Current and Emerging Role of HER2-Directed Antibody-Drug Conjugates (ADCs) — Hope S Rugo, MD

DR RUGO: Hello, I'm Hope Rugo, director of the Women's Cancers Program and division chief of Breast Medical Oncology at the City of Hope Comprehensive Cancer Center, where I specialize in breast medical oncology. It's a pleasure to talk to you today about “Year in Review 2025: The Current and Emerging Role of HER2 Antibody-Drug Conjugates,” and then we're also going to talk a little bit about oral TKIs with the most updated data and some symptom management areas, which I think are particularly pertinent.

So here are our topics. I've divided these into metastatic HER2-positive disease and our focus will be on HER2-positive disease throughout this discussion. So we'll talk about DESTINY-Breast09, which led to, of course, regulatory approval of T-DXd in the first-line setting for metastatic HER2-positive disease. Another, I think, critical presentation from the San Antonio Breast Cancer Meeting in 2025 was HER2CLIMB-05, looking at maintenance with tucatinib after response to a CLEOPATRA-like therapy. We'll talk about the subtype by HR status in DB12 that looked at T-DXd in patients with brain metastases. And then a novel HER2 ADC compared to T-DM1 from China, briefly, as well as a study with the oral TKI pyrotinib in patients with HER2-positive breast cancer that was compared to a novel HER2 ADC, again, a study from China.

We'll talk about 2 critical studies in the early-stage HER2-positive setting looking at T-DXd as neoadjuvant therapy or post-neoadjuvant therapy in DB11 and DB05. And I think this data is of critical importance now because we're already starting to incorporate it prior to regulatory approval into our treatment practices. We'll also talk about HER2-low disease briefly and talk about the publication from last year on the updated data from DB04, as well as patient-reported outcome from DB06, so second-line and first-line T-DXd.

In terms of symptom management, a really important study done in Japan looking at olanzapine for the delayed and persistent nausea with T-DXd in HER2-positive HER2-low breast cancer. And then a study we presented looking at what happens in the real-world setting when you re-challenge patients who've had Grade 1 ILD from T-DXd.

So let's get started with metastatic HER2-positive disease. Of course, CLEOPATRA has been our standard of care now for quite some time. This is the end of study results looking at adding pertuzumab to a trastuzumab taxane regimen with docetaxel compared to trastuzumab alone. This is an interesting group of patients where 90% had no prior trastuzumab, quite different from what we see now, although I think as we move forward, and particularly with the data we'll talk about now, we're going to see most of our patients in the metastatic setting with HER2-positive disease being patients with de novo metastatic disease, so similar, in fact, to this CLEOPATRA population.

Interestingly, although half of the patients had hormone receptor-positive disease, endocrine therapy was not allowed in the maintenance setting in CLEOPATRA, but this is now the standard of care, but it apparently, as I'll show you in a moment, hasn't been socialized well around the world. So a remarkable improvement in median overall survival of 16 months and overall survival of almost 40% at 8 years. And I think also importantly, almost 20% of patients hadn't progressed at a median follow-up of 8 years. So those patients we think are cured of their metastatic HER2-positive disease.

So the question is by better therapies, could we improve this outcome, really capitalizing on the CLEOPATRA trial, which has become our standard of care with paclitaxel and subsequent studies showing similar efficacy to docetaxel?

So DESTINY-Breast09 moved T-DXd into the first-line setting after superior efficacy shown in both the second and greater line setting compared to our standard of care in DB03 and DB02. So DB09 randomized patients who were at least 6 months from their last chemotherapy or HER2-targeted therapy in the neoadjuvant or adjuvant setting and permitted 1 line of prior endocrine therapy, but no other treatment for metastatic disease. There are 3 arms. Patients are randomized in a 1 to 1 to 1 ratio to standard CLEOPATRA regimen, T-DXd and pertuzumab, or T-DXd and placebo. The T-DXd and placebo arm has not reached its median follow-up. So they've only reported, and we only have approval, for the middle arm with T-DXd and pertuzumab versus THP. So we'll see that T-DXd and placebo arm perhaps in 2026.

Endocrine therapy, importantly, was allowed after 6 cycles of T-DXd or after you completed the taxane. And it's actually very interesting to look at the patient population. So 49% were treated in Asia and that may have contributed to the lack of standard endocrine therapy, 52% had de novo metastatic disease, 6% brain mets, and only 7% had prior pertuzumab, 1% prior T-DM1 and under 30% prior trastuzumab. So it's more than what we saw in CLEOPATRA, but still pretty low.

I mean, half of the patients had de novo disease, 40% had prior chemo. So what that means is that some of these patients were treated with chemo without HER2-targeted therapy, which is fascinating because that's not our standard of care.

Here you can see the progression-free survival by Blinded Independent Central Review was significantly improved with T-DXd and pertuzumab versus THP, 41 months versus 27 months with a hazard ratio of 0.56, really remarkable data. And I think strikingly, if you look at 24 months, you can see that that difference is about 18% in terms of the patients who are free from progression, the median being almost 14 months. And then there was consistent benefit in patients with recurrent versus the de novo disease, HR-negative versus positive. About 30% had PIK3CA mutations. They also saw a benefit. And then there was an update at ESMO 2025 showing progression-free and response benefit, again, in these subsets, which are shown here, all with the hazard ratios as well.

So overall survival has less than 20% maturity. So it's still very early. And I think what was interesting to think about is, how long were patients treated with taxane versus T-DXd? So you were allowed, if you had toxicity, to switch to trastuzumab and pertuzumab if you stopped due to reasons other than progressive disease. But that only happened in 9% of patients.

So what was the median treatment duration? Twenty-two months for T-DXd and pertuzumab. But for THP, 17 months. And the median duration of treatment with chemotherapy was 5.5 or 4.4 months, depending on the taxane, and the median number of cycles, 6 to 8 cycles. So what happened was people continued the chemo with T-DXd and pertuzumab, but they dropped the chemo in the control arm and just continued HP.

So what happened with endocrine therapy? So it was interesting that concurrent endocrine therapy occurred in a tiny percentage of patients, 14% versus 38% in patients with HR-positive disease, which is really striking to me because this improves outcomes. So it's bizarre that nobody was put on endocrine therapy. But I think this is used much less commonly in Asia than it is in the US and that probably made a difference. So hard to know.

So in terms of safety, the drug was very safe. I mean, the T-DXd, a lot of nausea, and we'll talk about management of nausea at the end of this presentation, so stay tuned. More nausea and vomiting as expected with T-DXd and GI issues overall, but the transaminitis and thrombocytopenia were with the standard treatment, so it's interesting. If you look at this, you can see that almost a quarter of the patients had some thrombocytopenia, and 6.3% had a higher grade. And I tend not to see that so much in the metastatic setting, so it's intriguing that this was seen.

And then hypokalemia, interestingly, which we can manage, was common. Neutropenia, less common with T-DXd than with taxane. Now, what's really important to us thinking about T-DXd is pneumonitis. Even though it's a much less common toxicity than nausea, it can result in death. This study had a very low mortality, although still 2 patients died of Grade 5 ILD, but it was 0.5%, so that may be the lowest percentage we've seen outside of DB03 where there were no deaths. Overall, any grade was 12%, but most of it was Grade 1 or Grade 2, so that was encouraging. And cardiac toxicity hasn't really been an issue different from trastuzumab with T-DXd.

Now, the addition of pertuzumab to T-DXd is interesting. We don't know what T-DXd alone will do, but most of these patients had not been exposed to prior antibody therapy, so it does make sense that pertuzumab might benefit with the addition of T-DXd here, even though it didn't benefit T-DM1 in the MARIANNE trial. So this will be very interesting to see. We're interested to see whether or not diarrhea is increased. And what you can see is the diarrhea was identical here overall, but what we don't know is the duration of diarrhea. It may have been longer in the T-DXd and pertuzumab arm compared to the THP because this is just any episode rather than duration.

So on December 15, 2025, for our year in review, the US FDA approved T-DXd with pertuzumab as first-line treatment based on this trial, and of course, an associated laboratory test to confirm HER2 positivity.

Now, before we talk about how we put this into clinical practice now, it's important to talk about how we're treating patients now. So our current treatment standard is exactly what was done in DB09. We treat with THP. After best response, we drop the T, and we continue HP alone, and we add endocrine therapy for patients with hormone receptor-positive disease, although apparently not everybody adds endocrine therapy, as we found out.

So we had already seen, and I'll show you that in a moment, that adding a CDK4/6 inhibitor in HR-positive disease improved progression-free survival by a rather striking amount, and although that data was presented in the past and updated in 2025, it was published in 2026 in the New England Journal of Medicine called the PATINA trial.

So in 2025, we saw the results of HER2CLIMB-05, which was tucatinib as maintenance therapy, and here you can see that patients who received their THP for 4 to 8 cycles were randomized to get tucatinib or a placebo with HP, and then you could add endocrine therapy. Fifty percent of the patients had hormone receptor-positive disease and 12% had evidence of brain metastases. They received a median of 6 cycles of therapy.

So very similar to the control arm of DB09. PFS was prolonged from 16 to 25 months with a hazard ratio of 0.64, an improvement of 8.6 months. And this benefit occurred regardless of HR status, although clearly you can see the benefit was larger in the 46% of patients who had HR-negative disease with a delta of 12 months versus 6.9 months for HR-positive.

Now, the CNS-PFS was identical, but if you looked at the patients who had baseline brain metastases, there are 4 different events. But the hazard ratio is encouraging with a delta of 4.2 months, so we'll see what happens with longer follow-up. And the safety was exactly what you would predict, some liver enzyme elevation and more diarrhea with tucatinib, more dose reductions.

Now, PATINA, I think when it was first presented in 2024 and now published in 2026, showed a marked improvement in progression-free survival, but the median PFS went from 29 months to 44 months, so it was much longer than what we saw in the tucatinib trial, which is interesting. If you go back and look at the patients who were HR-positive, you can see that the median PFS in the HR-positive group was less than 20 months, and it went to 25 months, as opposed to in PATINA, where we saw 29 to 44 months. So this is like you're almost looking at different diseases here. But the delta was 15 months, and additional tiny data looked at at San Antonio, even though they didn't do brain imaging on a regular basis, it looked like you had less brain progression in the palbociclib treated group. So this has already become a standard of care. So what do we do with this as we move forward?

Well, we like the idea of maintenance, and DEMETHER is looking at that, T-DXd for 6 cycles. It's a little hard with a fixed number of cycles. But then it goes on to subQ HP with endocrine therapy for HR-positive disease. And for PIK3CA mutant disease, inavolisib is also being studied as well.

So what is our optimal therapy for HER-2-positive disease after 2025? So, accessibility is an issue. I think THP is still the standard of care, but I think most of us would use T-DXd in the first-line setting for patients with early relapse, patients presenting with brain metastases and I think in a maintenance-type strategy, it's very appealing to give T-DXd and pertuzumab for patients even with de novo disease. More nausea, less neuropathy, slightly higher mortality by 1% and this 0.5% death rate from ILD is something that we have to really monitor very closely.

Maintenance therapy, though, is a really critical question, and I've shown you the difference here in the PFS in the different studies showing how important endocrine therapy is. If you actually use endocrine therapy, you have a much better maintenance, and palbociclib, I think, is a good option, a good, I think, example there because everyone had to take endocrine therapy, 29 versus 44 months, so we've got to give endocrine therapy. I personally would use palbo for ER-positive disease as maintenance and tucatinib for ER-negative disease, and I think now what we need to do is study this.

After T-DXd and best response could we stop the T-DXd, switch to HP with endocrine therapy for ER-positive, tucatinib for ER-negative, palbociclib added to the ER-positive group? So this, I think, is our ideal treatment, and we hope that this will be studied in an upcoming Phase III trial, but I think people are already adopting this approach in clinical practice. Careful monitoring for ILD is, of course, critical.

Now what about in the patient with brain metastases? We know T-DXd has efficacy in brain metastases. It crosses the blood-brain barrier. It's been really interesting. So in DB12, 263 patients were treated with HER2-positive stable or active brain metastases with T-DXd, a single-arm trial. There was another arm without brain mets. Primary endpoints, PFS, almost all had 1 to 2 lines of prior therapy, and they saw this amazing PFS of 17 months and a 12-month CNS-PFS rate of 59% and a remarkable overall response rate.

So what they looked at was HR-positive and HR-negative disease, and what you can see here is that overall response was higher in the HR-negative disease, as well as, although this difference overlaps, but if you looked at the CNS overall response rate, you see 79% versus 67%, so that's a little more convincing. Still really remarkable. But if you looked at the overall response in measurable disease, the difference went down to about 9%. And if you looked at progression-free survival, which is shown in these blue bar graphs, there's absolutely no difference. So even though response was a little better, the duration of disease control by progression-free survival was identical, regardless of whether you had HR-positive or HR-negative disease.

So I think that shows us that the efficacy of T-DXd in HER2-positive metastatic disease in brain is maintained regardless of HR status, and I think prophylaxis, to avoid opportunistic infections, is really critical. I've shown here the ILD rate was the highest we've seen in any breast cancer study in DB12, at 15.8% versus 16.5% HR-positive versus HR-negative. And if you look at the actual number of patients who died from ILD, with 3 patients dying from ILD in each subgroup, what we believe that's due to is the concomitant opportunistic infection complication, because patients were receiving steroids for their brain mets and they didn't have PJP prophylaxis.

So this is totally critical, really important to keep in mind. Don't forget if you're on 20 mg of steroids for more than 2 weeks, generally prednisone, you should be prophylaxing, and even in patients who have sulfa allergy, you can give atovaquone now and not worry about the dapsone toxicities, which I think dogged us for some time. So this is really important.

Now, this is great because you don't even need a great response, but one of the things that comes up is if you had asymptomatic brain met, would you treat it with stereotactic radiation? And for HR-positive disease, I probably would. For HR-negative disease, I think we have equipoise, the response rates are really quite remarkable here. But sometimes it's easier if it's a small metastasis to treat it with SRS and go on with T-DXd. If I have, I think I would not, if I was going to retreat, and that was the question versus give T-DXd, I would give T-DXd instead of retreating to avoid the longer-term toxicity.

So now let's just talk about a couple of novel agents, trastuzumab botidotin, kind of a funny name. This is a novel trastuzumab with a MMAF derivative. So this is a microtubule inhibitor or a statin, but it has F not A, and we're used to MMAE, right? Rather than MMAF. These have unique toxicities, as I'll show you in just a moment, and we have another one that's being evaluated by J&J as well in the US. So these patients had 1 to 2 lines of prior therapy, about less than 50% had prior pertuzumab, and they randomized these patients to receive trastuzumab botidotin versus T-DM1. So this is exactly like DB03, but it uses this novel MMAF antibody-drug conjugate.

What they showed was a remarkable improvement in PFS as you would expect, 11 versus 4.4 months, highly statistically significant. Overall survival was immature, but a positive trend. Overall response was almost 24% higher in the experimental arm. There were adverse events. Very few people discontinued, but 62% had ocular events. And this is the main toxicity we see from MMAF. We don't see the neuropathy that we see with MMAE, but we see keratitis, and it can be quite irritating for patients, and I don't think we grade it well.

There's actually a new grading that's been proposed and adopted by my colleague, Neil Pasricha, from UCSF to try and improve the way we grade ocular toxicity. But we're crummy as oncologists, we can't grade keratitis, we can't even diagnose keratitis. But for patients, they have eye pain, and then they have blurry vision, and you can't look at the computer, you can't see the street signs when you're driving. As you can imagine, for all of us, that would be a horrible toxicity. Even Grade 2 keratitis can be very difficult to deal with. So there's a lot of work going on for prevention with specific eyedrop approaches, which I think are very exciting and will be effective, and may allow us to use an MMAF ADC, maybe in sequence, because using different payloads is going to be really important.

We now have a lot of emerging data, even in 2025 as part of our year in review, that I think shows us rather convincingly that a lot of the resistance to ADCs is because of the payload, and not necessarily because of downregulation of the receptor or alternative mutations or alternative resistance profiles but whether or not you can overcome that by using a new payload, or by even waiting and treating later or using a different drug that targets the same area, different payload, we don't really know.

And a lot of studies are going on looking at using the same target with a payload but a different antibody to see whether or not that will allow us to overcome toxicity and in who. The ILD rate with this ADC is very low at 1.1%, and no mortality. So it does bring up the question about whether or not these new ADCs would give us an alternative if patients can't take T-DXd, which is such a disaster for our patients, where you have such an effective drug, but if they have Grade 2 or more ILD, they can't be retreated with T-DXd. We'll talk about retreatment with Grade 1 ILD at the end of this presentation.

So the last trial in the metastatic setting is this Phase III HORIZON trial. So pyrotinib is a potent pan ErbB2 tyrosine kinase inhibitor that's approved in China in the second line in combination with capecitabine because it was better than lapatinib. Now, of course, we use tucatinib in the US, and we don't have pyrotinib approved. There have been a number of Phase III studies with pyrotinib, and this is an additional one, randomized Phase III open label. And because pyrotinib and capecitabine has become the standard of care in China, they wanted to compare it to a trastuzumab antibody-drug conjugate.

So this antibody-drug conjugate, we'll refer to as SHR, is trastuzumab rezetecan. And it has a topoisomerase I payload, a novel TOPO I inhibitor, so very similar to T-DXd in that. And patients were randomized 1 to 1 to their standard of care versus SHR, which is given every 3 weeks. So they had a median of 1 line of prior therapy. Very few patients had prior T-DM1. They all had to have prior trastuzumab and most had prior pertuzumab. So that's important because in the China studies, previously we've seen non-standard prior treatments. And then some had prior endocrine therapy. So what they saw was this remarkable improvement in progression-free survival, similar, and this is like DB02, where we compared T-DXd to lapatinib and capecitabine or trastuzumab and capecitabine. However, in DB02, everybody had prior T-DM1.

And so that's the main problem here, is that, in this comparison. But T-DM1 is not a standard of care before pyrotinib and capecitabine in China. So the 12-month PFS rate you can see is 35.5 versus 85, almost, percent. Median PFS going from 8 to 30.6 months. That's pretty amazing. A hazard ratio of 0.22. We almost never see a hazard ratio like that. And the PFS benefit was seen across all subgroups. So that was really encouraging data.

In terms of the post-progression therapy and overall survival, it's still early, but almost nobody got T-DXd. I mean, 23% in the control group. And the safety dose reductions were higher with pyrotinib. Discontinuations were higher with SHR, but very low at less than 5%. The primary toxicities for SHR are interesting because they're quite different from T-DXd. More bone marrow suppression in alopecia, less GI toxicity and diarrhea, but a very low ILD rate at 2.8% overall and only 0.7% Grade 3. No deaths in this study. So overall, it seems as though more bone marrow toxicity, but less ILD, much less GI toxicity. You have to balance all these toxicities together but a remarkable PFS benefit. So yet another potential contender for this space. But again, no studies in the Western population.

So let's go on to early-stage HER2-positive disease, where we've seen some unbelievable data, really remarkable data that will change our treatment practices, I think, right away in the US and in the world eventually. So the first trial to talk about is DESTINY-Breast11. So this is a Phase III trial looking at neoadjuvant T-DXd alone or followed by THP versus standard of care for patients with high-risk, early-stage HER2-positive breast cancer. So these patients had no prior treatment, newly diagnosed HER2-positive disease, but they had very high-risk disease. So they had to have T3 tumors. And it could be node negative up to N3, or if they were T 0 to 4, any positive node. And they also could go on with inflammatory breast cancer, which often is not immediately treatable by surgery. So I think really important groups.

So these are the 3 arms, 1 to 1 to 1, 930 patients. Sounds like a lot. But once you get down to just the 2 arms, you're not powering as a primary endpoint for overall survival. So that's important to keep in mind, 320 patients essentially in these arms. So the T-DXd alone arm closed a little bit early. They still enrolled a fair number of patients, but it closed at 286 patients because the Independent Data Monitoring Committee felt that it would be unlikely that this would ever be superior to the dose-dense AC-THP arm. The control arm was dose-dense ACT, AC followed by THP, 4 and 4 cycles. Now, that's come under some criticism. But indeed, around the world, this is still very much a standard in neoadjuvant therapy. Even in the US, we use TCHP much more commonly. And there's a lot of questions about whether or not you even need the C, the carboplatin, in that TCHP induction, neoadjuvant regimen. But that's not true in the rest of the world where young patients and patients with very aggressive disease, as were eligible in DB11, are treated with dose-dense AC-THP routinely. So, and we only switched to TCHP because dose-dense AC-THP resulted in—compared to TCHP—resulted in identical pCR and long-term outcome, so I feel like this is a reasonable comparator here because we can assume you'd get the same results with TCHP. Maybe a little different toxicity.

Again, almost 50% of the patients enrolled from Asia. So this is something we're seeing a lot. And, in fact, the FDA, because of the issue of sequencing, has said that for certainly metastatic trials now, they want to see 20 to 30% of patients enrolled from the US because we have different availability of drugs and sequence and they want to have good representation from the US. And what you can see is it was in the arms that ended up giving us interpretable data, less than 15% of patients overall. So almost 90% of patients had node-positive disease. Almost 50% had T3 to T4 disease. So this was a very high-risk group of patients.

Here you can see the primary endpoint, which was pathologic complete response, was significantly improved with T-DXd followed by THP compared to dose-dense AC-THP. It was a bigger difference in the HR-negative group where we already see higher pCR rates. So this is exactly as expected, a delta of 16 versus 9%. But so remarkable, 83% pCR rate in these extremely high-risk disease patients where they had inflammatory disease and all node-positive disease.

The bottom part of this slide shows RCB, which is residual cancer burden, looking at patients who are 0 or 1, because we know RCB1 patients do very well. Here you see a striking difference of 13% for HR-positive disease. This is the highest RCB0 and 1 score ever reported for HR-positive HER2-positive disease at 78%, really remarkable, 90% for HR-negative disease. So just incredible results, I think, from giving this sequence therapy.

Event-free survival is immature. And again, the trial wasn't powered for as a primary endpoint for EFS or OS. But looking at EFS, you can see that there's already a difference of about 3.8% favoring the T-DXd arm. But it is quite immature. The immaturity was just for EFS 4.5%. They expect it to be about 10% at the final analysis. But if you look at 24 months, you see this difference, which I think is interesting and I think encouraging.

So what about the T-DXd alone arm? Definitely want to mention that. I think that there's been very much a cookbook approach forever with neoadjuvant therapy so that we've looked at patients, we give a regimen A versus regimen B rather than changing treatment or evaluating as we go along. And I think we've learned that sequential non-cross-resistant therapy is a cornerstone of our treatment. And this newer trial has sort of cemented our oldest approach to treating cancer that was successful.

So T-DXd actually resulted in a lower pCR rate overall but then they took out the patients who'd switched. So doctors spoke with their feet. So they looked at patients who had received T-DXd and if they weren't having a great response, they switched them. So those patients were still in the intent to treat analysis. When they took them out, the difference in pCR looked to be relatively more similar and event-free survival was similar. But still, this is certainly not encouraging.

And there are other trials going on in triple-negative disease looking at ADC alone for 8 cycles. And I think this trial, if any, should tell us that we really shouldn't be doing that approach. We should either evaluate partway through and stop if they already have a pCR. Or we should use sequential therapy and capitalize on what we already know to be better.

In terms of toxicity, this is interesting. So in DESTINY-Breast11, we see the lowest rate of ILD ever reported at 4.4%. And what was interesting is that most of it occurred during the THP. And there was actually 1 Grade 5 event in both arms. Both of these events occurred during the second half, so during THP for both the experimental and the control arm. We need to understand those events better. I'd love to see the detailed analysis of those events. That would really help us in understanding why this happened. Because in my career, I've never seen a patient die of ILD in the neoadjuvant setting, and we treat a lot of patients. So I don't know if this was late recognition. We know that ILD rates are higher in the Japanese and Korean populations. Could this be where this occurred? We just don't know.

There weren't adverse events that led to any substantial surgical delay. So that was really helpful as well. Dose interruption occurred in almost 38% of patients with the experimental arm, but 55% with dose-dense AC-THP. And again, dose reductions are shown here. They're relatively identical between the arms. I was kind of interested that nausea was still greater with T-DXd compared to dose-dense AC-THP. I think the reason for that is because we are really crummy at treating for T-DXd nausea.

And that will lead us on to our next really important study published this last year about managing the important toxicity of nausea that has such a big impact on quality of life for our patients with T-DXd. More bone marrow suppression, of course, with the THP than with T-DXd, as you would expect. Similar diarrhea, but otherwise, I think it was very well tolerated with 4 cycles of T-DXd given extremely low rates of ILD. Really encouraging.

So T-DXd THP showed the highest reported pCR rate reported to date for HER2-positive early-stage breast cancer, even though a lot of HR-positive disease, 70%, low pCR rates in that group traditionally, and extremely high-risk disease. Anthracyclines don't improve pCR. They're less safe than non-anthracycline based chemotherapy. We cannot give anthracyclines, I think, now. And this is a great alternative regimen.

Sequential non-cross resistant chemotherapy is better than giving the same drug in a continued sequence without evaluating response. And the difference in toxicity, I think, is important. So I think that when we think about this, we need to take it into the context of DB05, which was based on KATHERINE showing an improvement in both invasive disease-free and overall survival at 8.4 years of median follow-up, favoring T-DM1 over continuing trastuzumab alone, not pertuzumab, in patients with residual disease after standard neoadjuvant therapy. Now, it's important to keep in mind the first efficacy data was seen in a median follow-up of 3.4 years in the KATHERINE trial, right? Remember, about 3 and a half years.

So then we get to T-DXd in the post neoadjuvant setting in DESTINY-Breast05. So here, patients with residual disease were randomized to T-DXd versus our KATHERINE approach, T-DM1, both given for 14 cycles. But they wanted to really understand the benefit of T-DXd in patients who had a high risk of recurrence, the highest risk. So patients had to present with either inoperable disease, and that was carefully defined, shown on this slide, or operable disease with node-positive disease at surgery.

So the only patients who could be treated with node-negative disease had to be inoperable at diagnosis. The primary endpoint is invasive disease-free survival. And this trial randomized over 1,600 patients. So it's powered also for overall survival as a secondary endpoint. Now, the data was presented at a median follow-up of just 30 months, so a little over 2 years to see a positive endpoint compared to 3 and a half years for KATHERINE. That already tells you something. Seventy percent of patients were HR-positive, similar to KATHERINE, because we see residual disease more frequently in that population, node-positive disease in 80% of patients and most of the patients received HP as HER2-targeted therapy. So that's very helpful. And I think important to looking at the toxicity that concurrent radiation was allowed and that was given for over 50% of patients in this trial.

So this is this first interim analysis at just 30 months, showing a marked improvement, almost a 9% improvement in invasive disease-free survival. And you can see the difference here, 83.7 versus 92.4%, hazard ratio of 0.47. Unbelievable results. And the curves separate very early. You're seeing this curve separation before 6 months, which I think corresponds to the earlier presentation of positive results. And what about the number of events? Is this local or distant? As we've been seeing now with MRIs and better surgery, the difference in events is all distant, 77 versus 42. And there's actually a trend towards less CNS events as the first invasive disease event. So it's 25 versus 17 events. So very, very encouraging in this trial population.

So they also looked at disease-free survival, which showed similar results. And all the subgroups showed a benefit for T-DXd versus T-DM1. Now what about some of these other events? Distant recurrence-free interval, brain metastasis-free interval and overall survival. Overall survival is 3% maturity, but at least it's positive. We'll see. It's just a trend. It's too early now. And the brain metastasis-free interval also is still too early, but it is at least going in the right direction with less events, as I showed you. And of course, distant recurrence-free interval we talked about earlier.

What about safety? That's key when we're thinking about this. So there was a 10% rate of ILD, 9.6% exactly, versus 1.6%. It's quite rare with T-DM1. And 2 patients died of ILD, so 0.3%. This is still an ongoing issue for us. It's a very low rate. It's less than the 0.5% seen in DESTINY-Breast09 in the metastatic setting. So it does suggest that longer duration results in a higher risk of mortality, even though most of the events are seen in the first year. So it's interesting, 9.6% is much lower than the 12% or 15% we've seen with longer exposure to T-DXd, but it's twice as much as we saw in DB11.

So it brings up the question of how you would treat these patients. Should you give them 4 doses or 14? The other thing that's important is that the median number of cycles that patients received was 10, not 14. So people stopped early, and about three-quarters of the patients completed 14 cycles. If they stopped early, they could finish their year with HP. And that seemed to work pretty well. So I think that's important when we're thinking about treating patients is that if they're having toxicity, you may still be able to get the benefit by stopping drug. T-DXd results in more nausea and it results in less liver enzyme elevations and thrombocytopenia compared to T-DM1. It results in more alopecia as well, which is not well reported here. So that's an important thing when we're thinking about the toxicity.

So what did we learn? So T-DXd for residual disease following at least 6 cycles improved invasive disease-free survival. It reduced the number of distant recurrences, and there are less numeric CNS metastases, but more ILD and 2 deaths. So we need to consider this. There is liver toxicity that can be fatal with T-DM1, but it's extremely rare. And there were similar deaths attributed to treatment.

So what should we do? Neoadjuvant versus adjuvant treatment. I think we know that more T-DXd wasn't better. So what if we give the DB11 approach, T-DXd times 4 followed by THP? What do we do if there's residual disease? I think most of us would still treat with T-DXd rather than T-DM1, and that's been a big discussion.

The other thing that we've been interested in is should we start with THP? And if they're not having as good a response as we want, give them T-DXd because we have data, particularly in ER-negative disease, that THP alone results in high pCR rates. In I-SPY, we've actually looked at starting with the experimental agent and stopping if patients have clear MRI and a biopsy that shows no residual disease. Could we give T-DXd times 4 alone for some of our patients with HER2-enriched ER-negative disease who have very high pCR rates? Individualizing therapy, I think, is going to be critical as we move forward. And I think the T-DXd for residual disease will become the standard of care internationally and already is being incorporated.

So now let's talk briefly about HER2-low disease where T-DXd also has had a tremendous impact on outcome in the metastatic setting. So we saw DB04. That was our first in-person presentation after the pandemic, standing ovation in the plenary session with Shanu Modi presenting this data. So now this is an update published in Nature Medicine. I will say that the data was presented at ESMO in 2023, and I've given you the reference for the primary data in the New England Journal as well. So this trial randomized patients who'd received a median of 1 line of prior chemotherapy for metastatic disease and had endocrine-resistant disease to T-DXd or treatment of physician choice. Most of the patients, as you can see, 50% received eribulin, 20% capecitabine and then a smattering of other disease.

But overall, 18% received taxanes. So they probably already had received taxanes in the first-line setting. Primary endpoint was PFS by Blinded Independent Central Review. That cannot be updated because that's a done deal. So this is PFS by investigator, overall survival is an update and safety.

So here you can see the PFS in the HR-positive versus, group, which was the primary endpoint. And this is still at the updated analysis, 9.6 versus 4.2 months in the HR-positive component. In the hormone receptor-positive component, the updated analysis also shows continued significant improvement with these remarkable hazard ratios. And indeed based on this data, the FDA approved T-DXd in HER2-low metastatic disease after 1 prior chemotherapy for advanced disease or recurrence within 6 months of adjuvant therapy.

There was an exploratory subgroup of HER2-low HR-negative disease, as you know, that included just 58 patients, 40 in the T-DXd arm, because this was a 2 to 1 randomization, and 18 in TPC. Updated analysis continued to show this doubling in progression-free survival and a remarkable improvement in overall survival from 8.3 to 17 months. And that led to the FDA approval being agnostic to HR status, even though only this tiny number of patients, 58 patients, were enrolled. So really remarkable data shows in the follow-up.

And interestingly, in DB04, unlike every subsequent study, sequencing was not an issue, because T-DXd was only approved based on the study. So people didn't get T-DXd in the control arm. And then we saw this huge difference in overall survival. So T-DXd is clearly a key treatment for us. Nausea is the most common toxicity. More patients discontinued, but they shouldn't now due to adverse events. ILD was seen in 12%. We didn't know as well how to manage it.

The median time to onset was 129 days. But look at that range, 26. So in the first cycle, just at the end of the first cycle, out to 710 days. So there were people who had their first ILD in the second year or further. So really important to keep that in mind. Four patients died. One of the patients died during the second safety follow-up evaluation. She had had previous Grade 3 ILD and ended up dying of Grade 5 ILD. So that was 4 patients overall.

So T-DXd became a standard of care based on this and an option for HER2-low triple-negative breast cancer but TROP2 ADCs have Level 1 evidence. So this is primarily for HR-positive, HER2-low metastatic disease. But then we had DB06 that showed T-DXd in patients who had not, visceral dominant disease, improved progression-free survival. But here, crossover is a big issue that impacts overall survival assessment. So I think that it is really now a standard of care in HER2-low and now the ultra-low disease as well to give T-DXd as first-line chemotherapy in endocrine-resistant disease for patients who have a high disease burden, short time to progression on their endocrine therapy with CDK4/6 inhibitors and visceral dominant disease. And we do need careful monitoring and management of ILD to maintain the benefit.

So that goes along with patient reported outcomes, where patient reported outcomes are very good with T-DXd. And this is from DESTINY-Breast06 in the first-line setting. And they evaluated this by standard questionnaires every 3 weeks starting at baseline and then after the end of treatment and actually through PFS2. And they maintained the global health status quality of life over 36 weeks between the 2 arms, similar time to deterioration. But a significant reduction in deterioration and pain by 49% versus the standard treatment. There were more GI symptoms. So that was a worse time to deterioration for GI symptoms with T-DXd, which leads us very nicely into our next paper from 2025. There were a little more skin and mucosal symptoms with standard treatment. So I think we all buy into this. We give T-DXd in this setting.

So how do we manage the symptoms to make this a better treatment for our patients? So this is a very nice trial from Japan called the ERICA trial. And here they randomized 162 patients in Japan who were receiving T-DXd for HER2-positive or HER2-low disease to receive olanzapine versus placebo, 5 mg a day on day 1 to 6. I give it at bedtime, because it does cause somnolence, and not during the middle of the day. That was recommended but not required. And everybody received premedication with a 5-HT3 receptor antagonist and dexamethasone, but at a kind of low dose compared to what we give.

Their primary endpoint was complete response in the 21-day observation period, so after the first dose. That's defined as no emetic events, no vomiting and no rescue meds in the delayed phase, which is 24 to 120 hours post drug. And then the persistent phase goes out to 21 days, that's a secondary endpoint, and adverse events. What they saw was a remarkable improvement in the delayed phase complete response, 70 versus 56%, and also an improvement in persistence, which we've coined the term in the supportive care world for long-delayed nausea. So these are patients who continue to have nausea after that first 5 days that we usually consist, say is delayed phase. And then less patients had no nausea at all. Look at that, 57.5 versus 37.8%, almost 20% different. And actually, if you look at it, there was less appetite loss.

But what's the side effects? Low-grade somnolence was seen. And you can see it's more than 2 and a half times. And there's a little more low-grade hyperglycemia, but it only goes up to Grade 2, so it's not much and not a big issue.

So what do we do with that in our clinical practice now? And this just shows you the daily complete response rates and the daily no nausea rates. Of course, pink is the olanzapine. So nausea is the most common toxicity from T-DXd. It impacts quality of life and adherence. Affects over 70% of patients with standard antiemetics.

Our recommendations for prophylaxis are bigger than those, and it's in the NCCN guidelines, more than those in Japan, 5-HT3 receptor antagonists, but we also give NK1 receptor antagonists and 10 mg of dexamethasone. But even with this, delayed and long-delayed nausea remain an issue. So my standard of care is to give olanzapine day 1 to 4 plus and day 1 to 5, but they should continue if they have long-delayed nausea. But I start at 2.5 mg, not 5 mg.

And there was a study done by Jyoti Bajpai, published in Lancet Oncology, that looked at 2.5 versus 10 and showed it was just as effective and less somnolence with AC, which is even more nauseating. So I think that should be our now standard of care. Everybody should get a prescription for olanzapine. Tell them about the somnolence. Tell them to take it at bedtime. But this should be given. If you have no nausea, you don't have to take it. You can stop it. But you should start it on day 1 with the first cycle.

So what about rechallenging patients with T-DXd who've had Grade 1 ILD? We did a pooled analysis of the trials that were done, prospective trials with T-DXd including mostly breast cancer patients. And we saw that of the 45 patients who were retreated, they didn't have dose reductions, that many patients were still receiving T-DXd at the data cutoffs, and that 33% of the patients were treated for more than 6 months, and almost 18% treated for more than 12 months. And we didn't see any fatal ILD in the patients who were retreated. And some patients were stopped again and were retreated and stayed on drug.

So that led us to do a real-world study at 5 US academic centers that was put together by, at the time, my senior fellow Kelsey Natsuhara, now a faculty member at UCSF. And what we looked at were outcomes after T-DXd rechallenge for patients with Grade 1 ILD. We still saw a low rate of rechallenge, which we need to fix. The median time to rechallenge was 42 days in our 44 patients. And the patients who received steroids actually were rechallenged earlier and overall did better.

After rechallenge, patients remained on T-DXd for 215 days median, so some for even longer, and only 12 patients developed recurrent ILD, and it took a long time to get that and they did well. There was no Grade 5 ILD, and not even much in the way of Grade 3 ILD in these patients. Three patients were rechallenged a second time and did very well. Also, no mortality in these patients. Nineteen patients with Grade 2 ILD were rechallenged outside of our guidelines. They developed higher grade ILD. Two out of those 3 patients had Grade 3 or Grade 4 ILD. One had Grade 2. I would not rechallenge for Grade 2 ILD at the present time unless you think the ILD was due to a virus or something else and not related to T-DXd.

So then we found that rechallenge was safe. Patients in a real-world population had ongoing clinical benefit and we could treat with steroids and that would result in faster radiographic improvement, and a higher number of patients could be rechallenged and the grade was very low. Patients did extremely well. And I think that this should be our standard of care.

With that, I'll thank you for your attention for our 2025 Year in Review.

Current and Emerging Role of TROP2-Directed ADCs — Sara M Tolaney, MD, MPH

DR TOLANEY: My name is Sara Tolaney. I’m a breast medical oncologist at Dana-Farber Cancer Institute, and today I’m going to be focusing on antibody-drug conjugates for the treatment of metastatic HER2-negative breast cancer, and I will say over the last year we have seen tremendous impact of ADCs within this space.

So for metastatic triple-negative disease we’ve seen a lot of data, particularly in 2025, that has focused on the use of TROP2-directed ADCs in the first-line setting for metastatic triple-negative disease. We’ve seen data focused on sacituzumab govitecan, which is a TROP2-directed ADC that has an SN-38 payload, as well as datopotamab deruxtecan, also known as Dato-DXd, which is also targeting TROP2 but has a deruxtecan payload. Both of these ADCs are able to function via bystander effect.

And we’ve seen data that was focused on those patients who are ineligible for immunotherapy. So there are 2 trials, I think of them as sister studies, that really focused on these patients that are not candidates for immunotherapy, one being ASCENT-03. This trial randomized patients in the up-front setting to get sacituzumab govitecan or treatment of physician’s choice chemotherapy. One unique aspect about this particular design is it did offer and provide crossover treatment with sacituzumab to those patients who had centrally confirmed disease progression on the control arm, so a unique thing that was done within this study. TROPION-Breast02 also was a study that focused on the up-front setting and randomized patients to get Dato-DXd of treatment of physician’s choice chemotherapy.

But the trials did have differences in design that resulted in differences in patient populations. So while they’re both studies that focused on the up-front PD-L1-negative patient population they did have differences in their control arms. So the treatment of physician’s choice therapy in ASCENT-03 allowed choice of a taxane or carboplatin with gemcitabine. However, TROPION-Breast02 was a bit more restrictive in the way it had choice. So if you had de novo disease or you relapsed 12 or more months out from completion of adjuvant therapy you had to receive a taxane in the control arm, whereas if you had early relapse then you had choice of either capecitabine or carboplatin or eribulin. There was no doublet chemotherapy offered in the control.

Importantly, TROPION-Breast02 did allow up to 15% of patients to have what we consider very early relapse, so recurring within 6 months of completion of adjuvant systemic therapy, whereas those very early recurrences were not allowed on ASCENT-03. On ASCENT-03 you had to be at least 6 months out from your adjuvant systemic treatment.

The trials also defined patients who were not candidates for immunotherapy differently. So both studies said that you had to either have a PD-L1-negative tumor or if you were PD-L1-positive you could not be a candidate for immunotherapy, either because you had immune checkpoint inhibitor in the early disease setting or you had some comorbidity that made you not a candidate to immunotherapy. But TROPION-Breast-02 also defined you as being ineligible for immunotherapy if you were in a region where immunotherapy was not accessible. So you could be PD-L1-positive but just didn’t have access to IO, and so therefore they considered you eligible for this trial.

And so you can see that these differences resulted in very different patient populations. Obviously, TROPION-Breast02 did have those very early relapsers being 15% of their population. There were more PD-L1-positive tumors on TROPION-Breast02, comprising 10% of their population. Taxane utilization in the control arm was higher in TROPION-Breast02, again given the limitations of choice in the control arm. There was no doublet chemo in TROPION-Breast02. There was more crossover to ADC in ASCENT-03, given they provided ADC as crossover treatment. And follow up time was much longer in TROPION-Breast02.

And so I think I would keep that in mind as you put these 2 results next to each other because, again, cross-trial comparison is quite dangerous when you have very different patient populations. But you can see that both studies showed improvement in progression-free survival favoring the TROP2 ADC over chemo with hazard ratios of around 0.6, so very consistent in terms of relative benefit of ADC over chemo.

You can see response rates were numerically higher for Dato-DXd compared to sacituzumab. Again, dangerous to put these side by side, particularly because we do see higher response rates in PD-L1-positive patients, and there were more PD-L1-positive patients on TROPION-Breast02. There were more Asian patients on TROPION-Breast02, which can be associated with a — those patients can have higher response rates to TOPO1 ADCs.

So again, I would cautiously compare these studies, but clearly very robust response rates. And importantly there was overall survival benefit seen in TROPION-Breast02 that was statistically significant. However, in ASCENT-3 the OS data is immature, but you’re not seeing a trend for OS at this early timepoint, and I think many of us are cautious about this because of the high crossover rate that it’s unclear if we will see overall survival benefit in ASCENT-03.

And so I think it’s as we anticipate seeing potential approvals for both sacituzumab and Dato-DXd in this up-front setting I think we’re going to have to figure out which drug are we going to give if someone comes in with a PD-L1-negative tumor. And again, there were differences in results. One has OS benefit, the other doesn’t yet. There are differences in toxicity profiles. Sacituzumab has toxicities that include neutropenia and diarrhea, whereas datopotamab deruxtecan has ocular toxicity, mucositis and some risk of ILD. And there are differences in schedules, Dato-DXd being given every 3 weeks, whereas sacituzumab is 2 weeks on, 1 week off.

And so if I were seeing a patient, and I had to choose between these 2 drugs, I would really base it on certain factors. If someone had early relapse, within 6 months, I’d give them Dato-DXd because we actually have data about performance of this ADC in that population, whereas those patients were excluded from ASCENT-03. If someone has issues with pneumonitis or ILD then sacituzumab would be preferred. If someone has cytopenias, GI issues, maybe can’t get to clinic for weekly treatment then I’d do Dato-DXd. If someone maybe wears contact lenses and doesn’t want to stop wearing them then I’d give them sacituzumab, or if they have other ocular issues or mucositis issues then sacituzumab would be preferred. So I think these factors would help us figure out what to choose for a particular patient in front of us.

But I will say we don’t really know how these drugs perform, maybe in a slightly more modern era of patients, or someone who’s recurred after immunotherapy in the early disease setting because in both of these of these trials only about 5% of patients had received prior immunotherapy from the early-stage setting, so data here is a bit more limited. That being said, I think ADCs are going to work very well irrespective of prior IO or not and so I think very reasonable to use even in someone who’s seen prior immunotherapy.

However, there’s also interest in combining these ADCs with immunotherapy knowing that these drugs can potentially cause immunogenic cell death and could result in synergy between a checkpoint inhibitor and the antibody-drug conjugate.

And so there are 2 trials that have been designed to focus on ADC/checkpoint inhibitor combinations in the first-line PD-L1-positive setting: ASCENT-04 looking at sacituzumab plus pembrolizumab and TROPION-Breast05 that looked at Dato-DXd with durvalumab. The TROPION-Breast05 study is still enrolling, so we don’t have data from this trial, but we have seen data from the ASCENT-04 trial, and this study did demonstrate that sacituzumab and pembrolizumab did result in a significant improvement in progression-free survival compared to chemotherapy and pembrolizumab, with about a 3.4-month delta between the 2 arms and a hazard ratio of about 0.65 for progression-free survival. The OS data at the time of the presentation was immature. There’s a very slight trend favoring OS, but again, this study did also offer and provide crossover treatment to those patients in the control arm, so we’re going to have to await longer follow up to see if it will hit OS.

There’s also other TROP2-directed ADCs that are in development. This is sacituzumab tirumotecan, also called sac-TMT for short. This targets TROP2 and has a TOPO1 payload. And we’ve seen Phase III data in pretreated metastatic triple-negative disease in a population very similar to what the original ASCENT study had looked at, and in fact the data looks almost identical to what we saw in ASCENT, where sac-TMT does much better than chemo of physician’s choice therapy, almost tripling progression-free survival and in essence doubling overall survival.

And so this agent is currently approved in China for pretreated triple-negative breast cancer. And we’ve seen some smaller datasets that have looked at its performance in the first-line triple-negative setting, where the PFS was around 13 months, so looks very robust. And so I think another promising TROP2 ADC.

We’ve also been quite curious to see if we combine immunotherapy with an ADC in patients who have PD-L1-negative triple-negative breast cancer could we see enough synergy where immunotherapy actually could have a role in the PD-L1-negative setting. And there was some suggestion of this from the BEGONIA trial, where they had combined Dato-DXd with durvalumab as first-line treatment for metastatic triple-negative breast cancer. And in this study the vast majority, 90%, of patients actually had tumors that were PD-L1-negative, and yet we were seeing a progression-free survival that was 14 months, so much longer than what we’ve seen in the first-line setting with Dato-DXd in the PD-L1-negative population, making you think there may be synergistic activity that’s driving this longer PFS. But obviously this is a single-arm study, and one can’t really draw that conclusion unless we had randomized data.

So there is an ongoing randomized trial, the DIAMOND study, that is looking at Dato-DXd with or without durvalumab in the first-line PD-L1-negative, triple-negative setting. This is a randomized Phase II study and so hopefully will give us a suggestion about whether or not IO is providing synergy even in PD-L1-negative patients.

Similarly, there’s the saci/IO triple-negative trial kind of doing the same thing, in essence, with sacituzumab plus/minus pembro in the PD-L1-negative setting. But there is a more definitive trial, TroFuse-11, that is a Phase III study that is taking sac-TMT with or without pembrolizumab and comparing it to treatment of physician’s choice chemotherapy. And this study is powered for PFS so would really more definitively tell us if ADC plus a checkpoint inhibitor can have a role in the PD-L1-negative setting. So that trial is enrolling at this time.

And so assuming we see approvals based on ASCENT-03, ASCENT-04 and TROPION-Breast02, I think our new algorithm post approval would involve giving a TROP2 ADC to the vast majority of our first-line triple-negative patients. So if someone were PD-L1-positive we’d be giving sacituzumab and pembrolizumab. If they were PD-L1-negative then you’d be choosing between Dato-DXd and sacituzumab, though I will say if someone has a germline BRCA mutation and has a PD-L1-negative tumor I still think PARP inhibition can be considered as a choice in this setting. These agents have a very good quality of life compared to chemotherapy, and so if someone maybe has lower-volume disease I think a PARP inhibitor is certainly very reasonable to give up front, and you could always give the TROP2 ADC subsequently to those patients.

If someone has HER2-low metastatic triple-negative disease, which is about a third of our triple-negative patients, you could consider giving T-DXd subsequently. But our data for sequencing ADCs is a bit limited, but I still think reasonable to try, otherwise you’re looking at chemotherapy for the vast majority of our patients in the pretreated setting.

For metastatic hormone receptor-positive disease we’ve also seen a lot of data emerge with the use of ADCs in this setting. There are 3 ADCs that are currently approved for metastatic hormone receptor-positive breast cancer: T-DXd for those patients with HER2-low or -ultralow metastatic hormone receptor-positive disease, sacituzumab govitecan, the TROP2 ADC, and Dato-DXd, also a TROP2 ADC.

So in hormone receptor-positive disease the data for sacituzumab was really based on the TROPiCS-02 study, where patients had pretreated metastatic hormone receptor-positive breast cancer. So these were patients who were actually quite heavily pretreated, they had progressed on prior taxane, prior CDK4/6 inhibitor and needed to have at least 2 lines of chemotherapy and no more than 4 in the metastatic setting, and they were randomized to sacituzumab or treatment of physician’s choice chemo. And we saw a significant improvement in progression-free and overall survival favoring sacituzumab compared to chemotherapy, leading to its approval in the pretreated setting.

We also saw the response rate was numerically higher with sacituzumab compared to chemotherapy, and we saw that sacituzumab led to extending time to deterioration in terms of global health status compared to chemotherapy.

The toxicities that we’ve seen with sacituzumab, again, have been quite consistent irrespective of which setting they’re being studied in. And so we do see again neutropenia and diarrhea being very common with sacituzumab, and usually almost half of our patients do require growth factor support when using this agent. We do not, however, see interstitial lung disease as a toxicity to sacituzumab.

There’s been a lot of interest in trying to understand what the impact on quality of life is, and I think 1 interesting analysis that was done was really what we call a Q-TWiST analysis. So it’s really trying to understand the time at which patients are experiencing toxicity relative to the time where they’re not having any symptoms and how long they’re living without disease progression while on treatment.

And so this Q-TWiST factors all of that together, and what they found was that in fact these efficacy improvements that we’re seeing with sacituzumab compared to chemotherapy don’t come with a cost of unmanageable toxicities, because in fact the time spent in the toxicity category was not a lot longer with sacituzumab compared to standard chemotherapy, and with the Q-TWiST analysis you can actually see that there was a gain in terms of increased time outside of toxicity relative to chemotherapy. So I think reassuring that this is an agent that generally has manageable toxicities for our patients.

Dato-DXd is another TROP2-directed ADC and has also been studied in hormone receptor-positive disease in the TROPION-Breast01 trial. This trial is in a slightly different setting than the TROPiCS-02 agent, where it was studied in patients who had just 1-2 prior lines of chemotherapy, so slightly less pretreated than TROPiCS-02, and patients where randomized to get Dato-DXd or chemo. And we saw an improvement in progression-free survival with a delta of around 2 months favoring Dato-DXd compared to chemotherapy, but there was no difference in overall survival that was seen in this trial.

We did, however, see that there were more patients in the control arm of this study that went on to get a subsequent ADC compared to the data-DXd arm, with about twice as many patients getting subsequent ADC.

And so when they did a sensitivity analysis for overall survival you can see that when you adjust for patients who received a subsequent ADC there now is a trend at least favoring survival for Dato-DXd relative to chemotherapy. And so I think it’s important to remember. I think some people say well, TROPiCS-02 with sacituzumab has a survival benefit, TROPION-Breast01 has no OS difference, so maybe we should use sacituzumab and not use Dato-DXd. But I think we have to be fair in a sense that when TROPiCS-02 was conducted there weren’t ADCs that were available for patients to go cross over to, and so they weren’t getting subsequent ADC in the control arm, whereas here they were — they had access to T-DXd, which was approved during the conduct of TROPION-Breast01, and so we did see that crossover occur.

The toxicity profile with Dato-DXd is a little bit unique, I think, compared to sacituzumab. Overall we see that it is very tolerable. Certainly, there was a higher response rate with Dato-DXd, but we didn’t see significant impact on quality of life. In fact, there was longer time to deterioration with Dato-DXd relative to chemo.

The major side effects that we see do include nausea and mucositis, as well as ocular toxicity and a small risk of interstitial lung disease. So it is really important when administering Dato-DXd to use a prophylactic steroid mouthwash. We recommend it 4 times a day. We also recommend using rewetting drops for prevention of ocular toxicity, also 4 times a day, and we also recommend getting a baseline eye exam in patients who are initiating Dato-DXd. So some things to consider when prescribing this drug.

And so while we’ve seen both sacituzumab and Dato-DXd get approvals in pretreated metastatic hormone receptor-positive breast cancer there is obviously a question about whether we can move these ADCs to be the very first chemo patients get after they progress on endocrine therapy. And so ASCENT-07 tried to move sacituzumab out of that pretreated setting into that first-line chemo setting and really compared sacituzumab to chemo choice being capecitabine or taxane in patients who had just progressed on endocrine-based treatment and no chemotherapy in the metastatic hormone receptor-positive breast cancer setting.

And we actually just recently saw these data come out at San Antonio, where in fact we saw no difference in progression-free survival between sacituzumab and chemo of physician’s choice. In fact, the PFS looked identical. It is interesting, though. This is PFS by blinded independent central review, but when you looked at PFS by investigator assessment, in fact, there was a trend that favored sacituzumab over treatment of physician’s choice chemotherapy.

There was a lot of early censoring that occurred within this trial, and we did see that there was a lot of crossover from the control arm to subsequent ADC. So I think that is important when we also consider the overall survival data, where there actually is a trend, again not mature data, but a slight trend favoring sacituzumab over chemo despite the fact that there was a high crossover rate in the control arm. And yet we saw no difference in PFS by blinded independent central review.

So here you can see when you look at the crossover you see that about 60% of patients in the control arm went on to get an ADC compared to about 30% in the sacituzumab arm. Again, this was not — patients were not blinded to what arm they were getting, and so you could imagine if a physician had someone on the chemo arm they may move them on readily to get an ADC upon progression, which certainly would make sense in this setting.

So I think it was a little disappointing, frankly, that the ASCENT-07 study was negative because it really did not suggest that we could be using sacituzumab instead of standard chemotherapy as first-line treatment for our metastatic hormone receptor-positive breast cancer patients. I think there T-DXd really remains as a standard for the vast majority of patients who have either HER2-low or -ultralow disease and that these TROP2 ADCs may just not be quite as potent as the HER2-directed ADC in that up-front setting.

The sac-TMT agent that we had discussed for triple-negative disease was also studied in metastatic hormone receptor-positive breast cancer. This was the OptiTROP-Breast02 study, which looked at a population that was pretty broad. So these were patients who had 1-4 lines of chemotherapy for metastatic hormone receptor-positive breast cancer, and then they were randomized to sac-TMT or treatment of physician’s choice chemo.

And important to realize, again, these were heavily pretreated patients, where patients had all received prior CDK4/6 inhibition and the vast majority of patients had received 2 or more lines of chemotherapy in the metastatic setting.

And yet, despite this, we saw a very big difference in progression-free survival favoring sac-TMT over chemo, really doubling progression-free survival, in essence going from 4 to 8 months, which is very profound. Very big differences between these 2 curves, so I think we were all very impressed with these data. And certainly a really nice trend for overall survival also favoring sac-TMT over chemotherapy. So I think we’re excited about sac-TMT as a potential alternative TROP2 ADC also in this space. This was data that was just, however, conducted in China, so we don’t have a US approval for sac-TMT at this time.

When you look at the toxicities for sac-TMT I kind of think of it as a little bit of sacituzumab toxicity and a little bit of Dato-DXd toxicity in a sense that you see neutropenia with sac-TMT, just like we do with sacituzumab, but it’s a little bit less in terms of high-grade neutropenia. But interestingly you also see a bit of mucositis with this agent, we don’t see that with sacituzumab, but we do see it with Dato-DXd, and so you are seeing it with the sac-TMT drug. And rates of pneumonitis are really low, only around 1.5%. So with this agent prophylactic dexamethasone mouthwash is also recommended to be utilized.

And so here you can see the data kind of side by side for all of the TROP2 ADCs in metastatic hormone receptor-positive breast cancer. And again, you are seeing benefit in pretreated hormone receptor-positive disease for these TROP2 ADCs over chemo, but no benefit yet seen in the first-line chemotherapy setting for metastatic hormone receptor-positive breast cancer, at least based on ASCENT-07 with sacituzumab.

So I think our algorithm for metastatic hormone receptor-positive breast cancer is actually quite complicated and continues to get even more complicated as we see more endocrine drugs and targeted agents thankfully move into this space. But once patients get past their endocrine-based therapy and move onto chemotherapy-based treatments T-DXd, based on the data that we’ve seen from both DESTINY-Breast04 and DESTINY-Breast06 really is a standard of care for our patients who have some level of HER2 expression. And the TROP2 ADCs, whether it’s sacituzumab govitecan or Dato-DXd, remain a choice in the second and beyond line setting once we get into that chemo setting.

I think the challenge, though, is that for the vast majority of patients you’d be using the TROP2 ADC after they’ve had T-DXd, since most people are either ultralow or low expressing for HER2, and we do think that the benefits of ADC2 tend to be a little bit less than what we would see after our first ADC. And so I think this is an area we better need to understand in terms of optimal sequencing for ADCs in this space.

So thank you so much.