HR-Positive Breast Cancer — Rebecca A Dent, MD, MSc

PROF DENT: My name is Rebecca Dent. I’m a medical oncologist at the National Cancer Centre in Singapore and DUKE-NUS Medical School. I’m going today focus on the ER-positive subset of patients.

So I thought we’d start in the early setting, so in the adjuvant context. And I think you’re all familiar now with the monarchE trial, which was looking at the role of adjuvant abemaciclib, a CDK inhibitor, in combination with endocrine therapy in high-risk, node-positive, ER-positive, HER2-negative breast cancer.

So as many of you know, well over 5,000 patients were randomized to either receive abemaciclib in combination with endocrine therapy versus endocrine therapy alone. And what’s interesting is that they chose a high-risk population, so over 90% of the patients in Cohort 1 had greater than or equal to 4 nodes positive or 1 to 3 nodes that were Grade 3 or had a tumor that was over or equal to 5 cm. Less than 10% were this group of 1 to 3 nodes that had a high Ki-67, Grade 1 or 2, tumor size less than 5 cm. And their primary endpoint was invasive disease-free survival.

So I think when this data first came out a few years ago, around the 2- to 3-year mark, I think many of us were chatting with our patients, but we were really kind of wanting to see longer follow-up on these patients. And I think what you can see here, not unexpectedly, we know that in ER-positive breast cancer, as compared to ER-negative breast cancer, you continue to see the events continue up to 5, 10, 15 years.

So it’s not surprising that here at 60-month follow-up we’re seeing a delta of almost 8%, so an improvement in invasive disease-free survival of 76 to 84%. And I think for me, who was a little bit cautious early on, I think now all the patients are off abemaciclib, and they’ve all had much longer follow-up, I think many of us now are convinced that there is some signal happening here, with a hazard ratio of 0.68, and benefit across all of the relevant subgroups and independent of Ki-67 status.

So some interesting data presented by Erika Hamilton last year looking at benefit by age. And what’s interesting is you see the benefit regardless of patients under or over 65, maybe a slightly bigger delta, as you can see, 7% versus 5%. But I think what’s most notable is that in the patients that were greater or equal to 75 there was significantly more Grade 3 diarrhea, fatigue and more discontinuations. And in fact, up to 20% of patients stopped without a dose reduction.

So I think for me what is really important about this compound, now that we’re actually seeing greater efficacy, is that we need to be very prudent about making sure we educate patients about taking their antidiarrheal medication. And I think you’ll see a lot of studies emerge about starting, especially in the older population, at 100 twice a day rather than the full-dose 150 and then quickly escalating once the patients get the hang of it. Because it’s otherwise fairly well tolerated, but I think just getting accustomed to the therapy and then escalating. So I think you’ll see a lot of these real-world studies and side effect monitoring.

Now, looking at the NATALEE study, now we’ve seen data with adjuvant ribociclib in combination with aromatase inhibitors in ER-positive, HER2-negative breast cancer.

Now, I want to focus on what’s different about this study. So first of all, they allowed endocrine therapy up to 12 months before randomization, which is compared to just 12 weeks with the monarchE study. They included a lower-risk population, so anatomical Stage IIA, so that included node-negative patients with Grade 2 and evidence of high risk, which was defined as Ki-67 that was greater than or equal to 20%, and Oncotype Score over 26 or high-risk via genomic profiling, looking at MammaPrint, or they were Grade 3, included N1 and then the Stage IIB or IIIs.

And again over 5,000 patients were randomized to either receive standard endocrine therapy or standard endocrine plus ribociclib. Now what’s important is that they got 1 dose lower than we typically use in the metastatic setting, so it’s 400 versus 600, and it was continued for 3 years versus 2 years in the monarchE study, and their primary endpoint was invasive disease-free survival.

So what’s really interesting, if you match up the NATALEE and the monarchE, when you look at the early median follow-up there’s a fairly modest benefit. It’s only when you start to look at 48 months you’re starting to see that delta of 5% improvement in terms of invasive disease-free survival.

And then when you look at the node positive and node negative, again, both seem to have this delta, improvement in invasive disease-free survival. Even, I would say, in this lower risk-population of about 5%. And why this is so important for me as a clinician is 5% is kind of the threshold where I feel compelled to start really discussing this more seriously with my patients, because this is, I think, as a community, we think as the threshold for balancing benefit and risk, and we need to discuss it with our patients.

Now, I think a couple of weeks ago Angela DeMichele presented at the St Gallen meeting, and I think I really liked how she just kind of put this together. So the longer follow-up, so both NATALEE and the monarchE study, both ribo and abemaciclib, both are showing, I would say, better than anticipated improvements in invasive disease-free survival, where the curves are really likely to continue to separate. But neither of these studies are actually showing an overall survival benefit at this time. And I think that’s where I think some of us do struggle, because we like to see that survival benefit that we see with PARP inhibitors now and other therapies. But I think it’s going to be difficult to show this given the heterogeneity of the ER-positive breast cancer, just inherent heterogeneity, heterogeneity in practice, and how long we’re going to need to follow up these patients and how heterogeneous the treatment’s going to be. So I think as a community we are really going to struggle in this regard, and we’ll have to personalize therapy and discuss it with our patients.

Now, I wanted to talk about now the metastatic landscape, which has become extremely complex for those of us in clinical practice. And I wanted to start by just going through this ESMO guideline because I think it really highlights some of the key bottlenecks where we’re having to make decisions. So the first one is do we go with an endocrine/CDK approach first or chemotherapy? And then once we get past that, my goodness, we have a lot of options, and how do we navigate through that at this point? And part of that, obviously, will depend on where we’re living and what our approval process is, but also toxicities.

So first I wanted to talk about the RIGHT Choice. And this was a trial mostly actually conducted in Asia, but more than 200 patients were randomized to receive CDK inhibitor ribociclib and endocrine therapy versus chemotherapy for these “high-risk” ER-positive metastatic patients. Now what’s important? Well, these patients did have elevations in their AST/ALT. They were allowed to be included if their bilirubin was increased to less than or equal to 1.5 times upper limit of normal. But it’s still not entirely clear who these patients were. So it is a slightly higher-risk group of patients. 86% of them, though, were greater than or equal to 50% ER-positive, 65% were de novo metastatic, and about 50% were deemed to have visceral crises.

And they were randomized to receive ribo at the full dose versus physician’s choice of combination chemotherapy. So I think many of us have shifted to using single-agent chemotherapy, but in this context a doublet was used, and I think it’s because I think physicians otherwise might have been a bit nervous to use single-agent chemotherapy. But ironically, when we actually look at the results, even with doublet chemotherapy ribociclib outperformed in terms of progression-free survival combination chemotherapy by about 9 months.

This is a randomized over 200-patient study, but clearly patients had fewer symptoms, and I was really quite impressed how this data performed.

So then we had the PADMA data presented this year, which again I think has given us a lot of comfort when we see our patients to approach patients who have even visceral disease with an endocrine therapy combination with CDK inhibitor. Because here we have a study, 150 patients, again, a small study, looking at palbo and endocrine therapy versus single-agent chemotherapy. Here we have a slightly lower rate of de novo, only 40% of patients. But again, what you’re seeing is an improvement in progression-free survival, 18.7 months versus 7.8. So palbo plus endocrine outperformed standard of care chemo. Again, small numbers, but for me in my practice, if I have a patient who is needing to be admitted because they’re sick and need an urgent diagnosis of their metastatic disease, I’m going to give them chemotherapy. But if they’ve got visceral disease, and their liver function tests are not too aberrant, I think it is very reasonable to offer this patient a CDK plus endocrine therapy. And so I think this data does give us that reassurance.

Now what happens in clinical practice? Well, we know that when we have patients on adjuvant endocrine therapy for now up to 10 years, if they’re on endocrine and CDK for the first-line setting it could be several years before we need to switch. But what that means is that we see emergence of mutations, such as an ESR1 mutation, which render these patients resistant to the ongoing therapy.

And so I think we’re getting used to using fulvestrant assuming that these patients have an ESR1, but we haven’t really up until now understood why we’re doing it. And I think what’s interesting is this probably represents up to 40-50% of patients, again, once they’ve been on several years of endocrine and CDK inhibition.

What’s interesting to me is I always thought an ESR1 mutation was an ESR1 mutation, but in fact there are different kinds of ESR1 mutations. Most of the aberrations lie in the ligand-binding domain. And in fact, you can have ESR1 mutation now. It’s beyond the scope of today’s discussion, but I think, as you’ll see as we’re doing other trials, there may be some drugs that are more suitable for ESR1 mutations, but certainly not now.

So in clinical practice if a patients on a CDK inhibitor and endocrine therapy what do we do when they progress? So this was the basis for the postMONARCH study. Now these patients ended up being patients who progressed on CDK and AI as their advanced therapy or they progressed on or after adjuvant. But in reality what it ended up being is most of the patients were treated for advanced disease, progressed on a CDK, in the majority of the patients it was ribo and palbociclib. Most of them were not on abema.

So when these patients progressed they were randomized to go to either single-agent fulvestrant or abemaciclib plus fulvestrant. There were about 370 patients.

And so what you can see here is in the investigator-assessed PFS very modest improvement in PFS. And what was really interesting was that the bigger assessment, which we considered to be much more objective, there was a much bigger improvement in PFS, 5.6 versus 12.9 months, and you can see the 6-month PFS rate, which suggested that certainly there was clearly a group of patients that still benefited when we switched the type of CDK and the endocrine therapy.

And what you can see here is in the subgroup analysis of the investigator-assessed PFS when patients had less than 12-month PFS, you can see these patients on single-agent fulvestrant, only 3 months. It improved with abema and fulvestrant to 5.5. When the PFS was greater than 12 months, again, there was a modest improvement, about 2 and a half months, but clearly these patients that were on their CDK and endocrine longer overall did better.

I think the most important message I took home from the postMONARCH is that patients without visceral disease seem to be the ones that got the most benefit from switching to abema from palbo or ribo. You can see 5.6 looking at fulvestrant alone, so single-agent endocrine therapy, versus the combo of fulvestrant/abema we got 11.1 months. Those patients with visceral disease, they’re not doing very well regardless. So I think this indicates to us we need to personalize therapy.

Now what about SERENA-2? We’re starting to see the emergence of looking at the oral SERDs, and in this particular study it was camizestrant. This was a randomized Phase II. They were looking at patients who’d all had a prior CDK inhibitor, had lung or liver metastases. They were exploring different doses of camizestrant versus fulvestrant IM. And this is a fairly small study.

But what it showed us is an early signal that camizestrant, again, an oral SERD, looked to clearly be superior than our traditional fulvestrant at 500 mg, so 3.7 versus the oral SERDs of well over 7 months.

And then as expected, the benefit was largely confined to those patients that had a detectable ESR1 mutation. So you can see there, those with fulvestrant 500, if they had an ESR1 mutation, their first scan, they were progressing. Median PFS was 2.2 months versus the camizestrant arms that were at 6 and 9 months. Now what you can see is in those patients that did not have an ESR1 mutation detected the results looked very similar for fulvestrant in the oral SERDs.

So I wanted to take a moment to walk us through the SERENA-6 design because this is relevant this year because the SERENA-6 results are going to be reading out.

Now why is this so important? This is going to fundamentally change how we look at patients that are on endocrine and CDK inhibitor therapy in this first-line setting. Their goal was to get ahead of clinical progression with the idea to extend the benefit of this first-line therapy.

So what they were trying to do is look at patients that are on this traditional endocrine AI plus CDK inhibitor, and they can be on any CDK inhibitor first line. And then what they were doing is they were doing serial plasma ctDNA testing every 2 to 3 cycles looking for the emergence of these ESR1 mutations, then they were doing tumor imaging as was standard of care, and if there was no emergence of ESR1 mutations then the patients discontinued on the therapy indefinitely. But if there was this emergence in the plasma ctDNA of an ESR1 mutation, and no radiological evidence of progression, so they find this mutation, they do the scan, they don’t find anything, then patients are randomized to an early switch to camizestrant, so the oral SERD. They maintain the same CDK inhibitor and endocrine therapy or they continue on the AI, maintain the same CDK inhibitor and placebo for camizestrant. So again, an early switch without radiological progression when they find the ESR1 mutation, and the primary endpoint is progression-free survival.

So we had a press release that came out last month really revealing to us that the study is positive for progression-free survival, and so I think we’re all anxiously awaiting the delta, what is the impact of this data, which will be coming out this year.

So in the same vein looking at those oral SERDs, here we look at EMBER-3. And this data was presented at San Antonio last year looking at imlunestrant plus or minus abemaciclib for ER-positive, HER2-negative disease. So who were these patients? They had recurred on or within 12 months of completing their AI plus or minus CDK inhibitor or they had advanced on first-line AI plus CDK inhibitor. One arm was imlunestrant, so looking at the oral SERD on its own. The second arm was looking at standard of care endocrine therapy, which could have included fulvestrant or exemestane. And then later they added a third arm. As we know, the breast cancer world is quite dynamic. So they added an arm that looked at imlunestrant plus abemaciclib. And then the primary endpoint was looking at PFS in ESR1 mutants but also all patients.

What you can see in those patients that harbored an ESR1 mutation improvement from 5.5 months with the oral SERD on its own, imlunestrant, in combination with abema was 11.1 months, so quite an impressive delta. 0.53 was the hazard ratio. But what was interesting is they also saw results or improvements in those patients without an ESR1 mutation, so looking at imlunestrant 5.5 versus 9.1, so not as much as those patients with an ESR1 mutation, but there still was a benefit and a hazard ratio of almost 0.6. Similarly, we saw benefit in patients who got a prior CDK inhibitor, as well as patients who had aberrations in the PIK3CA pathway. So I think we’re anxiously awaiting the overall survival data on this particular oral SERD.

This is some of the numerical data that we saw at the interim analysis with only 31% maturity, but certainly numerically looks like there is an improved survival.

Now, I think one pathway that we’ve really been focused on over the years, because we know it drives tumor progression and resistance mechanisms to different treatments, and I think also importantly is that up to 50% of these patients will have aberrations in PIK3CA, PTEN or AKT.

So what we know from the CAPItello 291 study, this was looking at the AKT inhibitor capivasertib in combination with fulvestrant versus fulvestrant alone. There was an improvement in progression-free survival from 3.1 to 7.3 months, hazard ratio of 0.5. You can see these curves separate quite early.

And I think for those of us in clinical practice you do see diarrhea and rash. You do see hyperglycemia, but it’s much less than we’d previously seen with alpelisib. You can see here 2% Grade 3 hyperglycemia with capiva and about 16.3% overall.

Now, looking at some of the quality-of-life domains, again, I want to highlight the diarrhea here. And so I think why this is important, much like we see with abema and other compounds, we really have to get on this early and help teach patients and provide education about how to manage these side effects. Because I think these are side effects we’ve become used to managing and should be able to help our patients in this regard.

The INAVO study is another new compound that I think really brought a lot of excitement to the field, that was presented first at San Antonio in 2023 by Komal Jhaveri and published in New England by Nick Turner, was looking at this triplet of inavo plus palbo plus fulvestrant. And why this is interesting is that inavo is a selective inhibitor of the catalytic alpha isoform subunit. So if you go back 20 years, we started off having more broad inhibitors, then we started looking at different subunits, and now we’re looking at actually mutation-specific PI3 kinase inhibitors. So as we start to focus in a bit more I think we’re seeing greater efficacy with fewer side effects.

Now, this was a group of patients with a very poor prognosis. They all had PIK3CA mutations as determined by central ctDNA or local tissue or ctDNA test. They’d had progression during or within 12 months of their adjuvant endocrine therapy. So really impressive for the investigators to find these patients, over 300 patients, again, randomized to either palbo plus fulvestrant versus the triplet with the addition of inavo PIK3CA inhibitor.

And this was the result. So first presented we saw an improvement from 7.3 months to 15 months, hazard ratio of 0.43. So again, a very poor-prognosis group of patients with this triplet, impressive improvements in terms of efficacy. Additional analyses we’ve seen in terms of time to discontinuation of the next line of treatment or death. So this is, as we know, this proxy for PFS2, 15 months with the doublet, 24 months with the addition of inavo. And then time to first subsequent chemo, as we know is so important to patients, 15 months with the doublet, and we have not reached the median for the triplet combination. So again, we await the overall survival data for this combination.

But again, I wanted to highlight how far we’ve come. Going back 20 years, some of the older compounds that we used to use, these were very difficult to tolerate, did not have, I would say, that impressive in toxicity, but now we see alpelisib, capivasertib, and now with inavo hazard ratios of 0.3, and impressive improvement in terms of progression-free survival, with compounds that I would say as a clinician are much better tolerated.

And so for the last part I just want to talk about I think many of us have heard about these antibody-drug conjugates. DESTINY-Breast06, as we know, is a Phase III study looking at trastuzumab deruxtecan versus chemotherapy. What makes this study different from DESTINY-Breast04, (1) it included HER2-low and HER2-ultralow patients. These patients in this study had not had prior chemotherapy, so they have just had endocrine therapy, and so in this study we compared T-DXd versus physician’s choice chemotherapy. And as I said, HER2-low and -ultralow, almost 900 patients were randomized. Primary endpoint of progression-free survival.

Now, I think you’ve all seen the initial data in terms of PFS. Interestingly enough, we’re seeing a very similar PFS to what we saw with DESTINY-Breast04. But this presentation by Aditya Bardia at this year’s San Antonio was, I would say, very important for the clinic because here we look at PFS by time to progression on first line. So if you relapsed within 6 months of getting endocrine and CDK inhibitor therapy there was an improvement from 6.5 to 14 months. So if you got T-DXd it was 14 months, standard of care chemo only 6.5 months. Hazard ratio of 0.38, which let’s be honest, we don’t see too much in breast cancer.

When we looked at 6- to 12-month time to progression there was an improvement, 7 to 13 months, but as I said, not as robust as this early-relapsing group. Greater than 12 months, 8 months for physician’s choice, 13 months for T-DXd. So I think this is important as we personalize therapy, and then what you can see here as PFS2 in the overall ITT population we see a delta of almost 6 months. So for me, again, I don’t think this compound is for everybody that has just progressed on endocrine therapy, but it gives us some clues who is most likely to get the biggest benefit with this agent.

I think you’ve all started to hear about Dato-DXd, which was recently FDA approved in the US. This is another TROP2-directed antibody-drug conjugate. This study was in ER-positive disease. They would have had 1 or 2 lines of prior chemo, randomized to Dato versus standard of care chemotherapy.

And what you can see is a progression-free survival of about 2 months, which is hazard ratio of 0.63. And this is very similar data to actually what we saw with sacituzumab with the early PFS readout. But what we see is in the final overall survival data it did not look like it improved overall survival. Now, this may, in fact, I think, partly be because patients have access to a number of other therapies and would have had access to saci and other antibody-drug conjugates. It’s hard to know.

Now, what is interesting is looking at the PRO endpoints. And I think why this is really important is that I think a lot of these ADCs, except for maybe T-DXd, which I think is in a class of its own, the efficacy looks quite similar. I think how we might choose our ADC likely has to do with the schedule and the side effect profile that might be well suited to one patient versus another.

The HER3-DXd data. This was presented ICARUS. This is really impressive, this waterfall plot, and I think this compound has struggled to find its place because it’s not clear which subtype of breast cancer it might work best in. There are no ongoing Phase IIIs that I do know about. Interesting enough, there is some interesting literature in the lung field. And from what I’ve seen, actually it looks like the drug that’s the most penetrant in the CNS. So I think we’re anxiously awaiting some interesting data in that domain.

And then finally I want to end with, yes, ER-positive, HER2-positive disease. So we all know based on the CLEOPATRA study that our go-to first-line therapy, at least for now, is dual blockade with HER2 therapy in combination with chemotherapy that we use as induction. Then we usually continue the patient on dual blockade HER2 antibodies, and if they’re ER-positive, then we’ll give them endocrine therapy. And then we move on to usually T-DXd second line.

But the question is, is there a role, potentially, for these patients to give them a CDK inhibitor. So in this study, again, they looked at patients who completed their induction chemotherapy, were ER-positive and HER2-positive, this is the PATINA study. Over 500 patients then were randomized to continue on their dual blockade with endocrine or get the addition of palbociclib.

And so this was a very, I think, simple design, but such an important study, where you see when you actually added palbociclib, the CDK inhibitor, to the anti-HER2 and endocrine therapy, you see a median PFS of 44 months versus 29 months without the CDK inhibitor. So what’s, I think, nice for patients is that there is no chemo, there’s no IV drip, potentially, you’re getting oral therapies with subcutaneous. So for patients I think this was really interesting, very simple design. Maybe not for everybody, and as I said, the landscape may change.

But again, this is really interesting. Looking at overall survival we don’t see a benefit. So I do wonder whether this is the same concept as we see with chemo, where for the longest time we’ve been arguing singlet versus doublet. And I think many of us would say as long as you get the chemo sequentially maybe it doesn’t matter. So will this hold true for CDK inhibitors? I don’t know, and I don’t know whether those studies have been done, but I think this is certainly data to watch.

So speaking of which, there’s a lot more to come in 2025. We’ve got ESMO Breast, AACR and of course the ASCO Meeting. I look forward to seeing you all there. Thank you for your attention.

DR LOVE: That was an awesome presentation. If I could, I was just going to ask you a few follow-up questions. The 2 trials you were talking about with chemo versus CDK, one of the things I don’t think they looked at, and I’m not even sure how often people do this or whether it’s considered a legitimate strategy, is “chemo induction” followed by hormone maintenance.

PROF DENT: Yeah. They didn’t.

DR LOVE: Given the patient a few doses of chemo. Do you think that’s something that people do at all? Or they just go right to hormonal therapy?

PROF DENT: Oh, yeah. No, no, absolutely. What was really interesting, actually, is I’m hoping my clinical judgment’s intact because a lot of the patients I’ve done that end up not doing so well. So I’ve had 2 that they were clearly in visceral crisis, I had them on chemo, they wanted off chemo, and then I put them on endocrine and CDK, and they relapsed within 3 months.

So yeah, so bottom line is it wasn’t done for the trials. I know a lot of people do that in clinical practice. What’s interesting is that the patients that you feel compelled to give chemo on are patients you want to watch closely, because if you felt to give them chemo in the first place then you’re going to watch them cautiously.

One thing I didn’t talk about, to be honest with you, is where you really run into trouble is with ribo. Because we’ve seen a lot of transaminitis. We’ve seen a lot of liver dysfunction in ribo.

So I had a patient that I put on ribo, and it’s rare that really regret something that I’ve done, but she had some liver disease. I think her transaminases were just slightly above normal, and then after a month they went sky high. Bottom line is you can’t tell is it liver disease or is it the ribo.

DR LOVE: Right.

PROF DENT: And so I tend to give CDK inhibitors first line if people have lung disease, because I had a patient literally whiteout of one lung. She was a 26-year-old from Bali who had had chemo in the adjuvant setting and said there’s no way in hell I’m taking chemo. And so I was so nervous, and she was on it for 3 years. I mean she did so well.

DR LOVE: Wow.

PROF DENT: But she’s the one who gave me the courage to do it. I didn’t want to do it.

DR LOVE: Interesting.

PROF DENT: So I get a little more nervous. This is where I actually go back to palbo sometimes, if patients really don’t want chemo I’ll give them palbo and endocrine. And I have to say I’ve had some great results with palbo and endocrine in that first-line setting.

DR LOVE: So another question. You showed some data that I’ve seen several times, but when you showed it today I saw it differently. It was the data from, I forget which DESTINY trial it was, but the one where Bardia —

PROF DENT: Breast06.

DR LOVE: Right, yeah, 06, where he presents time on CDK correlating with T-DXd benefit, right? But this is T-DXd. Why would endocrine sensitivity affect T-DXd?

PROF DENT: No. Actually, this has to do more with resistance. So the idea is if you relapse within 6 months of endocrine and CDK —

DR LOVE: Right, right.

PROF DENT: — your biology is very different. You’ve developed a very resistant tumor. And so that’s why going to some — I would say a very novel mechanism of action is helpful.

DR LOVE: Yeah, sure. Right. But this is randomized against chemo not against hormone therapy, right? So why would T-DXd be better than chemo in people who are endocrine sensitive?

PROF DENT: To be honest, I think it’s just a more aggressive phenotype. I think one of the biggest challenges, I’m sure you struggle with this, how is it possible after so many years of giving chemo we have no chemosensitivity assay, right? Patients come to me for second opinions, and “I don’t think my doctor knows what they’re doing. They just keep throwing chemos at me.” And look, I’m going to do the same thing. I’m not going to do anything different. I’m always honest. And that’s the truth. Whereas, I think with ADCs, and especially T-DXd, to be honest, is fundamentally different is it just figures out a way — does it deliver drug better to the tumor by, again, it’s not blocking HER2, it’s using HER2 as a vehicle to get chemo into the cell.

DR LOVE: That’s interesting.

PROF DENT: And traditionally chemo can’t do that. No, that’s why I love this data, honestly. So I’m one of the authors on DESTINY-Breast06, and I said, “This is the data.

DR LOVE: So ER-positive metastatic disease. I’d like to know right now, I don’t know whether you have Dato available, but assuming you have Dato available, where would you sequence it in a HER2-low or HER2 0 patient? And do you give sacituzumab before? Do you go T-DXd, saci, Dato? And then what happens if it’s HER2 0?

PROF DENT: Great question. So first of all, we do not have access to Dato by any means, and to be honest, we mostly have saci access for triple-negative, okay? So I don’t even have that much access for ER-positive.

DR LOVE: Right.

PROF DENT: Yeah. So you know that data with T-DXd with DESTINY-Breast06, I think the same is probably true for saci. So patients that I go to saci are the really heavy burdens, where I need 1 kick, and I don’t have time to waste time sequencing patients through chemo. Which drug I give? I think T-DXd is in a class of its own. So if someone’s HER2-low they’re always going to get T-DXd. And I’ve done a lot of rebiopsying and alerting my pathologists, and I think they’ve become really good at finding these patients.

So saci really is for the clearly HER2 0s. I haven’t had too much luck with sequencing, meaning one after the other, but of course I’ve had the occasional one where the sequencing works, so now I’m compelled to do it if I can get it reimbursed.

Where Dato works? Where Dato fits? I honestly don’t know. I mean, Dato has the difficulty of being last to market. I think the big thing is that it’s an every 3-week dosing. So we have a big issue with getting chair time for patients, and patients hate coming day 1 and 8, so every 3 weeks is really a very manageable schedule for patients. And I work in Asia, where people fly from Jakarta for their treatment, so an every 3-week dosing is very acceptable for them.

I think it also comes down to side effects. So some patients, they through a few cycles of saci, and they’re just ready to die. They’re tired. They have diarrhea. They just don’t want to continue, and if you have triple-negative, well that’s your only choice, so you just carry on. But you’re ER-positives, you kind of feel like I’ve got other options, so that’s where I see Dato having a role. The fatigue, for me, is not nearly as profound with Dato.

I’ll admit a conflict of interest. I’m leading the triple-negative study with Dato, so I’ve had a little bit more experience with Dato.

The mouth sores are the main thing. If you use the prophylactic mouthwash it seems to not be a problem.

One of my colleagues in Brazil, we were on a call the other day, and he was saying “ This is the best tolerant systemic therapy I’ve seen in a while.” It doesn’t seem to have the ILD. It has this rare dry eye business. To be honest, I’ve been fortunate, and most of the Phase I people I know at MD Anderson say it’s more that once you start looking for it when they do the eye exams you see the dryness. But it’ll be interesting to see how it plays out because, as I said, I think they’re all going to be quite similar. It’s really a toxicity profile and a scheduling issue.

DR LOVE: And with all these ADCs coming in, where does capecitabine fit in?

PROF DENT: Capecitabine is the cheap and easy-to-give drug. You’ll just kind of sequence it when your patients have had enough —

DR LOVE: Do you think people will use it as a spacer between ADCs?

PROF DENT: Yeah, yeah. I do.

DR LOVE: I don’t know.

PROF DENT: I think they’ll use it as a bridge. They’ll use it as a bridge. So if people have exhausted their endocrine therapies.

HER2-Positive Breast Cancer and Triple-Negative Breast Cancer (TNBC) — Nancy U Lin, MD

DR LIN: Hello. Thank you for joining me. My name is Nancy Lin. I’m a medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts. And today, we’ll be reviewing topics in HER2-positive breast cancer and triple-negative breast cancer.

So the first topic is KATHERINE. And this is an update of the KATHERINE data in the final analysis. As a reminder, this trial took patients who received neoadjuvant therapy with HER2-directed therapy and chemotherapy, and patients who had residual disease were randomized 1:1 to either T-DM1 or trastuzumab.

At the final analysis in terms of invasive disease-free survival, the 7-year estimated IDFS was 80.8% in the T-DM1 arm and 67.1% in the trastuzumab arm for 13.7% absolute gain in IDFS. The 7-year overall survival was 89.1% in the T-DM1 arm and 84.4% in the trastuzumab arm. So for the first time showing a significant gain in overall survival of 4.7%. And remember, the median overall survival from the time of HER2-positive metastatic breast cancer in the modern era is at least 5 years. And so seeing survival differences at 7 years I think is quite impressive.

In terms of exploratory analyses, there were several key exploratory analyses that I want to highlight. The first is there was an analysis looking at the benefit of T-DM1 according to the HER2 IHC status. For patients who were 2+ IHC, they did need to be FISH-positive to enter the trial. But you can see that the hazard ratio for benefit for T-DM1 was more significant in those with 3+ disease compared to 2+ disease. And the interaction term here was significant. Another important subgroup was those patients who had residual disease that was less than 1 cm with ypN0 disease, so what we would normally think of as a somewhat lower-risk group. And there have been questions about what the value is of T-DM1 in this subset. And in fact, there was a significant value of T-DM1, 7-year IDFS of 85.7% versus 76.7% with a hazard ratio of 0.62. And importantly, there was a similar benefit including the ypT1a and ypT1b groups. A third important subset was those patients who had centrally confirmed HER2-positive disease on their pretreatment biopsy, but had HER2-negative disease in the residual disease after neoadjuvant therapy. There are 70 patients in this group. And, again, there was a difference in favor of T-DM1 even in this group of patients who converted to HER2-negative residual disease. And finally, looking at CNS recurrences as a component of the first IDFS event. Unfortunately, there was no benefit of T-DM1 in this setting.

So the conclusions for the KATHERINE study are that we now see in the final analysis a substantial improvement in IDFS and now demonstration of an improvement of approximately 5% absolute delta in overall survival with adjuvant T-DM1 compared to trastuzumab. This confirms the value of T-DM1 and inclusion in the standard of care. And then again, in the important subsets, more benefit in 3+ but still benefit in 2+ IHC. Substantial benefit in ypN0 patients even with ypT1a or T1b disease. And benefit in patients with HER2-negative residual disease. Obviously, the 7-year IDFS is only 80%, and that still leaves much room for improvement. And these will be looked at with additional trials including CompassHER2 RD, which will look at the addition of tucatinib to T-DM1, DESTINY-Breast05, which is comparing T-DXd versus T-DM1, and ASTEFANIA, which is asking whether immunotherapy adds to T-DM1.

Moving on to the next paper, this is the ATEMPT update at 5 years. This trial looked at an arm of T-DM1 and an arm of paclitaxel/trastuzumab for patients with Stage I HER2-positive breast cancer. Importantly, there was a 3:1 randomization and the arms were not designed to be directly compared for efficacy. Each arm was to be evaluated separately for efficacy. About half the patients enrolled in the trial had T1c tumors, 75% were hormone receptor-positive, and only 4% had N1mic disease. The rest had N0 disease. In this study, there were only 11 IDFS events in the T-DM1 arm representing only 3 distant metastases among 383 patients enrolled to that arm. The 5-year IDFS was 97% and the 5-year breast cancer specific survival was 99.4%. If we look at the TH arm with paclitaxel/trastuzumab, the 5-year IDFS was 91% but the confidence interval goes up to 97%, similar to what was seen in the previous APT trial even if the point estimate for 5-year DFS is lower in this smaller patient population of only 114 patients in this arm. And again, the 5-year breast cancer specific survival, 99%.

An important exploratory analysis or correlative analysis within ATEMPT was looking at the predictive value of the HER2DX Risk Score. To remind people, this is a 27-gene expression and a clinical feature-based classifier. The score comes out as shown on the lefthand panel. There is a relapse risk score, a PCR likelihood score, and an ERBB2 mRNA score. And for this analysis, the focus was on the lefthand score, the relapse risk score, which was either high or low. On the right, you can see that the score did separate the patients with excellent versus less than excellent IDFS, so 96.3% in the low-risk group, 81.8% in the high-risk group. It is important to note that only 6.4% of patients in this trial had high-risk disease according to the HER2DX assay.

So for my conclusions and thoughts for ATEMPT. We see that there are excellent 5-year outcomes with adjuvant T-DM1 for a year in Stage I HER2-positive breast cancer. Again, the trial was not designed to formally compare T-DM1 and TH. If we look at the toxicity tradeoffs, clinically relevant toxicities were higher with T-DM1 although you can see that many of those toxicities were hematologic toxicities, which one could argue are not necessarily symptomatic. Patient-reported outcomes favored T-DM1, particularly with alopecia and work productivity. And there was less neuropathy with T-DM1 and actually, less amenorrhea at 18 months also with T-DM1. This data adds to a body of literature that HER2DX risk score predicts risk of recurrence. And I think that what it tells us is that T-DM1 is an option for patients, particularly if there’s a desire to avoid paclitaxel/trastuzumab for whatever reason. And then, remember that if you are going to be giving paclitaxel/trastuzumab, which still remains our standard go-to for Stage I HER2-positive disease, scalp cooling can be effective at preventing alopecia in about 75% of patients. In terms of ongoing trials, the ATEMPT 2.0 trial will substitute 6 cycles of T-DM1 as opposed to 1 year, and then trastuzumab to complete a year in hopes that this will be an equally efficacious but less toxic regimen. And the ADEPT trial is looking at a chemotherapy-free regimen of trastuzumab/pertuzumab in combination with endocrine therapy for those patients with Stage I ER-positive HER2-positive breast cancer.

Moving on to DESTINY-Breast01. We’ve seen this data before, but this is an update because median overall survival had not been reached in the primary analysis, and this updates that primary analysis. As a reminder, the trial enrolled 184 patients treated at 5.4 mg/kg. Patients had received a median of 6 prior lines of therapy for their metastatic disease. And 100% of patients had received prior trastuzumab and prior T-DM1. The confirmed response rate as previously reported was 62%. And ILD was noted in 15.8% of patients, 2.7% of which was Grade 5. So now, let’s look at the updated results.

If we look at a median follow-up of 26.5 months, only 28 patients were still on treatment at the date of cutoff. Median PFS was 19.4 months as shown on the left. And median overall survival, 29.1 months as shown on the right.

So I think these data further solidify the value of T-DXd in patients with HER2-positive metastatic breast cancer. We’re looking at a median overall survival of 29 months and response rate of 62% in heavily refractory patients with a median of 6 prior lines of therapy before study entry. These data certainly are consistent with data from DESTINY-Breast02, which enrolled a less heavily pretreated population and showed a median overall survival of 39 months. And then if we look at other third-line and beyond trials such as SOPHIA and HER2CLIMB, the overall survival certainly compares reasonably to those. Although I’ll point out that there are certainly important differences in the patient populations. For example, the HER2CLIMB trial enrolled half of patients with brain metastases as compared to a relatively small proportion of DB01. I think these data do not change our current sequencing where we’re usually putting T-DXd in a second-line standard of care. But it does tell us that for those who missed out on T-DXd in earlier lines of therapy, T-DXd remains and is very effective in later lines. And of course, we’re eagerly awaiting results of the DB09 trial, which will evaluate the role of T-DXd with or without pertuzumab in the first-line setting.

Moving on to DESTINY-Breast02. As a reminder, this was a trial that compared T-DXd versus treatment of provider choice. And that provider choice could either be trastuzumab/capecitabine or lapatinib/capecitabine. The key eligibility were HER2-positive metastatic breast cancer progressing on or after T-DM1. And patients in the trial had a median of 2 prior lines of metastatic therapy. The overall trial results have been previously presented and showed an improvement in PFS and improvement in overall survival.

Now with the updated data including the patient-reported outcomes. On the left are Kaplan Meier curves that depict the time to deterioration of global quality of life with T-DXd versus treatment of provider choice. So the events here are deterioration of quality of life. The blue line is the T-DXd. The green line is treatment of provider choice. And you can see that there is a longer time to quality-of-life deterioration with T-DXd compared to treatment of provider choice. On the right, the forest plots are just showing the different components of quality of life including physical functioning, emotional functioning, social functioning, et cetera. And in all of the domains, the T-DXd arm is favored. Importantly, if they look at specific toxicities, there are more treatment emergent nausea and vomiting with T-DXd in early treatment cycles, but this improved after cycle 3, presumably because prophylactic antiemetics were not initially built into the protocol. But then over time as patients were managed for their nausea, the nausea improved. And there was more diarrhea in the treatment of provider choice. Remember, this included capecitabine. And this diarrhea persisted over time.

So my conclusions and thoughts for DB02 in terms of the PROs is that T-DXd convincingly extends time to deterioration of quality-of-life compared to trastuzumab/capecitabine or lapatinib/capecitabine. And I think this is important just given the perception of the toxicity profile of T-DXd. Still when the side effects are well managed, you are able to preserve quality of life. I think it speaks to careful attention to the antiemetic regimen. And I’ll point out that in the 2024 NCCN guidelines, T-DXd is listed as having high emetic risk. And for those with high emetic risk, the NCCN recommends 1 of 3 regimens, either elanzepine, NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone, or elanzepine, palonosetron and dexamethasone, or an NK1 receptor antagonist, 5-HT receptor antagonist and dexamethasone.

Now moving on to DESTINY-Breast03. This trial was a Phase III trial which compared T-DXd versus T-DM1 in patients with pretreated HER2-positive metastatic breast cancer. Just a reminder of the patient and treatment characteristics, 15% of patients had CNS metastases at baseline although they had to be inactive or asymptomatic, 15% had prior HER2 TKI exposure, and there was a median of 2 prior lines in the metastatic breast cancer setting. About 40% of patients had 1 prior line. As previously reported, the confirmed objective response rate was 79% versus 37%. And now, we’re seeing the updated analysis at a median of follow-up of 43 months for T-DXd and 35 months for T-DM1.

And here’s what we see with the update. The median PFS for T-DXd is now 29.0 months versus 7.2 months with T-DM1 for a hazard ratio of 0.30. And a 3-year progression-free survival of 46% versus 12%. And you can see that there really does seem to be a bit of a plateau on the curve, particularly in the T-DXd arms. And it’s consistently a wide difference compared to T-DM1. On the right are showing the overall survival curves. The median overall survival was 52.6 months versus 42.7 months with T-DM1. Hazard ratio of 0.73.

So in terms of DB03, just as a reminder. There’s careful attention still needed for ILD counseling, surveillance and management. The overall any grade ILD rates in DB03 were similar to other trials, 16%. But importantly, in this trial, there were no Grade 4 or 5 events. And that, I think, speaks to a greater awareness and vigilance for ILD as trials have progressed in this space. The overall ILD rate with T-DM1 was only 3.4%. Importantly, about one-third of patients in the T-DM1 arm subsequently received T-DXd. And it's possible that this cross-over may have diluted the overall survival differences, and we would have seen a larger survival delta had there not been cross-over. When they did try to adjust for this in sensitivity analysis, it did, as expected, widen the OS difference between arms. There were relatively few patients with brain metastases enrolled in DB03 and none with our traditional definition of progressive brain metastases after prior local therapy. And so I think that leaves the CNS question open. But I think the substantial benefits in both PFS and OS confirm that T-DXd should be the preferred second-line regimen for the vast majority of patients with HER2-positive metastatic breast cancer despite the toxicity tradeoff versus T-DM1.

Now moving on to DESTINY-Breast12. This study looked at the role of T-DXd in patients with or without brain metastases. But for today, I’m going to focus on the cohort of patients with baseline brain metastases, which comprised 263 patients. Importantly, in this trial, patients with either stable previously treated brain metastases or active brain metastases were allowed. And active brain metastases included those with previously untreated disease. Or if they had previous treatment with local therapy, they had to have a progression after that local therapy to enter.

Here are the main data for the DB12 study in the brain metastasis cohort. The median progression-free survival was 17.3 months. The 12-month PFS was 61.6%. And the 12-month overall survival was 90.3%. The overall response rate including extracranial disease was 51.7%, but it went up to 64% if we just restrict to those patients who had measurable disease by RECIST. And then I’ll show you in the next slide the CNS response.

So if we look at the patients who had measurable CNS disease at baseline, overall, the CNS response rate was 71.7%. And you can see from the waterfall plot that very few patients had disease progression as best response. So we saw a small number of patients with minor responses and a large proportion of patients with a confirmed objective response. Looking specifically at the patients with active brain metastases, those with previously untreated disease experienced a response rate of 82.6% in the CNS. And impressively, the lower bound of the 95% confidence interval here is 67%. Looking at those patients with previously treated progressing disease, the response rate was lower at 50%, but I think still quite good in this heavily pretreated population.

So in terms of DESTINY-Breast12, we saw robust and durable intracranial activity of T-DXd in patients with both stable and active brain metastases. I think these data increase our confidence in the use of T-DXd in the second-line setting even in patients who have active CNS disease. It provides a systemic option for patients to be weighed against local therapy. You saw response rates in excess of 80% in patients with previously untreated disease. And so for those patients where the option might be whole-brain radiation, I think it does put T-DXd up as an attractive counterweight to that. ILD remains an issue. In this trial, there were more ILD events compared to other DESTINY-Breast series trials. Some of this is probably because the ILD was investigator-reported and not centrally confirmed ILD, which had been the case in most of the other DESTINY trials. And in addition, there were multiple patients who had co-occurring opportunistic infections including PJP and aspergillosis. And this really speaks to the importance of PJP prophylaxis and reduction of minimization of the steroid dose, if possible, in patients with brain metastases.

Alright. Now, we’ll move on to TBCRC 022. This is T-DM1 plus neratinib for patients with HER2-positive brain metastases. So just as a brief rationale for the combination. On the left are data from Memorial Sloan Kettering. In the red is the neratinib treated cells essentially showing that neratinib actually increases intracellular trafficking of HER2 from the cell surface into the cell. And because T-DM1 does not have a bystander effect, it is thought that by actively getting more drug into the cell, you’re actually increasing payload levels and potentially overcoming T-DM1 resistance. On the right are data from the laboratory of Jean Zhao at Dana-Farber. This is a PDX model of HER2-positive breast cancer brain metastases treated either with CONTROL, neratinib, T-DM1 or the combination. And you can see the brain tumors have some response to T-DM1 monotherapy, but the responses are deeper and more durable with the doublet.

And so this led to the conduct of the TBCRC 022 trial, the cohort that included the specific combination of T-DM1 and neratinib. I’m showing you 2 of the cohorts here. On top are those patients who had progressed after prior local therapy but had not had prior T-DM1, and the CNS response rate was 35% with a median PFS of 4.1 months and a median overall survival of almost 2 years. On the bottom are those patients who had progressed after prior local therapy and had had prior T-DM1, so we would not necessarily expect a response to T-DM1. And here, the CNS response rate was 28.6%. Median PFS, 4.1 months. And median overall survival of almost 21 months.

So in terms of TBCRC 022, I think the conclusions here are that even with the advent of T-DXd and the HER2CLIMB regimen, there’s still a substantial need for multiple lines of systemic therapy for patients who have active brain metastases. They ultimately progress on both regimens for the most part. And we need something to offer after that. The CNS objective response rate to the combination exceeds that of neratinib monotherapy where we’ve seen responses only in 8%. And we’ve seen that about one-third of patients with prior T-DM1 exposure still can respond in the CNS with the doublet. A major limitation of the study is that no patients had received prior tucatinib just based on the timing of the accrual. And only a few of the patients had prior T-DXd. We’re still awaiting more granular CNS data from HER2CLIMB-02, but I do think this provides another systemic option for those patients with HER2-positive brain metastases who have already received T-DXd and tucatinib.

Now moving on to SUMMIT trial. This trial evaluated neratinib or neratinib plus trastuzumab in a number of disease baskets. And here, we’re seeing data from the triple-negative breast cancer basket. So in this basket, patients with triple-negative HER2 mutant metastatic breast cancer were either assigned to neratinib, and that was the first 10 patients, or neratinib plus trastuzumab, and that was the next 17 patients.

Here are the data for the efficacy outcomes. The objective response rate was 40% with neratinib monotherapy and 35% with the doublet. The median progression-free survival, however, significantly favored the doublet. It was 2.89 months with monotherapy, 6.2 months with the doublet. On the right, you can see the waterfall plots that are color coded according to type of ERBB2 alteration. And at least from a qualitative standpoint, there’s no statistics here, the deepest responses were observed in those with exon 20 insertions.

So what do we do with this data? I think that these are actually very impressive response rates, 35 to 40% in pretreated, median of 2 to 2.5 prior lines, HER2-positive, triple-negative breast cancer. There’s a longer duration of response and progression-free survival with the doublet. So trastuzumab does seem to be contributing here. And these are small numbers, but I would argue that they compare very favorably to third-line and beyond chemotherapy in triple-negative breast cancer. So I do think that these are potentially practice changing results. The previously published data in hormone receptor-positive HER2-negative mutant metastatic breast cancer was a response rate of 38.6% and a median PFS of 8.3 months with a triplet that included endocrine therapy with fulvestrant. And then most recently, we have seen a publication with tucatinib and trastuzumab in HER2 mutant metastatic breast cancer. There, the response rate was very similar, 41%. Median PFS, 9.5 months. So really similar to what we’re seeing in the SUMMIT hormone receptor-positive cohort with a triplet including fulvestrant. Importantly, in that tucatinib report, there were only 4 patients with triple-negative breast cancer included. So I think at this point in time, the SUMMIT triple-negative basket really represents the largest dataset for triple-negative HER2-mutated metastatic breast cancer.

Alright. Now moving on to KEYNOTE-522. This is the neoadjuvant pembrolizumab study for triple-negative breast cancer. And here, we’re seeing the results for the key secondary endpoint of overall survival. As a reminder, this trial randomized patients 2:1 to chemotherapy with or without pembrolizumab. About half the enrolled patients were node-positive. This was a young population with a median age of 48 to 49. There were only 132 patients on the trial, 84 who received pembro who were age 65 and over.

Here's the results of the key secondary endpoint of overall survival. You can see that there is now a separation of the curves going from 81.7% to 86.6% at 5 years for a hazard ratio of 0.66, and this is statistically significant. On the right are the forest plots showing that across clinically relevant subsets including node-positive, node-negative, PD-L1-positive and PD-L1-negative as well as the carboplatin schedule of weekly or every 3-week, we are seeing consistent benefits with pembrolizumab. And then I just point out again that there are very few patients above the age of 65 enrolled, and so the confidence interval for the benefit here is very wide.

If we look at overall survival by pathologic response, you can see that for those with a PCR, there really doesn’t appear to be any major separation of the curves for overall survival. But for those patients who did not achieve a PCR, a significant improvement in overall survival from 65 to 71%.

So at a median follow-up of 75 months, we’re seeing a 5% gain in 5-year overall survival with the addition of pembrolizumab to neoadjuvant chemotherapy in patients with triple-negative breast cancer. There’s a similar hazard ratio for benefit in node-positive and node-negative. And the benefits are seen regardless of PD-L1 status. So I think these data support the use of the KN-522 regimen as standard of care, including for patients with T2N0 disease or node-positive triple-negative disease. There are still, of course, many questions. One important question is whether we really need to give the adjuvant pembrolizumab portion of therapy for those patients who achieved a PCR. And this is being tested in the OPTIMICE-PCR trial. Obviously, for those patients who we want to avoid anthracyclines, we want to understand in whom can we safely de-escalate the anthracycline. Of course, we have data already from the NeoPACT trial of carboplatin/docetaxel/pembrolizumab for 6 cycles. And again, there were very few patients who were treated in the older age groups on KEYNOTE-522. Who can do well with chemotherapy alone and not need the toxicity associated with pembrolizumab? And how can we better improve outcomes in those with residual disease where the 5-year overall survival is still only about 70%?

Alright. Now moving on to OlympiA. This adjuvant olaparib in germline BRCA1 and 2 carriers. I just want to highlight the eligibility criteria. For those patients who received neoadjuvant therapy, triple-negative just required residual disease of any kind. But for ER-positive patients, it required a CPS+EG score greater than or equal to 3. In the pure adjuvant group, triple-negative required pT2 or N1 or higher disease. But for ER-positive patients, 4 or more positive nodes were required for eligibility. In this trial, most patients had BRCA1 alterations, 70%. And 80% had triple-negative breast cancer. And it was about half and half split in terms of adjuvant and post-neoadjuvant treatment.

Here are the IDFS data for the ITT population on the left, and then the triple-negative in the middle, and ER-positive on the right. Across all 3 groups, you can see that the IDFS delta is about 10%, both for ITT, triple-negative and ER-positive. So similar magnitude of benefit is seen according to breast cancer subtype. Not shown here are the DDFS curves, which looked very similar. Importantly, there were very similar rates of MDS/AML in the olaparib versus placebo arm. There did not seem to be a signal there. There were numerically fewer CNS events as the first IDFS event with patients who received olaparib, 2.8% versus 4.4%. And there were fewer new primary cancers with olaparib.

If we look at overall survival, we are also seeing an overall survival delta. At 6 years, the gap is 4.4% with a hazard ratio of 0.72. And on the right with the forest plot, you can see that the benefit was seen in both HR-positive and triple-negative. The HR-positive confidence intervals are quite wide because of the smaller numbers, and also seen in both BRCA1 and BRCA2.

So in terms of OlympiA, again, we’re seeing a significant IDFS benefit, DDFS benefit and overall survival benefit with adjuvant olaparib. And this was seen in both the HR-positive and the triple-negative patients as well as those with BRCA1 or BRCA2 alterations. And there’s no signal of increase in MDS or AML at 6.1 years median follow-up. I think one of the conclusions from this study is that all patients who meet anatomic eligibility criteria for olaparib who have access to olaparib really should be offered germline genetic testing. This is a really important treatment to be offering our patients, and we want to know who is potentially eligible regardless of family history. In terms of triple-negative breast cancer, one of the important questions is for patients post-neoadjuvant chemotherapy, should we be giving capecitabine or should we be offering olaparib? There’s no direct comparison. If we look at the CREATE-X trial which looked at adjuvant capecitabine after neoadjuvant therapy, there was an 8% absolute gain. So fairly comparable, in the ballpark of what we’re seeing with OlympiA. But on the other hand, if we look at the OlympiAD metastatic breast cancer trial where olaparib was compared to chemo of provider choice, half the patients received capecitabine in the provider choice arm, and olaparib far outperformed the chemo of provider choice.

So in general, at least at Dana-Farber, we’re tending to favor olaparib over capecitabine in these patients who are dual eligible. For those patients with ER-positive breast cancer, the question has to do with whether we offer CDK4/6 inhibitor or olaparib or a sequence. Again, no direct comparisons are available and we probably will never have them. If we look at monarchE, the hazard ratio for benefit of IDFS was 0.68 for a 7.6% absolute gain, but not yet a statistically significant overall survival benefit. For NATALEE, a smaller absolute gain but a lower-risk population. And again, the hazard ratios are very similar. In general, for those patients with 4 or more positive nodes, we generally prefer olaparib. Or for very high-risk patients, we might consider a sequence of a year of olaparib followed by offering the CDK4/6 inhibitor in sequence. For those patients with 1 to 3 positive nodes, and remember, if they were treated in the pure adjuvant setting, they were not actually eligible for OlympiA. One could definitely consider a CDK4/6 inhibitor. Although I will say that we tend to lean towards olaparib because of the shorter duration of therapy at 1 year, and that there’s already an overall survival benefit demonstrated. And for node-negative disease, we’re really far out from the OlympiA eligibility. We tend to think about ribociclib, and carefully select patients who would have met eligibility for NATALEE.

Alright. Moving on with the PARP theme is TBCRC 048. This is olaparib expanded. This is for patients with HER2-negative metastatic breast cancer. Shown here are the initial data from the publication in 2020. And this showed that among a small cohort of 11 patients with germline PALB2 mutations, there was a response rate of 82%. And among those with somatic BRCA1 or 2 alterations, a response rate of 50%.

So this most recent report updates these data with expansion cohorts for germline PALB2 and somatic BRCA1 or 2. In the 24 patients in the expansion treated with olaparib for germline PALB2 alterations, the objective response rate was 75% and the clinical benefit rate was 83% with a median PFS of 9.6 months. For the somatic BRCA1 and 2 where the previous response rate was 50%, here we’re seeing a response rate of 37% with a larger number of patients included. And the clinical benefit rate was 53% with a median PFS of 7.2 months. Importantly, this study excluded patients with prior PARP exposure and also excluded patients with prior progression on platinum.

And then if we look at specific subsets of interest, you can see that in the somatic BRCA, there were responses seen both for BRCA1 and BRCA2. You can also see that the response rate actually did seem to be higher if the BRCA alterations were identified on tumor biopsy. And whether that’s because of differences in variant allele fraction or other potential explanations I think remains to be seen. And then interestingly, if there were biallelic BRCA copy loss, there were only 2 patients, but both of those patients responded.

So TBCRC 048 confirms a very high response rate and durability of benefit of olaparib in germline PALB2 carriers. And I would say that the activity in the somatic BRCA carriers, although it’s less than in the initial cohort, is still very respectable. And the durability of responses is good. The estimates of frequency for somatic BRCA in primary tumors is somewhere in the 3 to 4% range. And honestly, the frequency in metastatic breast cancer, especially in the later-line setting, is not, I think, very well described. I think that these data do indicate sufficient activity to consider testing or NGS testing on a routine basis. And this would justify routine germline testing in metastatic breast cancer patients to identify those with germline BRCA1, BRCA2 and PALB2 mutations as well as NGS testing to identify somatic alterations in those patients to be candidates for olaparib.

Now, we’re going to switch gears and move on to antibody-drug conjugates. And we saw the first data from a Phase III trial of sacituzumab tirumotecan or Sac-TMT for metastatic triple-negative breast cancer, the OptiTROP-Breast01 trial. To review, Sac-TMT is a TROP2-targeted ADC that is conjugated to a topo I inhibitor with a DAR of 7.4.

And this is the trial design. The trial enrolled patients with metastatic triple-negative breast cancer relapsed or refractory to 2 or more prior chemotherapy regimens. And they had to have received a taxane in any setting. The randomization 1:1 was to Sac-TMT or physician choice of chemotherapy. And the primary endpoint was progression-free survival by BICR.

As you can see on the left for progression-free survival, there was a dramatic separation of the curves in favor of Sac-TMT with a median PFS of 6.7 months versus 2.5 months. Hazard ratio was 0.32. So we’re seeing really, the kinds of separation of the curves that we had seen in some of the DESTINY-Breast trials with T-DXd. On the right, you can see the interim analysis for overall survival. The median overall survival was not reached in the Sac-TMT arm, and was 9.4 months in the treatment of provider choice arm. The response rates also strongly favored Sac-TMT, 45% versus 12%. And from a toxicity standpoint, the main toxicities were anemia, neutropenia, stomatitis and thrombocytopenia. Only 1.5% of patients reported neuropathy. And the ILD rate was less than 1%.

So this certainly looks like an exciting new agent with significant improvement in both PFS and OS versus treatment of provider choice in heavily pretreated triple-negative breast cancer. The toxicity profile was mostly hematologic and stomatitis, and there was minimal neuropathy or ILD. There are several Phase III ongoing trials. One is looking at hormone receptor-positive HER2-negative metastatic breast cancer, another in the first-line for PD-L1-negative metastatic triple-negative breast cancer, and then a post-neoadjuvant trial comparing to pembrolizumab with or without capecitabine. So I think some of the important questions here are ADC selection. How will this compare to the existing ADCs, T-DXd, sacituzumab and Dato-DXd? This is importantly another topo I payload, so we’re not really switching out the payloads to a substantial degree. And how much activity will there be if we sequence one after another?

Moving on to a similar and related ADC is we’ve seen a publication of the TROPION-PanTumor01 Phase I data. And this was looking specifically at the breast cancer cohorts. On the left is hormone receptor-positive HER2-negative. On the right, triple-negative. You can see from the waterfall plots that there are significant responses seen in both hormone receptor-positive and triple-negative patients. And on the bottom for the progression-free survival that these responses can be durable.

If we hone in more carefully, we look at the response rate, 26.8% in hormone receptor-positive, 31.8% in triple-negative, and 40% in triple-negative that is topo I naïve, that is no prior sacituzumab. The median PFS was 8.3 months in hormone receptor-positive, 4.4 months in triple-negative, and up to 7.3 months in topo I naïve triple-negative breast cancer.

So how do we put this all into context? So here first is the hormone receptor-positive metastatic breast cancer. I put a number of relevant trials. So if we go from the left to right, on the left are the T-DXd trials, DB06 and DB04. These trials enrolled patients with low or ultra-low HER2 status, 0 prior lines of DB06, 1 to 2 for DB04. And both showed a benefit of T-DXd over chemotherapy of provider choice with response rates around 50%. If we look at TROPION-PanTumor01, there was no upper limit on the number of prior lines. And actually, there were 5 prior lines in this hormone receptor-positive cohort, so certainly a much more heavily pretreated population. Still seeing a very good median PFS. And the response rate, as expected, is lower. We have now recently seen results of the Phase III TROPION-Breast01 trial that compared Dato-DXd versus treatment of provider choice, 1 to 2 prior lines of chemotherapy allowed. And here, the median PFS was 6.9 months versus 4.9 months with the control arm. And the response rate of 36%. And finally, TROPiCS-02 looking at sacituzumab versus treatment of provider choice. A more heavily pretreated population, 2 to 4 prior lines. Median PFS, as you can see, with a hazard ratio that looks really very similar to TROPION-Breast01. And then response rates of 21%. I think my takeaway from this is that all of these ADCs have activity. I think some of the differences that we are seeing in the activity really has to do with the line of therapy that these drugs are being given in. And I think the real question is, how are we going to sequence from one to another?

What about triple-negative metastatic breast cancer? Again, I’m arranging these from left to right as HER2-targeted and then on the right is TROP2-targeted. So on the left is DB04. Again, 1 to 2 prior lines. Remember, the triple-negative cohort in this — subset in this study was rather small with wide confidence intervals, but there was a significant benefit in favor of T-DXd. I’ve put TROPION-PanTumor01 in context here. Again, for the triple-negative patients in this set. They had a median of 3 prior lines for metastatic breast cancer. And we’re seeing response rates of 30 to 40%, 40% in the topo I naïve patients. TROPION-Breast02 is still awaiting reporting, and we’ll see how that looks. That’s a first-line trial. I show here ASCENT looking at sacituzumab, at least 1 prior chemotherapy. Response rate, 35%. Median PFS is 5.6 months. And finally, just to add in the new data that we’ve seen, the OptiTROP Phase I trial Sac-TMT versus treatment of provider choice. Median PFS, 6.7 months. Response rate of 45%.

So I think my takeaway from all of this is we have a lot of ADCs. They’re all active. And we’re going to have to figure out how to use them one after another. Thank you.