting from KEYNOTE-355, taxane or gem/carbo plus pembro in PD-L1-negative patients, it had a response rate of around 40 to 45%. In this same group of patients if you used dato-DXd, one of those ADCs, together with immune checkpoint inhibitor, 87% of those patients were PD-L1 negative, the objective responses were 80%. That’s an unheard response rate. High activity there.

And that suggests that we need to look into whether our biomarker selection strategy that’s very clear for chemotherapy and immune therapy, with the benefit being limited to PD-L1-positive patients, whether that’s still the case when we treat with ADCs. So in other words can we, by combining ADCs with immune checkpoint inhibitors, possibly widen the indication for immune checkpoint inhibitors and have some benefit in PD-L1-negative patients. That’s a completely open question, and that’s something we need to look into in trials.

DR LOVE: So yeah, as I mentioned an ADC and IO just got approved first line in bladder cancer, enfortumab vedotin plus pembro.

I’m curious also, Komal, a number of people are in equipoise about choice of a PARP inhibitor, olaparib versus talazoparib, but several of you prefer olaparib. Why do you, Komal?

DR JHAVERI: I think it’s just the first kid on the block and the ease of use, and I think the toxicity profile that we see with olaparib. We were talking about — our colleagues talking about some low-grade nausea, maybe some fatigue. It seems like a little more easier from the perspective. I think the anemia that we saw, we saw a little bit more with the talazoparib compound. But I think it was just what was available first, how we got comfortable utilizing that. We know both are active, both have efficacy. It’s the comfort of what we got first and used first.

DR LOVE: Yeah. There was just a big prostate trial that was positive for talazoparib so now they’re trying to figure that out.

Do you see hair loss with that incidentally, talazoparib? Because I heard that in the beginning, and then I stopped hearing it. Hope? No?

DR RUGO: No.

DR JHAVERI: I haven’t seen it.

DR LOVE: All right. Well, let’s — actually, let’s go to Peter’s talk. Maybe we’ll come back and talk about some of these issues. Here’s HER2 0 we were just talking about. So Peter, let’s talk about reprogramming the options in triple-negative.

Faculty presentation: Prof Schmid

PROF SCHMID: Yeah. If we just go back 5 years the treatment options we had in metastatic triple-negative breast cancer were fairly limited. We’ve seen and we’ve discussed in the early disease setting we really had to shift away from primary surgery to primary chemotherapy. But when it came to the metastatic setting, we have taxanes, we have platinum in the first-line setting. We then have maybe eribulin in the second-line setting, and often we’re running out of effective options in the third-line setting. And it’s difficult to remember, but the median overall survival at that time was only around 12 to 15 months for patients with metastatic TNBC.

And part of it is, we’re all aware, it’s down to the heterogeneity of TNBC. We’ve looked, and we keep looking at these gene expressions, sometimes which have been really interesting in sharpening our understanding of the biology of triple-negative breast cancer. But therapeutically I don’t think they are going to play a role. Therapeutically we are moving towards therapeutic strategies, IO, PARP inhibitors, ADCs to mention the 3 frontrunners in there. And each of those strategies has either a defined target population or a defined target, although we can discuss, obviously, how we are widening those target population as we go forward.

What is really important the ADCs we’re using now with novel technology is no longer dependent on targeting the oncogenic driver, and that was one of the big problems in TNBC, we didn’t really have oncogenic drivers. But now with novel ADC technology you just use the surface protein as an anchor, and therefore we will see a lot of new ADCs coming through in TNBC.

The second point probably to make is if you look at those different target population subgroups they’re overlapping. You can be PD-1 positive with a BRCA germline mutation, TROP2 high, HER2 low, HER3 positive and have an androgen receptor. And I think in the future we just have to classify patients accordingly, and then you can all decide which treatment to choose in which order.

We have already looked at the data. PARP inhibitors obviously clear benefit, although slightly disappointing PFS, in my opinion, in those studies. What’s really interesting, we see the benefit in first-, second-, and third-line setting. We see high response rate, again, maintained in first-, second-, and third-line setting. So it doesn’t have to be that a PARP inhibitor is given in the first-line setting.

And we also know that there isn’t a clear survival benefit with this strategy. If we’re only speaking about widening the target indication to non-BRCA germline mutations, in particular PALB2, where we see high activity, but also to somatic mutations, and I think there’s a little bit more work required to move this forward.

If you look at the immune therapy strategies in PD-L1 positive patients we’ve got 2 trials. Both trials actually show remarkably similar data regardless, and we can discuss the specifics of the statistical analysis plan. But if you look at the hazard ratio, 0.67 and 0.73 between the 2 different strategies, we have pembrolizumab and atezolizumab, very remarkably similar data. Both providing a benefit only in patients with PD-L1-positive tumors, and that’s defined as SP142 with 1% or higher or CPS with 10 or higher.

We also see obviously a clear benefit in PFS, and again only in PD-L1-positive patients, not in PD-1-negative patients.

A question that remains open is who benefits most from immune therapy. And there’s often confusion around those 2 assays that are being used. Now just to highlight this, if you use the 22C3 antibody CPS with a cutoff of 1 you have 80% of patients being PD-L1 positive. If you use the SP142 assay with a cutoff of 1% it’s 41% positive. If you use the CPS score with a cutoff of 10 it’s again around 40%. But there’s only 25% overlap — or 75% overlap there. So in other words, if you want to optimize the use of immune therapy in metastatic TNBC, and you have access to both drugs, which you don’t have in the US, but you probably ought to use both assays because you can identify about 50% of patients who are PD-L1-positive.

We need a little bit more work in trying to find out can we come up with other biomarkers that show us who benefits from immune therapy, and the honest answer is the best biomarker at the moment is PD-L1. If you look at the immune phenotype, excluded immunity, immune desert compared to inflamed tumor types you see all these subtypes in patients who are PD-L1-positive or PD-L1-negative.

In the same way, if you look at the molecular subtypes, basal activated, basal immune suppressed, again you see this across all subtypes.

So from a selection point of view it’s PD-L1 status and nothing else has been as effective in metastatic TNBC.

 Now if you look at the ADCs, we’ve already spoken about this in detail, and I think again the most established drug at the moment is sacituzumab targeting TROP2. And now all of us who have seen the Phase I data we’re expecting this trial to be positive, which it is in terms of progression-free survival, a tripling of PFS from 1.7 to 5.6. OS doubling from 6 to about 12 months. But really, and I’m slightly old-fashioned in this way, important endpoint is response rates. If you look at the dramatic shift in response rate from 5% with chemotherapy to 35% with sacituzumab it just highlights how rubbish chemotherapy is in those heavily pretreated patients.

But clearly in patients who have advanced disease, symptomatic disease, that response benefit is also driving a benefit in quality of life. The PFS benefit is consistent across all subgroups, whether it’s earlier or later line, but also equally important it’s seen in patients who start their journey as TNBC and then — sorry — start their journey as ER positive and then turned into TNBC. Again, important from a clinical point of view.

We see slightly better responses in patients with high expression, but ultimately even in patients with low TROP2 expression it’s still better compared to standard chemotherapy.

Safety profile. As we had earlier with these new ADCs, there are like single-agent chemotherapy. They’re not just antibodies. They are like single-agent chemotherapy. We just have to be aware of the specifics of the safety profile, and then they are very well manageable.

There’s a number of other drugs. We already spoke about dato-DXd targeting also TROP2 but using a different platform, providing impressive single-agent response data but with a slightly different safety profile compared to sacituzumab.

And what is interesting, as you can see in the waterfall plots, you see activity with dato-DXd in patients who have been pretreated with sacituzumab, so targeting the same target with an ADC is possible. We also see activity in patients who have already been treated with the same payload, and that highlights the work we need to do in understanding resistance to ADCs. It is driven either by the payload or by the receptor, and that will allow us to have effective sequential strategies.

We also mentioned T-DXd data. You’ve seen the data in ER-positive disease, but here very similar data, although limited slightly by the low number of patients in there, in TNBC. And again, just to emphasize the high response rates of around 50%, again unheard of with chemotherapy. Another ADC coming through targeting HER3, promising, encouraging response rate, different safety profile.

And ultimately we have this battery of different ADCs that are coming through, some of them established, some of them a little bit behind. But I think the future is really how to use those drugs optimally there.

You’ve seen how the treatment of early TNBC has changed with immune therapy being there, but if you now look at the management of metastatic disease, clear standard, PD-L1 positive chemo plus IO, in second line clearly moving in ADCs with sacituzumab and possibly T-DXd, and again in the third-line setting as well.

What I mentioned earlier, what I’m intrigued about is the combination of ADCs with immune checkpoint inhibitor. This is first-line unselected patients, predominantly PD-L1 negative, HER2 low, T-DXd plus immune checkpoint inhibitor, a response rate of nearly 60%, with a very decent median PFS in this group of patients. Even better, again, from the BEGONIA trial, unselected patients, predominantly PD-L1 negative, response rate 80% of dato-DXd plus an immune checkpoint inhibitor in the first-line setting. And you can imagine these combinations are now moving forward into Phase III trials.

So where are we? This is where we are. What we need to work out is really the role of immunotherapy post immune therapy in the early disease setting, and we haven’t got an answer to that, the role of ADC/immune therapy combinations and how we best sequence the different ADCs, but also there are a few other drugs coming through, new DNA damage repair targeted agents, and we mustn’t forget about the Phase III trial with AKT inhibitor which is expected to read out later in the year.

So the treatment options for TNBC are becoming more colorful. There’s a lot of hope. We are improving the outcomes dramatically. The median overall survival is now beyond 2 years. That’s a doubling compared to where we were only 5 years ago, and that doesn’t include all the ADCs that are coming through.

DR LOVE: So we’ve got so many great — I was just leafing through all these great questions we got from the audience. We’ll do 1 more. Ayad, incidentally, says why is nobody mentioning palbo? It’s my ultimate favorite. Maybe it’ll come back with cell-free DNA, you can use it. Who knows? But we’ll see.

So here’s a question for you, Hope, from Jaspreet. Is the aggressiveness of disease in young women related to menopausal status, estrogen effect, or a different biology? If a young woman gets a BSO, rendered postmenopausal, does that reverse the negative outcome that we see with these young women, Hope?

DR RUGO: I would say that the answer is not in for this. We don’t understand why it is that younger women could get the same treatment for the same-looking cancer as an older woman and have a worse outcome, and I think there’s not a lot of — people looked at PAM50 subtypes, that’s what was first presented on Friday, but not a lot on looking at all the genomics and gene expression differences. I think it may take much more complicated panels than we have right now to understand.

But maybe it has something to do with tumors that grow in a very high estrogen environment and are ER positive and highly proliferative. But even when they have low proliferation they seem to have worse outcomes.

So how that interacts with how we treat patients, this data from SOFT was quite fascinating, and I think that we’re still not understanding it. I would say that we don’t yet know that suppressing the ovaries, taking out the ovaries, or doing any of that affects that different biology.

DR LOVE: Final comment from Peter.

PROF SCHMID: So we saw interesting data in this context from the WSG group last year. And if you look at preoperative window trials where we look at downregulation of proliferation of Ki-67 with endocrine therapy we’ve always known that in premenopausal, and especially in young women, that wasn’t very effective if you gave tamoxifen or other drugs. But they showed data if this is combined with ovarian suppression that the downregulation is as effective as it is in postmenopausal women. And so that suggests that this isn’t just driven by biology, but it’s probably driven the inferior outcome by suboptimal management. I think the ovarian suppression is a key factor in this.

DR RUGO: The only thing I would say is that SOFT, the data was presented for SOFT, the people were getting ovarian suppression, and then they still had a worse outcome. So that’s where — and that’s just a little — 1 data set, right? But that was what I think was perplexing on Friday.

DR LOVE: So I want to thank our faculty here on the stage, particularly to thank Sara, Sara and Tiffany for working with us to put these videos together.

One more program. We’re just doing it as a webinar. You don’t have to even get out of bed. Tomorrow 7 am, just pull your computer over, you’ll learn a little bit about RCC. Have a great night. Thank you so much.