Introduction: A New Paradigm for Triple-Positive Breast Cancer?

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about the management of breast cancer and key papers and presentations from the past year. We have a great faculty today: Dr Rebecca Dent, from the National Cancer Centre in Singapore, and Dr Nancy Lin, from the Dana-Farber Cancer Institute in Boston.

Today, we’re here to talk about breast cancer. And as in all of our programs, we will be talking about the use of non-FDA-approved agents and regimens, so check out the package inserts for specific products and approved indications.

So as we do in all of our Year in Review programs, I’ve met with both of our faculty individually in the last couple of weeks to record pretty extensive presentations, reviewing in detail a lot of the great papers from the past year. Really encourage you to check out these presentations, they go through in detail. What we’ll do today, what we do in all these webinars, we pick out some, not all, but some of the papers that were discussed and sort of try to take it to the next level, get input from the other faculty member, talk about clinical implications as well as research implications. Here are a list of papers that our 2 faculty discuss. As you can see there’s a lot of great content in there. Again, I highly recommend that you check it out.

Here’s where we’re heading. We’re going to go through a bunch of different strategies and updates. But before we do, I just want to lead into the introduction by telling you a little bit about what our December as a CME group looks like every year. I know your December is always oriented around the San Antonio Breast Cancer Symposium but for us, as well as all general oncologists, we also have the ASH meeting usually one week afterwards as the San Antonio. Although one year they were in the same week, and we went from San Antonio to ASH in New Orleans and arrived at 1:00 in the morning and started the next — we do all the programs in 1 day at ASH so it’s usually a crazy time for us.

But I’m bringing this up because I’m kind of leading into the first paper I want to talk about in breast cancer and I was just reflecting back on, last night we actually did a program — Nancy, we had your colleague from Dana- Farber, head of the CLL program, Jennifer Brown, on last night. And one of the main things we talked about was a study that she just presented at the ASH meeting the week before San Antonio this year, thankfully, on the AMPLIFY study which is a new approach to first-line therapy, maybe is going to be practice-changing. A lot of people are going to get this. This is a time-limited treatment with BTK inhibition, acalabrutinib. It used to be indefinite, now it’s going to be for a little more than a year with venetoclax. All oral regimen and for the first time, patients are going to have the option of this kind of combination. A lot of people are going to get treated. I bring that up because the paper I wanted to put out in front of you is something that actually, although it only affects maybe 10% of breast cancer, is actually almost the same number of patients that get CLL. And from my point of view, the PATINA study, which looked at triple-positive breast cancer, so PR-positive as well as HER2-positive. We’ll talk about that in a second.

But Nancy, just looking at my own personal history of some of our highlights, at least from our CME perspective of HER2-positive breast cancer, last night we were talking about CLL and how the AMPLIFY data in terms of the history. We just had BTK approved for the first time, 2013. So a whole paradigm shift there. And I think in terms of triple-positive breast cancer, maybe we’re looking at the same thing. I reflected back on 2005 when the adjuvant trastuzumab data came out, CLEOPATRA 2011, KATHERINE data, which was recently updated, 2018, T-DXd getting approved, that was 2019. It’s now been 6 years we’ve had T-DXd. HERCLIMB the next year and then the HER2-low paper, DESTINY-Breast04. And now from my point of view, one of the most interesting papers of the year and in a long time that I’ve seen in HER2-positive disease, was this PATINA trial.

So Nancy, can you comment a little bit on what the PATINA trial looked at, what they found? And in particular what I’m really curious about is both of your opinions about is this practice changing? And what does it — also biologically, what does this mean? So Nancy, any thoughts?

DR LIN: Yeah. Historically we’ve used CDK4/6 inhibitors in patients with ER-positive, HER2-negative breast cancer. But actually, the preclinical data is very strong in the HER2-positive breast cancer triple-positive state as well. And work from Shom Goel and Jean Zhao at Dana-Farber really showed that the CDK4 inhibitors can actually overcome HER2 resistance. So this was tested in the PATINA trial. So patients got induction chemotherapy, trastuzumab with or without pertuzumab, and then they went on in the setting of stable disease when you would normally be giving them maintenance therapy with HER2-directed therapy. They got HER2-directed therapy plus endocrine therapy with or without a CDK4 inhibitor, this case, palbociclib. And the results were really astounding. The PFS delta was 29 months in the control arm to 44 months in the experimental arm. So this is like a very dramatic absolute gain in progression-free survival and this is chemotherapy-free time for patients.

DR LOVE: So before I get to Rebecca, Nancy, what does this mean in terms of first-line therapy in metastatic HER2-positive disease? Have you since San Antonio, I don’t even know whether you can access palbo, but have you been utilizing it?

DR LIN: We actually have been utilizing it. We’ve been offering it to patients, in patients who are coming right into that sort of maintenance phase we’re offering it. And then also for patients who are, and this is arbitrary, but for us we’ve kind of said, within a year, 6 months to a year of that maintenance period, we are actually telling people about the results of this study and offering it as an add-on. The patients who’ve already been 5 years on trastuzumab or HP maintenance, we’re not really recommending it. But for people who are earlier on, we are, because I think this is such a dramatic result and the toxicity profile is very, very manageable.

DR LOVE: So Rebecca, I’m also interested in how you view this in terms of current patient care but also the biology. What’s going on here? One of the things that always fascinated me was why post-adjuvant neratinib worked better in ER-positive than in ER-negative/HER2-positive disease and I’ve been hearing stuff about — cross talk is about as far as I’ve gotten on that. But any granularity about what’s really going on here, Rebecca, biologically? And again clinically, is this something that you think is going to become a standard quickly?

PROF DENT: No. I appreciate your candidness because for the longest time I’ve sort of thought about HER2-positive breast cancer and I think we’ve really gotten excited. We have such important developments in targeting HER2 and what’s driving these cancers. But ironically this is such a heterogeneous group of patients. If you look at some of the neoadjuvant data, specifically NeoSphere let’s say, where you’re giving HER2-targeted therapy in the ER-negative versus the ER-positive, the pCR rates with just 2 antibodies alone was nearing 40% without even chemotherapy. And so I think it’s really important to recognize that biologically these are very different. And so I thought this was such a great study and I think building on preclinical data, understanding that it could overcome resistance in this context.

I don’t know about you, Nancy, but for the longest time there wasn’t even data about to put people back on endocrine therapy after they were on maintenance. And then finally I think some of us were like, wait, why wouldn’t we do that, right? So we started doing that. Then this study emerged and I think people are like, we’ve really forgotten this group of patients. And what I see in my own clinical practice is that these really long-term responders, where you’re seeing HP for years and years, tends to be more of the sort of HER2-enriched. And so those are the patients that I think continue on HP alone. But the ER-positive HER2-positive, they are different biologically. And so I think again, this is looking at your clinical practice, looking at a clinical question matched with the preclinical important data and then you see results. You see something that’s clinically meaningful. So I think the big thing is that if you’re able to give the subQ HP and you’re giving oral palbo and you’re giving an oral agent, it still allows people to continue on a chemo-free regimen.

One thing I have thought about though is, in trying to think through, and I love Nancy’s comment, okay so what are we going to do with people that are many years out? No, no, we’re not going to start giving them palbo if they’re 4 years out. But my only sort of thing is, who are those patients that can continue HP without adding therapies, especially if you’re trying to sort of address costs. And I think the question is, could you sort of assess those patients and then on progression could you give it? Or have things biologically changed by that time under the selective pressure of different treatments? After so many years on endocrine and HER2, will you be able to rescue those patients? And I’m not sure that question will ever be answered. So I would tend to agree with Nancy for the, I think, higher risk initially patients, who you feel you want to give something, this is a really nice addition. It gives you a lot of comfort.

DR LOVE: So we could keep going for a long time, but this is just like a tasting menu. I love tasting menus and we’re just going to take a little bit. You notice here that even the response rate and clinical benefit rate is somewhat increased, although right now we don’t have a survival benefit.

CDK4/6 Inhibitors for HR-Positive, HER2-Negative Breast Cancer

DR LOVE: Alright. Well, let’s start, again we’re not going to really focus on all the details of these trials. What I really want to focus on are clinical implication. And Rebecca, one of the things that you go through is the updates on the monarchE study of adjuvant abemaciclib. You see data on age, et cetera, she goes through all that, as well as the update on the NATALEE trial. But I want to just use these new papers and more updated data even presented at the St Gallen meeting, kind of as always in oncology, our indirect comparisons.

So let’s just talk about it clinically. In patients, Rebecca, who are eligible for both of the CDK inhibitors, how do you think it through? How does it vary based on comorbidity, if they have GI problems, et cetera, et cetera? Right now, can you just paint a little bit of a picture about how you think through adjuvant CDK. Which one? Which patients? Do you stick with the approvals or the trial bar or do you go under that?

PROF DENT: So great question. So yeah. So this is Angela DeMichele, and I thought she put nicely in a table to sort of give us a sense. And I think to be honest, the data are remarkably similar. They’re just looking at different follow-ups, right? So we know with ER-positive breast cancer these curves will continue to separate. I’ll be honest, I was a bit of a naysayer. So it’s when it sort of reached the 5% mark where we all sort of feel compelled we have to start talking to patients about it.

So the monarchE, I think we’re creatures of habit. So I’ve gotten quite comfortable at giving abema in the adjuvant context. I know how to dose adjust, dose escalate, dose deescalate managing the side effects, which for me is fatigue and diarrhea. I can manage the counts. I can manage everything else. So I really follow the monarchE for the majority of my patients. Also in Singapore, monarchE has been approved for some time whereas NATALEE is just sort of emerging. I think where NATALEE comes in is it gives us more choices, right, lower risk patients. We know that surgeons are deescalating their surgery a lot so they don’t have to do surgery just to make the patient eligible for adjuvant CDK. So I think that really opens up the opportunity for patients that are keen to go on CDK inhibitors.

I think for us, those in clinical practice, what’s hard is we’re so used to our algorithm. And so now once again we have to adjust it. And it’s almost like you have to screen your patients in clinic and sort of say, okay, what’s the other thing I have to think about for these patients? And that’s the challenge. And I think the other challenge for me is, you’re combining it with hormonal therapy, right? And so we tend to shy away, especially with abema, from giving tamoxifen because of the risk of blood clots. And so you really have to be committed to doing the AI, ovarian suppression and CDK in sort of that higher risk group.

So there’s a lot to think about. And I guess the other thing, when you’re sitting down talking to patients, scheduling is really important. So I’ll be honest, in the adjuvant setting I have to say, I’ve gotten comfortable with abema because I don’t have to bring them classically, 3 weeks on, 1 week off. I can kind of stretch it here and there once I’ve gotten comfortable with their schedule. But we have to remember, there is no overall survival benefit when we’re talking to patients, and I don’t think we’ll ever see that survival advantage because there’s such heterogeneity in adjuvant ER-positive breast cancer in terms of just biology. The second thing is, if patients relapse, there’s such heterogeneity in how we treat these patients and the biology is also heterogeneous. So It’s going to be hard to navigate for us.

DR LOVE: So Nancy, curious about your thoughts, also about dosing. In the NATALEE trial they use 400, a lower dose and then when Rebecca was recording her presentation she brought up the issue, she usually starts abema, I hope I’m quoting you correctly, at 100. I’m curious whether you do that. Also, we have a Research To Practice poll every webinar on how long it’s going to take somebody in the chat room to bring up cell-free DNA, and in this case it’s 13 minutes. Hasan wants to know about cell-free DNA before starting palbo and whether you would look at that. But again, getting back to dosing, also the issue of 2 versus 3 years and how that factors into your thinking.

DR LIN: That’s right. Yeah. So I think because it’s apples and oranges comparisons, it really is a discussion with the patient for the patients who are so-called dual eligible. For the low-risk patients I offer ribociclib because that’s really the population that was included in NATALEE and not in monarchE. But there’s a large group of patients who would’ve been eligible for both. Abemaciclib is 2 years but there are GI side effects. With ribociclib it’s 3 years and more LFT issues but less of the GI issues. And I think to some extent patients help us sort this out by telling us. And also, somebody who has baseline mild elevation of LFTs, I’m going to shy away from the ribociclib. Somebody who has baseline irritable bowel syndrome, I’m going to shy away from the abemaciclib. So I think that from a practical standpoint, that’s kind of how I’ve sorted out patients.

Watch out for ASCO because Erica Mayer will be presenting results of the TRADE trial, which is actually a dose escalation of abemaciclib in the adjuvant setting, so starting low and having a ramp-up to try to mitigate the GI side effects. So we’ll see what the data look like with that strategy. In practice, I’ll admit, I’ve done a poor man’s ramp-up strategy because in the US you have to get every dose approved, right? So I put people on 150, which is the usual starting dose, but I have them start it once a day and then I have them go up to twice a day. There’s no evidence for this, but this is what I do. I just find it’s more tolerable than starting with the 150 BID. But I think we’ll see what the TRADE study looks like. Because I think if it looks interesting and promising, that that may sort of give us more evidence-based way to escalate the dose and improve tolerability.

DR LOVE: That’s interesting. It reminds me of the trial looking at dose escalation in neratinib and how successful that was.

DR LIN: Right. Exactly. Oh, I didn’t get to the ctDNA.

DR LOVE: Oh yeah, ctDNA before Rebecca comments, yeah, ctDNA.

DR LIN: I personally would not check it. I think we don’t know what to do with the result. If it clears, I don’t know if we know what that means. If it doesn’t clear it probably means something bad, but I don’t know that we would know what to do in terms of changing our therapy based on it. We don’t have any idea what the clearance dynamics are in the adjuvant setting. So I would personally not advocate checking outside of a trial. I mean, there are trials to do this.

DR LOVE: So a couple more papers I wanted to just bring up, particularly because when we were chatting before we got started I was asking the faculty, they see a lot of people and second opinions, are there things that people do that maybe you wouldn’t do? And I was very surprised that Nancy brought up the issue of first-line therapy of ER-positive metastatic disease, that she sometimes see patients who get chemo. I’m not talking about chemo followed by endocrine maintenance, that’s something else, but just chemotherapy.

And Rebecca, you commented first on the RIGHT Choice trial looking at ribo versus chemo, and then the PADMA trial just from San Antonio looking at palbo. Any broad general clinical comments, Rebecca, when you think about visceral crisis in a patient who needs treatment right away? Are you comfortable using endocrine therapy in that situation? Do you try to give a little chemo first? Any comments?

PROF DENT: Yeah. So as we were discussing, I think both of these trials give us a lot of confidence that it’s very reasonable to give an endocrine and CDK inhibitor first-line and that these patients actually respond quickly. Because that’s I think the big thing people are uncomfortable with. Are they going to respond quick enough? Are we going to miss that window? And so both these studies I think give us a lot of comfort that even in the RIGHT Choice where they compared it to a doublet chemo, which we don’t use as much anymore, we’re getting those responses.

Again, I think back to Nancy’s point of individualizing therapy, so I always say, if a patient gets admitted and gets diagnosed in the hospital and has very bad disease, those are the patients I want to give chemo because I need responses within days. If you can wait a week or so, that’s where CDK and endocrine are helpful. Now, my patients have made me braver than I am brave, meaning they often say to me, I don’t want chemo, I want endocrine and CDK. I’ve had patients with huge pleural effusions, symptomatic, and they’ve responded after like a week or two. So I’m more inclined to do this approach with visceral in terms of lung disease. I’m a little bit shyer in terms of if someone has quite a significant elevate in liver functions, even though on the RIGHT Choice that was allowed. There weren’t that many patients I would say who were “true visceral crisis.” And those patients I’m more inclined to use palbo or to give abema where — we’ve had a few patients with ribo who had that increase in LFTs right away. So yeah. So I think this is very reassuring for patients.

DR LOVE: So next serving on our tasting menu is the postMONARCH study, the use of AI versus AI. Nancy, kind of to me a little bit counterintuitive of why this turned out to be positive. But it certainly does look like it’s positive and in a way kind of also leads into the EMBER-3 study that we’re going to talk about in a couple minutes. But can you just summarize what was seen there? These are, I guess, mainly people who got either palbo or ribo previously who now are being — abema was compared to placebo, we saw more follow-up. What’s the bottom line in terms of the quality of benefit that you see there, Nancy? And is this the strategy that you use?

DR LIN: Yeah. So this study was looking at patients who had already been treated with an AI plus a CDK4/6 inhibitor in the metastatic setting. And the question is, is there value in continuing or actually switching to an alternative CDK4/6 inhibitor, this case abemaciclib, and then all patients receive fulvestrant, so they switch the endocrine partner. And I think that when we think about, well, how do people develop resistance to endocrine therapy? They could develop resistance to the endocrine component, right? They could develop ESR1 mutations, or they could develop resistance to the CDK4/6 inhibitor. But all the CDK4/6 inhibitors are also not identical and Rinath Jeselsohn in our group has done some very elegant work to show that even the proteomics and the sort of genomics that happen in the sort of dynamic range after ribo versus palbo versus abema are actually not identical. So they’re not totally identical drugs. And what we’re seeing is that we do see a PFS advantage with the continuation of CDK4/6 inhibitor, but specifically with abemaciclib.

And remember, there was a very similar trial that looked at essentially palbo after palbo with a very similar design, AI palbo followed by fulvestrant, palbo or not, and that did not show a benefit. So there is something to say about the switching here, I think, from 1 CDK4/6 to another. And again, all patients had switched the endocrine backbone.

Oral Selective Estrogen Receptor Degraders for HR-Positive, HER2-Negative Breast Cancer

DR LOVE: So moving on to oral selective estrogen receptor degraders. Last night, believe it or not, we were talking about Bruton tyrosine kinase inhibitor degraders. There’s androgen receptor degraders being looked at in prostate cancer, but of course leading the group here is breast cancer. And first SERENA-2, another oral SERD, camizestrant, and we can talk about the difference, it doesn’t seem to be huge between elacestrant, camizestrant, imlunestrant that we’ll talk about. But it’s very similar data that’s been presented for camizestrant as monotherapy.

But Rebecca, the thing that really got everybody’s attention, and this is often the case in oncology, is a press release on this trial, which everybody’s been really looking forward to, the SERENA-6 study. We haven’t seen the data, but there’s a press release out there, as is often the case, which came out last month, saying that this strategy, which is pretty unique in breast cancer research, at least it’s been reported up to now, has a positive result. We’re going to have to see the details and whether it’s positive enough to want to do this. But can you talk basically about what they did here, Rebecca?

PROF DENT: So yeah. So in my talk I sort of lead in with the camizestrant, the earlier data, which looked like camizestrant seemed to be particularly active in those patients that harbored an ESR1 mutation. And very often this is detected, as we know, under the selective pressure of treatment, specifically aromatase inhibitors. And so the idea was, and we’ve seen hints of this from other studies, that when these ESR1 mutations emerge that a shift to an oral SERD such as camizestrant might prolong or extend the amount of time people spend on this first-line endocrine plus CDK inhibitor approach. Because in our patients, this is the most important, preserving that sort of first-line therapy and when to switch, and usually we do it on radiological progression. But the idea here is in SERENA-6 that looking serially every 2 to 3 cycles and looking at tumor imaging as per standard of care, and if within that time they have ctDNA that’s positive for an ESR1 mutation, then the patients are randomized to either switch to camizestrant plus the same CDK plus endocrine therapy or discontinue the same treatment. So it’s this earlier switch before radiological progression when you just see this emergence.

Now, I think the key thing, and the primary endpoint was PFS, the key thing for clinical practice is that PFS is going to have to be quite impressive for us to change clinical practice. I think the second thing is, how many patients do they have to screen to get to that randomization, right, because this could be thousands of patients. And how often in clinical practice are we going to have to go looking for these ESR1 mutations, because we have patients on this combination for 3 years. We’re not going to be testing every 3 months, it’s certainly not cost-effective. So I think we’re going to see a lot of studies emerge trying to look at the longitudinal course of these ESR1 mutations, looking at detecting them, but also comparing the technologies. They’re not all the same. This is using a Guardant assay. Does this apply to all assays? So I think it’s very exciting. It could provide this paradigm shift. I think the hope is in the future we won’t even have to do scans but we are far, far from that. And I think that’s really important for those people that are out in clinical practice. And so we’ll have to await the actual results.

DR LOVE: Nancy, any thoughts? I can imagine a lot of patients hearing about that and bringing it up to their physicians. I would imagine a lot of them would be tempted to at least look for ESR1. Who knows what to do? I guess we’ll have to see the data, it’s often the case. A lot of the endocrine trials that have come out in the last few years have pretty good hazard rates too, so I guess it wouldn’t be totally shocking if it was a really strong hazard rate. The AKT trials have pretty good hazard rates. Anything you want to add to Rebecca’s comments, Nancy?

DR LIN: Yeah. I agree with Rebecca that a 2-month delta in PFS is not going to change practice. But I think a more dramatic delta in PFS could change practice because it allows people to be on endocrine therapy for longer and it’s a reasonably well-tolerated drug.

I think one of the practical questions that will come up is how are we going to test for ESR1 mutations? Do we really need to send a full NGS panel every time? Can we just develop ESR1, like they literally just detect ESR1 and they’re cheap tests and you can repeat them on a regular basis. I think that will make it much more practical, but it remains to be seen how it ultimately ends up being implemented.

DR LOVE: So we were talking about our experience going to San Antonio and ASH in the same week and of course ASH, we do everything in one day so it’s kind of hard, before the meeting even starts. In San Antonio, we usually do 3 meetings, and as we’re presenting stuff’s being presented and I get to run it by the faculty. And this year I had Komal Jhaveri as usual in one of our programs and we were doing 3 programs. I was asking everybody, because it had already been presented, what the heck does this EMBER-3 trial mean in terms of clinical practice? What an amazing study. But Rebecca, a little challenging, at least for me to figure out exactly how it’s going to be applied. Can you kind of give us, I guess 35,000-foot view of the study and then where you see the implications heading?

PROF DENT: So yeah. So I think all these studies are emerging at a time when the whole landscape is changing, right? So when someone is on an adjuvant CDK inhibitor and then they relapse, or they’re on a first-line therapy of endocrine and CDK, then what do they do when they progress? And this is what a lot of the trials are looking at. So this EMBER-3 is looking at imlunestrant, which is the Lilly compound, which is another oral SERD. And here, again, looking for those patients that are recurring in the adjuvant or recurring in the sort of first-line setting, and then looking at giving a single oral SERD, single-agent endocrine therapy or the combo, which was added later as this field is so dynamic, that third arm of imlunestrant plus abema. And so not surprisingly, this abema combination with oral SERD clearly seemed to be better. And I think the thing that really stood out for me was that the benefits were quite dramatic among those patients who have an ESR1 mutation. But it seemed to actually be beneficial in those even without an ESR1 mutation, even though the benefits were modest, which is a bit different than we were seeing with the other compounds. And then I guess the other 2 things are even in patients who had CDK inhibitors and then even in patients who harbored a PIK3CA mutation. Because we’re going to see with the INAVO data, we are going to have some options, but what this showed is that with that combination, we did see improvements in terms of efficacy. And then, of course, everybody would have liked to have seen a third arm of fulvestrant plus abema. Because I don’t think single-agent endocrine therapy is my bias after progression on a CDK. I really don’t think single-agent endocrine therapy is that active, quite honestly, unless you’ve been on your endocrine therapy in the adjuvant setting for more than 10 years or first-line for years and years. I think the majority of patients can’t get single-agent endocrine therapy.

DR LOVE: So Nancy, actually, another one of your colleagues, Hal Burstein, did the discussion of EMBER-3. And for years, he would present trials comparing — looking at CDK inhibitors and say I know I’m not supposed to do this, but here it is, they all look very similar. And then for EMBER-3, he said I know I’m not supposed to do this. But then, he presented all the second-line endocrine therapy and said this is the first time we’ve seen 9-plus months of PFS and everything else is more around 5 months.

DR LIN: Five, 6 months. Yeah.

DR LOVE: So with all the caveats of indirect comparison, it certainly is interesting, particularly as Rebecca said, even without ESR1, even with prior CDK.

DR LIN: CDK4.

DR LOVE: Any thoughts about how you, theoretically if you could apply it, how you would apply it?

DR LIN: Yeah. I think that it’s really interesting because it actually confirms, in a way, postMONARCH, this idea of CDK after CDK. So it’s another suggestion of this. But with all the caveats of cross-trial comparisons, the PFS here is longer than it was in postMONARCH. And so I do think that if this gets approved, I will use it in sequence. And I think one of the big questions if we, depending on how SERENA-6 turns out, is what happens if you’ve already switched somebody to camizestrant for an ESR1 mutation. What are you going to do in the second-line setting? I think we’ll have to sort that out.

DR LOVE: And also, I guess another thing that Hal talked about and, Rebecca, I’m curious about your thoughts on it, was the issue of the tolerability of SERDs. Because the imlunestrant monotherapy looks very similar to elacestrant. The camizestrant data looks very similar. So you imagine maybe we’ll have all 3 at some point. Are you able to distinguish the tolerability? I hear about things like photopsia, bradycardia, Rebecca. Anything? Is one better tolerated? Any evidence that one is better or more effective?

PROF DENT: So as I said, I think the bottom line is we have many options now. I think it’s going to be challenging, to be honest with you. I think one of the things, as I said, that comment on the imlunestrant, was that unlike the cami data and elacestrant and some of the others, it looked to see that signal was there regardless of an ESR1 mutation, which is, I think, fundamentally different. We’ll have to see larger datasets and longer follow-up to understand that better.

I think it’s really interesting. I find it’s quite individualized. I think we do get a bit nervous, I would say, following ECGs and doing those things. Thankfully, I think it has been a rare side effect and I think we’re much more vigilant than we were, let’s say, when we were starting some of these other trials 20 years ago. But I think time will tell as we use these also in more broader populations. I always say when you do things in trial, you’re getting the fittest, most well tolerated. It’s only when you get into clinical practice. It’s kind of like we’re seeing with all the CDK inhibitors, the pneumonitis and ILD that exists with all of them, but it’s rare, but it does happen. So I think we’re reassured. Some of the first generations that I saw in Phase I were concerning me. But now that we’re seeing them in Phase III at better doses, I think they are better tolerated.

Treatment of PIK3CA/PTEN/AKT-Mutated Breast Cancer

DR LOVE: So a couple words about PIK3, PTEN, AKT mutant breast cancer. I was mentioning there’s a press release saying capi works in prostate cancer. We haven’t seen how well it works, but we’re going to find out pretty soon, I hope. I guess Rebecca got into the biology of this in her talk. We saw some updated data looking at capi. We actually had 3 posters our group presented at the San Antonio meeting, and one of them was looking at investigator’s choice of treatment of PIK3-positive disease. And it was, like, a complete shift from alpelisib to capivasertib there. I think primarily based on toxicity. Before we get to the INAVO study, any comments about CAPItello and about capivasertib, Nancy? Rebecca was bringing up the issue of diarrhea. I’ve been curious about diabetes tolerance, what you’re seeing with capi compared to what you had been seeing with alpelisib.

DR LIN: Yeah. I think in our experience, capivasertib is indeed better tolerated than alpelisib. I think we are actually see it’s not just like the statistics and the numbers and the tables, but we are experiencing that in the patients that we’re treating. Alpelisib, I think my personal rate of discontinuation due to toxicity was rather high even despite doing all the prophylactic everything whereas with capivasertib, I think people are able to stay on a little bit better. I do think that with all of these drugs, and we’ll talk about inavo in a minute, but I think the glucose management is actually one of the more challenging things as an oncologist because I don’t personally feel like I was well trained in endocrinology. And endocrinologists are not so easy to find, actually, in the US on short notice. So I do think that that is a challenge with all of this class of drugs.

DR LOVE: We’ve been talking about doing a diabetes 101 course for oncologists. I certainly could use it. I’m really curious what happens with prostate. This trial, they’re giving it with abiraterone and prednisone. So I’m going to be really curious to see how they do with the glucose tolerance with replacement steroids on board.

We were talking about another practice-changing trial that came out at San Antonio the year before, the INAVO120 study of inavolisib with palbo and fulvestrant for patients with PIK3 mutant disease. Rebecca, can you kind of remind us of what the study looked at? We had really, again, another trial with a great hazard rate. And in particular, how it’s affecting your practice right now. This is an approved option. And this is in patients with endocrine resistant disease. So can you talk about in what situations you’re using this strategy, Rebecca, and what you’re seeing in terms of tolerability?

PROF DENT: Yeah. So just to remind everyone, we’ve come a long way with these PIK3 kinase inhibitors. They used to be very dirty drugs. And now, we’re getting to sort of being much more focused. So inavo, it is a selective inhibitor of the specific catalytic alpha isoform. And why that’s so important is that the efficacy seems to be improving and toxicity seems to be reducing. So this, you know, anybody who has been involved in the older BELLE-2 trials and a lot of these older drugs, these next-generation drugs are more active with fewer side effects. And that’s really relevant because, as you said, your own poster had shown that people are shifting away from alpelisib. So people want better efficacy, but they’re really struggling with the side effects.

So this study looked at specifically patients who had a PIK3CA mutation, so very poor prognosis patients who had this early relapse. And patients got the triplet, so looking at inavo, palbo and fulvestrant, versus just the doublet. And I think we were all quite, we all remember San Antonio, the data press releases Monday, presented Friday. And Hope amazingly, she did have the advantage of all of us there going “wuh.” So it was 7 months versus 15 months. And this was like a PFS we could all go, oh yeah, this is real. Hazard ratio of 0.43. Confidence interval was really tight. And then all of the other measures that we’ve seen in subsequent studies looking at time to discontinuation, 15 versus 25, time to going to subsequent chemo, again, hasn’t been reached in the triplet. So this is real data, the curves separate quickly.

Now I don’t have access to this compound yet. We’ve had to use it on trials here. My own sort of feeling is that we’re seeing side effects that are better than what we saw with alpelisib. People are quite motivated to do it. But I would tend to echo those comments that we do need a bit of a training for the hyperglycemia. We do, I think, await data on overall survival that should readout this year. But I think this is for a very poor prognosis group of patients. All of us who are seeing in clinic, these really early relapsers. And I think you can get these biopsies now. Because I think that’s the other thing is that you could do a liquid. The concordance in terms of PIK3CA mutations from tumor to liquid is very high. So this is a group of patients if somebody recurs quickly, you can get this information.

DR LOVE: Yeah. We were doing CME meetings that year too. And all the bodies were there working. Virginia Kaklamani who runs the San Antonio meeting was working with us and they were all trying to figure out how they can get this, break the world record for a presentation.

One thing I just want to mention about this, Nancy. I don’t know why I’ve never thought about it. I guess if you have a de novo metastatic PIK3 positive, they wouldn’t be eligible, right? Because they have to be endocrine resistant.

DR LIN: Yeah. And I think that we have generally stuck with the eligibility of the trial. The FDA label, interestingly, is broader, which I agree with.

DR LOVE: Right.

DR LIN: I think it gives clinicians flexibility based on the clinical scenario. But we’ve mostly stuck with the clinical trial eligibility just because there is the availability of PI3 kinase inhibitors in later lines. And so it’s not clear yet whether doing everything upfront for all patients is required versus a sequential approach of endocrine therapy, CDK4 and then an endocrine therapy/PI3 kinase combo later. But it’s really the high-risk patients, the patients with aggressive disease, the patients with a short disease-free, you know, they essentially relapsed on endocrine therapy. These are the patients where we think the additional toxicity is worth the gain.

DR LOVE: Yeah. The real challenge, I think, is the people who’ve had endocrine therapy and stopped. The trial allowed them to go in, I think, up until a year. But again, with the FDA thing, theoretically, it could be more than a year.

And this is just to show you a slide that Rebecca had that I thought makes this point I was saying about hazard rates, which you see with the AKT strategies, really good hazard rates. Even alpelisib also as well. But capi, hazard rate of 0.5. Inavolisib, 0.43.

DR LIN: Yeah.

DR LOVE: So hormonal targeted therapy works, I think you could say.

Antibody-Drug Conjugates (ADCs) for HR-Positive, HER2-Negative Breast Cancer

DR LOVE: Alright. Antibody-drug conjugates. We’re going to start out talking about HER2-negative disease and then HER2-positive. And of course, in terms of HER2-negative, we now have the approval of Dato-DXd. We saw some more data on that as well as T-DXd in the first-line and in particular, T-DXd in the ultralow patients. So let’s start out with T-DXd, Rebecca. And maybe you can kind of briefly remind us about the DESTINY-Breast06 presented last year at ASCO, again, looking at HER2-low, ultralow. But again, this is hormone receptor-positive disease. So can you talk about what the trial looked at, what they found, Rebecca, and from your point of view, the ideal approach to implementing it in practice?

PROF DENT: Yeah, thanks. So we know from Breast04 that looking at patients who had had endocrine and chemo that clearly, T-DXd was superior to standard of care chemo in patients that had had endocrine therapy followed by chemo. And so Breast06 was different in that it was right after patients have had endocrine therapy, so it was their first chemo for metastatic disease. It also included these ultralow patients that we weren’t as familiar with classifying.

And so I think what was — I picked out this one because I think this is really important because we have to individualize this. Who do we treat? And I think if you look at those patients that had less than 6 months first-line time to progression of endocrine and CDK, there is a dramatic improvement. So we’re seeing here up to 14 months with T-DXd versus standard of care chemotherapy. Hazard ratios in the 0.3 category, which again, we don’t see very often in breast. We do see the impact with 6 to 12 and greater than 12, but it’s most dramatic in this less than 6 months. And why this is so important in clinical practice is that we’re having to decide which patients should we use it on. A lot of people are not so comfortable with the early transition. But clearly, we have to personalize this. And there’s a group of patients where it matters.

This is the PFS2 data, 6 months. And I was really amazed how much the Breast06 and Breast04 data look quite similar. And I think expect to see some other data coming up likely in the next 6 months as well looking at some of these other subgroups that I think are relevant for Breast06 as we try to tease out who really should we put on T-DXd. I think this compound in terms of an ADC is very different from all the other compounds, quite honestly. HER2 really is the surface marker that is used to get the drug into the cell. And I think we’re seeing quite extraordinary paradigm shifts in activity in a group of patients on the study.

DR LOVE: Nancy, anything you want to add to that? And also, the issue of HER2 ultralow/ER-negative disease, which wasn’t looked at. Of course, there are very few patients. You can understand why. I don’t know if it is going to be looked at. But from a practical point of view, a patient who has hormone receptor-positive ultralow, no other options, would you use, have you used T-DXd?

DR LIN: Yeah. So I think that one very practical comment is that when you see a patient who has HER2 0 disease by IHC, now you have to go back to the pathologist and ask them if it’s ultralow. So that’s the practical aspect of it.

And I certainly would use this in the hormone receptor-positive HER2 ultralow patients who were certainly included in DB06. I think the question that you had was, what about the triple-negative ultralow patients? I’m not aware of any trials that are specifically looking at that population and I’m not sure we’ll have Phase III data. We might have some real-world type of data.

I actually have not tried getting this reimbursed as of yet. I will say from a practical standpoint, we tend to use any biopsy. So if any biopsy in a triple-negative patient is HER2-low, we will go for T-DXd, we will suggest T-DXd at some point in time. And that does get insurance reimbursement. So you’re really only talking about the patients who, like, every single biopsy has been HER2 0 and the triple-negative. And I would personally tend to give them sacituzumab, for example, first because I think there’s more data there. We allowed giving T-DXd, I think, if they were truly HER2 ultralow, but I haven’t actually, I will say, I haven’t tried doing it yet.

DR LOVE: Yeah. I’d be curious to know if anybody has done that or seen some responses. We just came back from the Society of Gynecologic Oncology meeting. We did a program on HER2-positive gynecologic cancers. And we showed a bunch of videos of gynecologic oncologists in practice presenting cases. And finally, we haven’t seen this until now, we start to hear cases of people really getting treated with T-DXd and responding. And I saw that same look on their face that I saw 4 or 5 years ago, an oncologist, they started to see what this really meant in terms of patient care. So now, you’re starting to see it outside of breast cancer.

Well just to try to make it a little more complicated, we have another ADC, Rebecca, available, now approved, Dato-DXd for HER2-positive disease. Maybe you can comment on what we know there in terms of the activity, tolerability. I’m curious what your experience has been with mucositis. This is an ADC that we’re hearing a little bit more about that. In particular, I’m really interested from both of you about where you think this — where you’re sequencing this. What comes first, saci or Dato? So any general comments, Rebecca?

PROF DENT: Well, first of all, if you haven’t heard of it, it’s another TROP2-directed ADC. I think most importantly, it’s given every 3 weeks intravenously. I think for those of us in clinical practice, these scheduling issues are important. The toxicity is really important. So these are patients that are randomized who’d had endocrine therapy, had chemotherapy. Randomized to either receive standard of care chemo versus Dato-DXd. Very similar data, to be honest, that we see with sacituzumab in this context, sort of a couple of months of improvement in PFS. Unfortunately, it did not reach its overall survival endpoint. I suspect it’s just in terms of historically when this trial was done. When they did the sacituzumab ER-positive trials, they had access — they didn’t have access to subsequent agents whereas in the TROPION-01 study, they would have had access to other ADCs and other therapies.

So I think these compounds, in terms of efficacy, quite honestly, are quite similar. How we’re going to choose our drugs I do think is going to be on schedule and side effects. So if someone is tolerating saci well and doesn’t have any issues about diarrhea and low blood counts, they might be able to do saci. The Dato, you mentioned it doesn’t seem to have ILD, doesn’t seem to have the diarrhea. And fatigue, actually, for me, that’s one thing I’ve noticed by using the same compounds. Ironically, I always tell people the longer you’re on treatment, that’s where things start to get — we’ve got a drug that works, can you continue that drug? And so in some patients, saci, they tolerate it well. In others, fatigue has become an issue for me and counts. In Dato, fatigue doesn’t seem to be low blood counts but the mucositis is very different and they have to use prophylaxis. Once it happens, it’s hard for it to reverse. So it’s really important, much like I think we’re seeing with everolimus. We’re much better now at giving it prophylactically. And I think we have to see larger, broader groups of patients get it. And then, as we talked about, we’ll have to see the first-line trials in TNBC. Again, just sort of looking at the side effect profile, I think, how we’re choosing drugs. My hope is that in the future, AI can kind of give us a sense, okay, you need to get this sort of surface marker-directed drug, this potential payload. I think that’s going to matter a lot for how we choose our drugs.

DR LOVE: AI, that’s interesting.

ADCs for HER2-Positive Breast Cancer

DR LOVE: Alright. Let’s talk about ADCs for HER2-positive disease. One thing I just want to comment on is you showed this slide, Rebecca, that I thought was interesting looking at the CLEOPATRA trial compared to, of course, CLEOPATRA looking at pertuzumab/trastuzumab and docetaxel. But then, as I mentioned before, presented originally in 2011. Then, the DESTINY second-line trial where you have a really incredible benefit there of T-DXd over T-DM1. And I guess the real question, Nancy, is going to do this trial, DESTINY-Breast09 looking at first-line T-DXd. We were talking before about endocrine therapy and palbo and CDK in HER2-positive disease. We may have to think through that whole thing if this trial is positive, which I don’t think they’re taking any more wagers in Las Vegas on this because most people are expecting it to be positive although I think there’ll be pretty good wagering going on about the pertuzumab. But, Nancy, any thoughts? We’re going to wake up one day and there may be another press release saying this is positive.

DR LIN: Yeah.

DR LOVE: And I believe they use it indefinitely too. So the question is, where’s palbo going to fit in? Are you really going to use it indefinitely? Do you expect it to be positive? And do you know when it’s going to be presented? This is like a memory test, Nancy, to see if you can remember all my questions.

DR LIN: Alright. So I don’t know when it’s going to be presented. I do think it’ll probably be positive. And if it is, I do think it’ll change practice assuming that it is sufficiently positive to overcome the toxicity profile.

I think the big question is really, as you say, well there’s a couple questions. One is it is possible that this is going to be so effective that it cures some proportion of patients with metastatic breast cancer. And then, the trick is going to be to figure out who can just stop everything. I think the other question is going to be for the majority of patients, do we really need to give it forever until progression? Are you really going to give people 4 or 5 years of continuous every 3-week T-DXd? Or can you give an induction and then give some sort of HP or HP-like maintenance or PATINA-like maintenance or what have you? So I think that’s going to be the big practical question that comes up if DB09 is positive.

DR LOVE: Anything you want to add to that, Rebecca? And also, where’s the next stop for T-DXd? In your talk, I think you were the one who did the update on the KATHERINE trial that you see there that Chuck Geyer from the NSABP presented. And in the post-adjuvant space, of course, there’s a lot of interest in. Tucatinib is being looked at there. I think T-DXd is looking at that. I don’t know if there are adjuvant, neoadjuvant trials in T-DXd. Rebecca, where do you see — what’s next after first-line therapy of mets for T-DXd?

PROF DENT: Well, I don’t want to steal Nancy’s fire, but I think the bottom line is Nancy has done some amazing work in CNS metastases with T-DXd and other compounds. And I think, truthfully, that’s been our really unmet need is these patients that have either isolated disease or that remains a challenge. So I think shifting these into the adjuvant or neoadjuvant context, we’re going to be seeing actually trials readout. So there’s T-DM1 versus T-DXd in that residual disease setting. There are some neoadjuvant trials going on. Yeah. So the move is going to be to see it in the early breast cancer setting. Can we actually prevent CNS metastases in the first place? Can we cure patients in that setting, is probably the most important question for all of us.

DR LOVE: And, of course, now we have some data. And I’m hearing different answers to the same question I asked a couple years ago in terms of how people deal with patients with brain mets, particularly in the second-line setting, Nancy. And here’s DESTINY-Breast12 that looked at HER2 — T-DXd actually with and without brain mets, but this is the segment that had brain mets. And pretty interesting activity there. And I’m hearing a lot of people talk, you know, prior to this, 2, 3 years ago when we said what’s your second-line therapy after TCP for metastatic disease with brain mets. We were hearing the HERCLIMB with tucatinib. Now, I’m hearing people, and even when we do surveys, they’re giving this answer, T-DXd. A 71% response rate. Any comments, Nancy?

DR LIN: Yeah. This is a very large cohort. It’s not a randomized study, but there are 263 patients involved. The median PFS was 17 months. And so that also, I think, alleviated some of the concern about whether T-DXd would suppress new brain mets from appearing as that wasn’t really known. But with this, CNS would be counted as an event. So we are seeing that there must be some suppression happening. The CNS response rate was 70% overall. It was actually over 80% in patients who had not previously had radiation. So we’re seeing very, very good activity. As a comparator, in HER2CLIMB, although with a more heavily pretreated population, the HER2CLIMB CNS response rate was around 50% and the PFS on average was shorter. So I think we are seeing really robust activity with T-DXd, really fairly in line with what we are seeing in the nonbrain met population, over 90% 1-year survival. So I really do feel comfortable using this now in the second-line setting in patients with even active brain metastases.

DR LOVE: So I guess another question, Nancy, this came up with HERCLIMB as well is, what are the situations where you would hold off on radiation therapy, particularly if it had to be whole brain, and use systemic therapy like HERCLIMB or now it seems like T-DXd? Is that a strategy you’ll use in somebody without CNS symptoms?

DR LIN: I do. The HER2-positive patients, even with brain mets, they can have extended survival. So we are seeing, in some of the academic databases, median survival of HER2-positive brain met of 3 years or longer and about 40% of people alive at 5 years. We never would have seen that before. And you do see whole-brain late toxicity when you give it early. So eventually, many people end up getting whole-brain radiation, but we’re trying to kick the can down the road and give it later so that we’re avoiding this late toxicity, which could be very devastating.

If somebody is a candidate for very simple SRS, they have 3 lesions, they’re on HP maintenance, I generally send them to radiation oncology. They get their SRS and they continue HP along their merry way. But for the patient who has multiple lesions or who has SRS and then 3 months later, there’s 6 new lesions that appear, that’s really the person I am putting on systemic therapy.

DR LOVE: So, and here’s Nancy’s conclusion about the DESTINY-Breast trial.

HER2-Targeting Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer

DR LOVE: I want to talk about a topic we don’t talk about that much. But we actually had one of our posters at San Antonio that looked at the issue of post-adjuvant neratinib. And we had a couple of papers this year looking at neratinib in metastatic disease. Nancy, can you comment on this? And this is, again, your area of interest and expertise. In this situation for brain mets, combining it with T-DM1. What’s the biology of the thinking behind this combination? And what about this regimen clinically?

DR LIN: Yeah. So I think that on the left is some data from Memorial Sloan Kettering showing that actually what neratinib does is it drives HER2 receptor intracellularly. And remember, T-DM1 does not have a bystander effect. So you need to get it in the cell to have an effect. So essentially, what neratinib is doing is driving T-DM1 into the cell.

And on the right is data from a brain met PDX model showing that neratinib monotherapy basically is inactive. T-DM1 has some activity. But with T-DM1 plus neratinib, you’re seeing complete responses. And so we looked at this combination, this was led by Rachel Freedman, in patients either without previous T-DM1 or who had actually progressed on prior T-DM1. So we’re looking to see does it overcome T-DM1 resistance. And I think that’s the most interesting cohort. So in the previous T-DM1 exposed patients, the response rate is 28% with a 12-month OS of 80%. So we are seeing this. And with monotherapy neratinib, we only see 8% CNS response rate. So there is something happening with the combination and I think it’s very interesting.

Very few patients had had previous tucatinib. Very few patients had previous T-DXd. So we really don’t know if this response rate will hold up. But I do think it’s, you know, we are needing to have regimens for patients who’ve had both tucatinib, cape as well as T-DXd. So it’s nice to have another option for these patients who have CNS disease.

DR LOVE: Nancy, what about the issue of HER2 mutant disease? Of course, in non-small cell lung cancer, this is the most common use of T-DXd is HER2 mutant disease. They use it in the first-line setting. But what about neratinib or neratinib plus trastuzumab with these mutant, it’s a TKI, neratinib in terms of HER2 mutations, the SUMMIT trial. Any comment? How often do you see HER2 mutant disease in breast cancer, Nancy? And any thoughts about this trial?

DR LIN: Yeah. I thought this was a fascinating trial. So we’ve already seen data for HER2-mutant ER-positive breast cancer where the triplet of neratinib/trastuzumab/fulvestrant is very active. But the question is, what about triple-negative breast cancer, a more aggressive type of breast cancer? And HER2 mutations here are found only about less than 2% of the time. So they’re not very common. But amazingly, the response rate here was between 35 to 40%. And with the doublet of neratinib/trastuzumab, you saw a median PFS of 6.2 months. So if you look at, if you think about data with eribulin or other sort of late-line triple-negative metastatic trials, these data look pretty compelling to me.

ADCs for Advanced Triple-Negative Breast Cancer

DR LOVE: So I just want to finish out with something I think, you know, we had some great other content that was presented we were going to get to tonight, but I want to try to finish on time. But I did want to get into the issue of ADCs. And particularly, Rebecca, the issue of sequencing ADCs. We talked about now that we have another ADC, Dato-DXd, now approved for hormone receptor-positive breast cancer, we talked about that. But Nancy put together some interesting slides looking at the different ADCs and the data, we’re not going to go through all the details, that are available right now with hormone receptor-positive but also triple-negative metastatic breast cancer. Anything you want to say about the way you sequence in this situation? Particularly, the issue of where Dato is fitting in, mainly we know it’s approved with hormone receptor-positive, but even theoretically with triple-negative. You went through some data looking at that as well. Any comments, Rebecca?

PROF DENT: Sure. I think first, as Nancy alluded to, the largest body of literature that we have in triple-negative is with sacituzumab. So I think this is sort of our go-to ADC for metastatic TNBC. I think a lot of us are using T-DXd in our patients that are sort of triple-negative HER2-low, but I think we prioritize saci over T-DXd except maybe in the context of someone that has CNS metastases. Because certainly, I haven’t had a lot of success with saci in brain mets. And so I’ve been actually prioritizing T-DXd, and I’ve had some modest sort of benefits.

What we have now though is we have a number of first-line trials looking at either an ADC on its own or an ADC plus immunotherapy in patients that are PD-L1-positive. And we think that that actually has some synergy in upregulating STING. And so I think bottom line is please watch out for those trials because those are going to readout essentially by the end of the year, all of those trials. We also have a newcomer sac-TMT, which looks like another highly potent TROP2-directed ADC. And that seems to be in the sort of stomatitis/myelosuppression toxicity.

And then when it comes to sequencing, you were asking me, I think there’s a lot to be learned. Most of the patients do better with their first ADC. But if you actually look at the plots, some of the patients actually go get benefits in their second. So if money permits, I think many of us are going into that second-line ADC as well.

DR LOVE: We have been talking up, there was a big ADC education session at San Antonio that I found fantastic. It really got into a lot of the issues of sequencing and resistance to ADCs. Of course, this goes way beyond breast cancer as well.

So I want to thank our faculty, Rebecca and Nancy, for working with us tonight and also doing these presentations. Audience, thank you for attending. Be safe, stay well and have a great night. Thanks so much, Rebecca. Thanks so much, Nancy. Have a good one.

PROF DENT: Thank you.

DR LIN: Thank you.