let me make a quick overview of TROP-2 directed antibody drug conjugates.

[00:13:01]

What Are Antibody–Drug Conjugates?

You all know that basically antibody–drug conjugates are composed of 3 components; the antigen binding site of the tumor antigen, the membrane receptor basically. The linker, which is very important to optimize the delivery of the drug, and the payload. The payload today, according to the drugs we have approved in the clinical practice, is basically chemotherapy. As you all know, there are many ongoing and many different payloads which have been explored. Usually the more homogeneous the expression is in the tumor, the higher affinity and the lower expression in healthy cells should be much more important to optimize the activity of any antibody drug conjugates.

[00:13:46]

TROP-2

TROP-2 is an important protein in different cancers including of course, breast cancer. It is basically a glycoprotein which is encoded by the TACSTD2 gene, and this could be important to understand different mechanisms of resistance. As you can see on this cartoon, TROP-2 is involved in different mechanisms of apoptosis, proliferation, angiogenesis, etc. Another important aspect with TROP-2 is that it is overexpressed in tumor cells compared with normal cells.

[00:14:22]

TROP-2 Expression in Metastatic Breast Cancer

In breast cancer in particular, it is highly expressed in both metastatic triple negative breast cancer and hormone receptor positive HER2 negative metastatic breast cancer. You can see here again in this picture, that moderate to strong expression of TROP-2 is observed in the range of 80% to 90% of tumor cells, with expression in the range of 10% and known expression in the range of 4% to 5%. This is not very different between TNBC and ER positive HER2 negative. Nevertheless, in the clinical practice we should not. It is not mandatory to look at the expression of TROP-2 because patients with or without expression of this glycoprotein benefited the same from anti–TROP-2 antibody–drug conjugates compared with a chemotherapy.

[00:15:11]

TROP-2-Directed ADCs: Sacituzumab Govitecan vs Dato-DXd

Which drugs do we have in the clinic today? We have sacituzumab govitecan and Dato-DXd, very similar according to the target, again TROP-2. The payload is very similar. It is an anti-topo I inhibitor, in the case of SG is basically a very similar compound compared with SN-38. The active metabolite of irinotecan in the case of Dato-DXd is exatecan derivative, again topo I inhibitor and the linker has specific differences. Basically, we might understand why the payload could be released sometimes before it is internalized in the tumor cell or only into a tumor cell. Again, it depends on basically physicochemical properties. Nevertheless, both of them do have the bystander effect.

[00:16:05]

Metastatic TNBC: Key Data, Approvals, and Guideline Recommendations

Let us review very quickly the data we have with these drugs in the metastatic TNBC. We have learned from ESCO 2025 very interesting data that we will try to summarize very quickly.

[00:16:17]

ASCENT: Phase III Study of Sacituzumab Govitecan in Metastatic TNBC

Now, let us start with the ASCENT study. This has been the first to the best of my knowledge in triple negative breast cancer. The randomized phase III study with an antibody drug conjugate, sacituzumab govitecan, was explored in second line or beyond against chemotherapy. Primary endpoint was PFS by BICR in those patients without brain metastases. Nevertheless, this trial also included patients with stable, untreated brain metastases, and this was observed in the secondary endpoints.

[00:16:52]

ASCENT: PFS by BICR in Patients Without Brain Mets (Primary Outcome)

You all know the results. Median PFS was clearly improved with SG compared with chemotherapy. The hazard ratio was 0.41 and the median PFS moved from roughly 2 months to 5.6 months.

[00:17:08]

ASCENT: PFS and OS in Metastatic TNBC With and Without CNS Metastasis

When we looked at patients with or without brain metastases, you can see here that the data basically in both progression free survival and overall survival was basically identical. You can see here hazard ratio 0.41 and 0.43 for patients without and with CNS metastasis and overall survival 0.48 and 0.51. Again, very consistent data in both patients with and without brain metastases.

[00:17:37]

ASCENT-03 vs ASCENT-04: 1L Sacituzumab Govitecan in PD-L1+ Untreated Advanced TNBC

Based on this data, this drug and also Dato-DXd moved into the first-line setting TNBC. Sara presented it at ASCO 2025, and I have the privilege to present at ESMO 2025, 2 randomized phase III studies, ASCENT-04 and ASCENT-03, respectively. ASCENT-04 was for those patients who were candidate to immune checkpoint inhibitors based on the CPS score of 10 or higher. As we all know, the standard of care at this time was chemotherapy plus pembrolizumab, and patients were randomized to receive the standard of care chemo pembro or sacituzumab pembrolizumab. In the case of the ASCENT-03, it was for patients who were not candidates to immune checkpoint inhibitors basically because patients were unable to receive it because they received it in the early breast cancer setting. According to the physician, they were not candidates to receive it again, and basically because the PD-L1 was negative. The primary endpoint of these 2 trials was progression free survival by BICR.

[00:18:47]

ASCENT-03: PFS by BICR and DoR

Of interest, those patients who received the standard of care, the control arm, and experienced progressive disease were able to cross over to sacituzumab govitecan, and this was provided by the sponsor. Here we have the progression free survival and duration of response in the ASCENT-03 study. Remember chemotherapy or sacituzumab for patients who were unable to receive immune checkpoint inhibitors. Hazard ratio 0.62 in favor of sacituzumab govitecan and duration of response much higher with sacituzumab compared with chemotherapy. Chemotherapy 7.2 months, sacituzumab govitecan 12.2 months.

[00:19:30]

ASCENT-03: Safety

What about safety? I think that the toxicity profile of SG is very well known. The most important adverse events are neutropenia. It was observed in this trial in the range of 67% of patients, being 43 grade 3 or higher. The other important adverse event to be considered is diarrhea, which was observed in the range of 54% all grades, 9% basically grade 3 diarrhea.

[00:19:59]

ASCENT-04/KEYNOTE-D19: PFS, OS and PROs

What about the ASCENT-04? Here we have the primary results. PFS was nicely improved by sacituzumab govitecan plus pembrolizumab compared with chemo plus pembrolizumab. Very similar hazard ratio as before 0.65. The median moved from 7.8 months to 11.2 months. Overall survival in both ASCENT-03 and ASCENT-04 were very immature at the time this data were communicate.

[00:20:33]

TROPION-Breast02: 1L Dato-DXd vs TPC in Locally Recurrent Inoperable or Metastatic TNBC

Another important trial that was presented at ESMO 2025 by Rebecca, then from Singapore, was the TROPION-Breast02. This is a very similar clinical trial compared with ASCENT-03 with some differences. Patients again not candidate to immune checkpoint inhibitors were randomized in this case to Dato-DXd or physician's choice. Patients who experience progressive disease in the first 6 months were allowed to be included here. It was not allowed to be included in the ASCENT-03. Coprimary endpoints were progression free survival by BICR and overall survival.

[00:21:16]

TROPION-Breast02: PFS(by BICR) and OS

Here we have the key results. Very similar hazard ratio 0.57 for progression free survival and also in this trial an improvement in overall survival. Hazard ratio 0.79 and the P value .0291. According to this data, datopotamab improved both progression free survival and also overall survival.

[00:21:41]

TROPION-Breast02: Most Common TRAEs

What about the adverse events? You can see here the most important adverse events by datopotamab deruxtecan basically dry eye that was observed in the range more or less of a 24% of patients being grade 3 or higher in 1%. Stomatitis in the range of 57% grade 3 or higher in the range of 8%. We have some time afterwards to discuss how to prevent or how to treat these 2 adverse events. The other important toxicity to be considered were gastrointestinal, basically nausea that was observed in the range of 45% of patients.

[00:22:25]

OptiTROP-Breast01 Trial of Sacituzumab Tirumotecan vs Chemotherapy for Advanced TNBC

Another important study that was published in Nature Medicine this year was the OptiTROP-Breast01. This is a randomized phase III trial with sacituzumab, govitecan or Sac TMT compared with chemotherapy randomized phase III study in patients who received at least 2 prior lines of therapy or therapy, at least 1 of them in the metastatic setting. You can see here also very nice improvement in the primary endpoint, progression free survival with a hazard ratio of 0.32. Median PFS moving from 2.5 months to 6.7 months. Also, improvement in overall survival 0.53 and in overall response rate from 12% with chemotherapy to 45% with Sac TMT.

[00:23:17]

ESMO Guidelines for Metastatic TNBC

Based on all this data, the guidelines still have not changed. We have to incorporate all these data into guidelines very soon I hope. But this is what we have today. In the first line setting PD-L1 positive continue to be pembrolizumab or atezolizumab. We should remember that at least in Europe, atezolizumab is also improved based on the SP-142 assess or antibody plus chemotherapy. For PD-L1 negative we can discuss the germline BRCA mutation status if it is positive. PARP inhibitors or chemotherapy are both approved. In the wild type chemotherapy continues to be the standard of care. Again, maybe this will change based on the TROP-Breast02 and ASCENT-03. Nevertheless, in Europe again a chemotherapy plus bevacizumab could be a good option. In patients who were pre-treated it will depend what the patient received. But according to the guidelines, the second line the standard of care is datopotamab deruxtecan and beyond progression we can discuss if trastuzumab deruxtecan and or chemotherapy are the best options.

[00:24:31]

NCCN Guidelines: Metastatic TNBC

Finally, according to the NCCN criteria and guidelines in the second line setting, also recommend or to consider olaparib and talazoparib based on the PARP mutation or the germline BRCA mutation. If no BRCA mutations or if they received carboplatin or PARP inhibitors before, datopotamab deruxtecan is the preferred option. Other options recommended here could be T-DXd or a chemotherapy.

[00:25:01]

Now, Let's Revisit Our Patient Case

Now, let us go back to revisit the clinical case Sara presented before.

[00:25:09]

Patient Case: 54-Yr-Old Woman With Recurrent TNBC

Assuming of course for the response that you can use any drug according to the best clinical practice, it is not just based on if the drugs are approved or not. It is just based on the data we have today. 54-year-old woman with a history of triple negative breast cancer, cT2N1 who received the KEYNOTE-522 strategy, paclitaxel, carboplatin, pembro, followed by AC pembro with a very good response. Surgery, she had residual disease of 11 mm with 1 positive node. She received cape and pembrolizumab and 14 months later she had some discomfort, so the imaging revealed liver and lung metastasis. Liver biopsy revealed triple negative breast cancer HER2 1 plus. PD-L1 testing was done on the liver biopsy with a 22C3 antibody and the results was CPS of 2.

[00:26:11]

Posttest 1

Let us go back to the clinical question that Sara asked before. What is the best treatment option?

A. Carbo gem;

B. Eribulin;

C. Saci govitecan; or

D. T-DXd;

Please vote now. Okay. Let us move on. About 66% of you voted for Sacituzumab govitecan and about 20%, 19% voted for T-DXd, about 15% preferred chemotherapy. Just let us remember that T-DXd is a good option, but we do not have data in the first line setting. We have data in second or third line in the exploratory analysis of these 58 patients in the DESTINY-Breast04, and according to the data, we have ASCENT-03 and ASCENT-04. I think that sacituzumab govitecan could be a good option in the first line setting without or with pembrolizumab. Also TROPION-Breast02 with datopotamab deruxtecan could be also a good approach to treat this patient.

[00:27:30]

Audience Question and Answer Session I

I would like to start maybe sometime from Q&A. Let me double check. We have like 3 or 4 minutes. If we have any questions let me check. Sara, I have 1 question for you. Let us assume that all these drugs are approved in the clinical practice. The FDA will approve much earlier than other countries. But when would you consider sacituzumab deruxtecan to treat your patients with metastatic triple negative breast cancer? Would you prefer to wait and to give the drug in the second line setting, or if it is approved, you would prefer to go into the first line setting with or without pembrolizumab?

Dr Tolaney: It is a good question. Obviously, as you pointed out, that we do have data from the very original ASCENT trial, which did demonstrate survival benefit with use of sacituzumab in the pretreated setting. But the data that I think you presented very nicely just recently at ESMO for ASCENT-03 does demonstrate that when you use sacituzumab in the first line setting compared to chemo, it is improving progression free survival. My worry is that if we do not use the ADC in the first line setting, there are some patients who cannot get to second line treatment. I think it is very dangerous in this particular subtype of disease to hold back on your most effective therapy, because unfortunately, we do know that there is attrition between first and second line of treatment. I realize it is complicated to know what that number is. There is a lot of real world series, some of which say up to 50% of patients do not make it to second line even if it is a little bit lower and it is a third or something like that. My worry is that there are sizable number of patients who ca not get to a subsequent line of treatment, so I would use the ADC up front. Really the vast majority of patients, it should be standard of care.

Dr Cortes: Sara, we do not have many time. But 2 very quick questions that I want to ask you. One of them, BRCA. You have a patient with a germline BRCA mutation, 1 or 2 does not matter. What would you prefer? To go for an antibody conjugate and maybe afterwards olaparib, the other way around, it depends on the amount of disease. Any comments or thoughts?

Dr Tolaney: I think in some of those PD-L1 negative disease whose germline BRCA mutant, I would make a decision between using a PARP inhibitor or using an ADC based on the volume of disease. For example, if someone had a little bit of cancer, meaning they do not have a lot of visceral involvement, they are not symptomatic from their cancer, obviously, PARP inhibition is really easy from a patient perspective. It is an oral pill, does not require coming in for infusions, and so I think many patients would really like that from a quality of life perspective. It does not have survival benefit overall when compared to chemo. There was a subset analysis suggesting survival benefit upfront in the first line, but again not powered for that analysis. Whereas with ADCs, I think we have not yet seen the data from the subset analysis of patients with germline BRCA mutant status by outcome for either datopotamab deruxtecan or sacituzumab. I know in ASCENT-03, I know you have plans to present those data in the future where there will be central testing for BRCA and outcomes. Again, I think we have choice here, and I think if someone has high volume disease, I would think the ADC would be standard. But if low volume disease I would probably pick a PARP. I do not know, Javier, if you agree or disagree.

Dr Cortes: I completely agree. I think that it will depend on the amount of the disease. I think that many things should be taken into account. This is my last question. I know that we are running out of time but I cannot omit this question, Sara. Patient in the late 70s, early 80s. Any quick comment? Because we have to move forward.

Dr Tolaney: That is an excellent question. I think we always worry about our older patients and their ability to tolerate therapies. Here, I do think you have to make a judgment call about how well that patient is going to tolerate treatment. Are they a candidate for chemotherapy in general? If they are, then I think you can think about using an ADC. I, however, do tend to dose reduce when I start an older patient who may have several comorbidities and start them off a little bit lower and make sure they tolerate it before escalating. But I do not think we should use age as a cutoff to say what drug someone is going to get or not get. In fact, if you look at the number of patients who required dose modifications with sacituzumab, it is actually less than that with chemotherapy. I think you have to make a judgment call if this patient can physically come in for regular infusions and so forth. If they can, I think starting with dose reduced ADC is probably a reasonable way to go.

Dr Cortes: Well, you need to have a lot of time to pick your brain up. Nevertheless, we have to move forward. Sara, back to you.

[00:32:35]

HR-Positive/HER2-Negative MBC

Dr Tolaney: Thank you very much. I think we will switch gears a little bit and talk about hormone receptor positive disease now.

[00:32:43]

Overview of Clinical Pathway for Treatment of HR+/HER2-MBC

When we think about how we are approaching these patients, obviously we have really nice endocrine therapy options in the upfront setting for our patients, whether it is endocrine therapy with CDK or even a triplet, if they have a PI3 kinase mutation, where you may give endocrine therapy with CDK and PI3K inhibition. Then sometimes we will move on to a subsequent line of endocrine therapy. But then we are usually ending up moving to chemotherapy, usually in the third or fourth line setting for patients.

[00:33:12]

TROPiCS-02: Sacituzumab Govitecan vs TPC for HR+/HER2- Advanced Breast Cancer

When we think about what our chemo choices are, I think we are fortunate to have many, we do now have antibody drug conjugates as an option. We have for example, sacituzumab govitecan is an option for patients who have pre-treated hormone receptor positive disease. This is based on the TROPiCS-02 trial, which had taken patients who had previously progressed on their endocrine treatment and a CDK4/6 inhibitor, and had received a minimum of 2 lines of chemo for their metastatic disease, but no more than 4 lines of chemotherapy. They were randomized to get sacituzumab or treatment of physician's choice chemotherapy.

[00:33:53]

TROPiCS-02: Updated PFS (by BICR) and OS in Overall Patient Population

What we saw was that the sacituzumab was associated with an improvement in progression free survival and an improvement in overall survival. It was improving both PFS and OS when compared to standard chemotherapy.

[00:34:09]

TROPiCS-02: PFS and OS by HER2 IHC Status

Here you can look at various subset analyses suggesting benefit of sacituzumab is seen irrespective of HER2 status, whether you are HER2, IHC zero or HER2 low. It did not matter. Your relative benefits from trastuzumab compared to chemo were the same.

[00:34:25]

TROPION-Breast01: Dato-DXd vs TPC in Inoperable or Metastatic HR+/HER2- Breast Cancer

We also have data for using datopotamab deruxtecan or Dato-DXd in patients with pretreated metastatic hormone receptor positive disease based on the TROPION-Breast01 study. I would note that the eligibility for this trial is slightly different than TROPiCS-02. Here patients were required to have progressed on their endocrine treatment, but then have had 1-2 prior lines of chemo. Remember in TROPiCS-02 it was more pre-treated. They had 2-4 prior lines of chemotherapy, and these patients were randomized to get Dato-DXd or treatment of physician's choice chemo.

[00:35:02]

TROPION-Breast01: Primary Analysis of PFS, ORR, and OS

What we saw was that the Dato-DXd was associated with better progression free survival than compared to chemo, with about a 2 month absolute difference between the 2 arms and was associated with a numerically higher objective response rate. Again, more active than standard chemo.

[00:35:19]

TROPION-Breast01: Dato-DXd vs CT in HR+ MBC Overall Survival

However, when we looked at the overall survival data, you could see that the curves are highly overlapping, that there was not an improvement in survival data. One thing I do think it is important to acknowledge is that during the conduct of TROPION-Breast01, T-DXd was approved for use in patients who had HER2 low breast cancer. There were patients who, for example, went on to TROPION-Breast01, but when they progressed did go on to a subsequent antibody drug conjugate.

[00:35:48]

TROPiCS-02 Trial of Sacituzumab Govitecan vs TROPION-Breast01 Trial of Dato-DXd

There was a sensitivity analysis that had been conducted that did suggest a trend when you pulled out the patients who received a subsequent ADC for improvement in overall survival. I think it is complicated as our space gets more and more agents to think about how to interpret survival when patients can get subsequent lines of ADCs but nonetheless that both of these agents, Dato-DXd and sacituzumab govitecan, are approved to be used in patients who have pretreated metastatic hormone receptor positive disease. When you put the trial side by side again, you can see differences in the eligibility, as we pointed out with TROPiCS-02, again being a more pretreated population relative to TROPION-Breast01.

[00:36:38]

OptiTROP-Breast02 Trial of Sacituzumab Tirumotecan vs Chemotherapy for HR+/HER2- Advanced Breast Cancer

There are other antibody drug conjugates that are in development. Exciting one that I think exists is sacituzumab tirumotecan or Sac TMT. This was studied in a trial that was conducted in Asia, so the OptiTROP-Breast02 trial. I thought these data were really exciting. They were just recently presented at ESMO and this was a trial population. Again, not exactly TROPION-Breast01 population, not exactly the TROPiCS-02 population, but a merger of the 2 in a sense that these were people who had to have 1-4 prior lines of chemo. Then they were randomized to get Sac TMT or treatment of physician's choice chemo. What you see is that the Sac TMT had about over a 4-month improvement in progression free survival compared to the control arm. A hazard ratio of 0.35. This is, I think, very impressive data favoring the Sac TMT arm. The overall survival data was immature at the time of this presentation. But you do see a very nice trend favoring OS for Sac TMT. I think again, really encouraging. Obviously, 1 challenge is that this was a trial that was only conducted in Asia and so it sometimes makes generalizability a little bit challenging to a more global population. But I think does provide a lot of excitement for this drug, and there is an ongoing trial, TroFuse-010, which is being conducted in metastatic hormone receptor positive disease for patients who have not had any prior chemotherapy for their hormone receptor positive breast cancer. I think we will see more to come from Sac TMT.

[00:38:20]

Where ADCs Fit Into Treatment of HR+ MBC

What are we doing now? I think this is obviously complex when we have several ADCs to consider. If someone is moving from endocrine therapy towards chemotherapy, you could give them T-DXd if they have HER2 low or HER2 ultra-low disease based on data we have seen from DESTINY-Breast06. I think a very standard thing to do would be to use first line T-DXd. However, if someone had HER2 null disease or maybe did not want to get T-DXd for some reason, did not want to come in for infusions and maybe preferred getting something like oral capecitabine, that is also an option. If someone then moves on to second line treatment, then I think the choice is to think about whether or not you want to use a subsequent ADC, if that patient already had T-DXd.

I do see a question in the chat about this exact question, and I think a popular question is, if you used first line T-DXd, would you feel comfortable using another ADC second line, either Dato-DXd or sacituzumab govitecan, knowing that these ADCs also have a topoisomerase I payload and the patient just got an ADC with a topo I payload. In truth, we do not have a lot of great data to guide us here. We do not have randomized registration trials, for example, looking at performance of the second ADC after the first. We do have some real world data, which has suggested that the PFS for the second ADC could be a little bit less than the first, but that is not always the case. Sometimes people do better on their second one than their first. I think this makes it a very complicated decision. But you do have choice here. You can choose to use Dato-DXd or sacituzumab if they have had prior T-DXd. Some people will not have had prior T-DXd, their HER2 null, for example. Then again, you are choosing between Dato-DXd or sacituzumab, and then again, you have choice of using single agent chemotherapy as you go through lines of treatment.

[00:40:25]

Implications of Resistance Mechanisms for ADC Sequencing

I think again, as was asked in the questions by the audience, is, you know, why may we be concerned about sequencing these ADCs? Part of it is because we do wonder if 1 of the mechanisms of resistance to an ADC is payload resistance. If you again have given a topo I payload drug, there is some data, as you can see here, to suggest that you could get mutations that result in resistance to a topoisomerase I payload. There is also data that there are other mechanisms of resistance that could be target that you have developed a mutation. For example, in the target you get downregulation of the target. You could also have issues with lysosomal processing of the ADC, which could also impair subsequent ADC benefit. I think this is complicated because it is not a 1 size fits all reason for resistance. I think that is why we are seeing mixed messages about how that second ADC does. Because again, it is not always just 1 resistance mechanism.

[00:41:29]

TRADE-DXd (TBCRC 064): Planned Trial of T-DXd or Dato-DXd for ADC-Refractory Advanced Breast Cancer

There are lots of trials that are ongoing trying to address this question. This is 1 of those studies at called TRADE-DXd where patients are randomized to either get Dato-DXd or T-DXd as their first ADC and then upon progression, go on to get the other 1, whatever they did not get first as their second ADC. There are serial biopsies that are being collected to understand why someone may or may not develop resistance to an ADC, and how that could inform and predict benefit of a subsequent ADC.

[00:41:59]

SERIES: Sequencing Sacituzumab Govitecan After T-DXd in ER+, HER2-Low Metastatic Breast Cancer

This is another study ongoing called the SERIES study, where patients who have had prior T-DXd move on to get sacituzumab, and also biopsies are being collected and ctDNA to help us understand again why patients may be benefiting from sequencing these drugs.

[00:42:14]

Key Ongoing Phase III Trials of TROP-2-Directed ADCs HR+ Breast Cancer

There is also interest in moving the TROP-2 ADCs into the first line setting. We alluded to 1 study, TroFuse-010, which is moving Sac TMT into that first line setting for when patients are just starting chemo. There is also ACSENT-07, which has completed enrollment, which looked at sacituzumab govitecan and compared it to standard chemotherapy in that first line of chemotherapy setting. We are hoping we may see data even later this year from that trial. There are also trials looking at TROP-2 ADCs in the early disease setting, with the SASCIA trial having looked at patients who had residual disease and randomized them to get sacituzumab or standard treatment. They did have a cohort of hormone receptor positive patients within that trial. I think we will learn more about how ADCs, particularly these TROP-2 ADCs, move up further.

[00:43:07]

Now, Let's Revisit Our Patient Case

It would be great to revisit some of the cases that we have presented at the beginning that we are focused on hormone receptor positive disease.

[00:43:15]

Patient Case: 59-Yr-Old Woman With Metastatic ER+ Breast Cancer

This was the patient who presented with de novo metastatic hormone receptor positive breast cancer, had progressed on prior endocrine therapy and had progressed on T-DXd.

[00:43:26]

Posttest 2

Now you are thinking about what to do after T-DXd progression. Would you think about using;

A. Dato-DXd;

B. Eribulin;

C. Vinorelbine; or

D. Sac TMT, at time of progression;

If you could just enter your responses in the poll. Here you can see that it looks like most of you did choose Dato-DXd, so 65% of people did, and I would agree with that. Given that the data that we have seen from TROPION-Breast01 suggested an improvement in PFS with Dato-DXd compared to chemo, and that this was a large phase III study that was conducted globally, I think becomes a very reasonable choice. We did not put sacituzumab govitecan here, although that would have also been an excellent choice based on the results ofTROPiCS-02. We did not want to have 2 right answers to confuse people, but I think that would have been also an excellent choice.

There is data for sacituzumab tirumotecan, and we just saw, but again, that was not a globally conducted trial, I think making it hard to generalize, at least at this point in time. Not yet approved for example across various countries. Dato-DXd, I think amongst these choices would be very appropriate. But I think as was brought up again by 1 of the people in the audience, we do not really know how Dato-DXd would perform in someone who just progressed on T-DXd, because again, they do have, in essence, the same payload. I think that does make this complicated. Again, 1 where we are a little bit data free.

[00:45:15]

Audience Question and Answer Session II

I guess I will turn to you if you had that case in real world what would you do? Would you actually give Dato-DXd immediately to someone after progressing on T-DXd?

Dr Cortes: I think this is the $1 million question. Do we have to sequence ADCs or should we go to chemotherapy? I think that we really do not know which is better. I think that data is a good option. Sac TMT when approved could be a good option as well or chemotherapy. We really do not know if 1 of these options is better than the other. I think that unfortunately in many countries we cannot sequence ADCs today. For me, in the clinical practice it is very easy. But I think that if I would have the opportunity to do both, I would try once again with another antibody conjugate. I think nothing to lose. Maybe if we have a user before there are patients who have very quick progressive disease and could have a very prolonged progression free survival with a subsequent antibody drug conjugate. I would try. I would try, Sara, but it is true that in clinical practice we cannot do it.

Dr Tolaney: I think this is, as you point out, a really challenging situation we are in clinically where we do not really have the answer. But hopefully again, we do have these ongoing trials and hopefully they will provide us more information for what to do.

[00:46:34]

Roundtable Discussion Points

Maybe I know we are short on time here for other questions, but I do think 1 question that comes up is if someone has HER2 IHC zero disease, I am curious, 1, are you getting information about whether or not their HER2 ultra-low or not, and does that influence you for using T-DXd? Two, if they did come back, HER2 null and someone is getting treatment as their very first chemo, what are you doing in that situation?

Dr Cortes: Sure. If I have an HER2 zero, I would try to find the HER2 ultra-low according to the DESTINY-06 if I could have the opportunity to use T-DXd. Of course, if not, it is not needed. But if it is HER2 null, maybe I would try to get another biopsy. Why not? But I would not be biopsy to biopsy to try to find because we have other antibody-drug conjugates, which might work very nicely as you saw before. Datopotamab deruxtecan, sacituzumab deruxtecan, again in the future maybe Sac TMT. I think that now is not so important to look for this HER2 whatever, but at least 1 or 2 times I would try to do it, because I think that T-DXd have very good data in the first line setting, and I think that we could have this disadvantage.

Dr Tolaney: I think that is a really good point. Thank you.

[00:47:57]

Managing AEs Associated With TROP-2-Directed ADCs

I know we have talked a lot about the efficacy for these agents, but I think also helpful is to put into context some of the side effects that we see. I will pass it over to you to walk us through some of the adverse events.

Dr Cortes: Thanks, Sara. I think that we are running quite out of time because we have many things to discuss, so maybe I will try to make maybe 2 or 3 key comments. If you want to add something, please feel free to do it absolutely.

[00:48:22]

Patient Case: 62-Yr-Old Woman With Previously Pretreated ER+/HER2- (IHC 0) MBC

Well, let us go for a clinical case. A 62-year-old woman with a T4N0, grade 2, ER positive, PR negative, HER2 zero. She received preoperative therapy with paclitaxel AC with a partial response. Surgery with residual disease 65mm PR positive, PR negative, HER2 zero, again, node positive involved, radiation therapy and letrozole. Three years later, liver and bone metastasis. A biopsy again very similar features. PIK3CA wild type should receive fulvestrant plus abemaciclib for ten months. Progressive disease in the liver, and capecitabine for 7 months, and datopotamab deruxtecan. She received, and this is very important, stomatitis prophylaxis adherence. However, she developed grade 2 stomatitis on datopotamab deruxtecan.

[00:49:22]

Pretest 3

The question here is, for this patient which of the following would you recommend it as the best management strategy for Dato-DXd associated stomatitis assuming prophylaxis adherence?

1. Continued treatment without delay based on the severity of stomatitis grade 2;

2. Delay Dato-DXd treatment until symptomatic improvement and reinitiate Dato-DXd at a reduced dose, use steroid containing mouth rinse 3, 4 times daily for 1-2 minutes;

3. Delay Dato-DXd treatment until symptomatic improvement and reinitiate Dato-DXd at the same dose, this is a difference with answer 2, use steroid containing mouth in a similar way;

4. Discontinue Dato-DXd and observe the patient for 2 weeks to see if symptoms worsen, since the patient received prophylaxis for stomatitis, no steroid containing mouth rinse is needed;

Please vote now. Okay. Basically continue stop and reduce the same dose, and a 2 weeks, and no steroid containing mouth rinse is needed.

[00:51:01]

PRIMED: Preventive Strategy for Sacituzumab Govitecan-Related AEs in TNBC

Let us move forward. Let us review very quickly some of the adverse events. Let us start with sacituzumab govitecan. Let us remember this, neutropenia and diarrhea. We conducted the PRIMED study that was presented by Jose Perez at San Antonio last year. Basically we offer primary prophylaxis with G-CSF the first 2 cycles. Days 3, 4, Days 10, 11. Also loperamide first 2 cycles. Days 2, 3, 4, 9, 10, 11. Two mg twice a day or 4 mg once a day. The primary objective was the incidence of grade 2 or higher diarrhea, incidence of grade 3 or higher neutropenia.

[00:51:51]

PRIMED: Results

Here we have the key results. For neutropenia, look at here all grades in the first 2 cycles 28% with the extended treatment 42%, which compares very nicely. Grade 3 or higher 16% after 2 cycles 24% in the total study. Diarrhea. You can see here also grade 3 diarrhea 4%, grade 2 and grade 3, 12% and 4% respectively. Regarding the modification in the first 2 cycles, 0% discontinuation 8% for the total study discontinuation, you can see here reduction 14, interruption 13% of patients.

[00:52:39]

Management of Neutropenia Associated With Sacituzumab Govitecan

Now, what about the neutropenia? Just to remind ourselves, when we do have to decrease the dose if grade 4 neutropenia for 7 days or higher, and or grade 3, 4 febrile neutropenia, or when at the time of scheduled treatment, grade 3,4 neutropenia is delaying the dose for 2-3 weeks until recovery to grade 1. We have to reduce the dose by 25% the first time to 50% the second time, and to stop the treatment permanently the third time. If we have to delay the dose for more than 3 weeks, then we have to discontinue the treatment.

[00:53:22]

Management of Diarrhea Associated With Sacituzumab Govitecan

What about the diarrhea? Grade 3 or 4 due to the treatment we should first decrease 25%, second 50%, third event we have to discontinue the treatment. If we do not control the diarrhea grade 3 or 4 with loperamide then and the delay of the dosing is higher than 3 weeks, also we have to stop the treatment permanently.

[00:53:47]

Identification of Mucositis/Stomatitis With Dato-DXd

What about stomatitis? Here we have the grade 1, 2, 3, and 4. I will not enter into detail. I will want to stop a little bit in the treatment of mucositis stomatitis.

[00:54:02]

Optimal Management of Mucositis/Stomatitis Associated With Dato-DXd: Prophylaxis Use

First what are the prophylaxis use? It is recommended to use mouthwashes, steroid containing mouth rinse with dexamethasone for example, 3-4 times for 1-2 minutes a day. Of course, also oral hygiene and patient education. We could consider cryotherapy and sometimes to do some inert bland rinses before the mouthwashes.

[00:54:32]

Management of Mucositis/Stomatitis With Dato-DXd

Now, what about the management? If we have grade 1 stomatitis with or without prophylaxis, we should start using the steroid mouth washes and continue afterwards with the same dose. If grade 2, we should differentiate if the patient was taking prophylaxis utterance or if the patient was not on the prophylaxis utterance. In the first case with prophylaxis utterance, again, mouth washes, but we should delay the treatment with Dato-DXd and reinitiate at a reduced dose. However, if the patient was not using a prophylaxis utterance, then we have to stop the treatment to wait and grade 1 or grade 0. But we could start the steroid containing mouth rinses, and we could start with the same doses of datopotamab. Grade 3, does it matter about the prophylaxis? We have always reduce the dose. Grade 4, we should not restart the treatment.

[00:55:40]

Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan

What about ocular surface toxicities and other adverse events associated with datopotamab? You can see here that it could be from eyes redness, to itching, sensitivity to light, blurred vision. We have different aspects which might differentiate between keratitis or other events. Nevertheless, if asymptomatic we could continue the treatment. Just use artificial tears but we maintain the dose. If grade 2, which is asymptomatic with moderate decrease in visual acuity, we have to stop the drug until we have grade 1 or grade 0. You have 3 grade 3 symptomatic with marked decrease in visual acuity. Then we have to stop the treatment, grade 1, grade 0, and we have to reduce the dose. If grade 4, we have to stop the treatment.

[00:56:38]

Interstitial Lung Disease Associated With Dato-DXd

Last but not least, maybe 2 or 3 comments of ILD pneumonitis. Very important to monitor these adverse events, very important to check the CT and to consider if grade 1 always stop the treatment. Consider corticosteroids as 0.5 mg of prednisolone or equivalent. If resolved in less than 4 weeks, we could continue with the same dose. If this results in more than 4 weeks, we have to reduce the dose. In my clinical practice, I always reduce the dose after ILD pneumonitis, but these are the guidelines. If grade 2 to 4 we have to start corticosteroids as soon as possible, and according to the guidelines we should stop the drug permanently.

[00:57:29]

Now, Let's Revisit Our Patient Case

Let us go back to the clinical case.

[00:57:31]

Patient Case: 62-Yr-Old Woman With Previously Pretreated ER+/HER2- (IHC 0) MBC

Just remember that this is a patient who was on treatment with datopotamab deruxtecan. She did have stomatitis, prophylaxis adherence, and she developed grade 2.

[00:57:45]

Posttest 3

Let us go back again for the questions.

1. Continue the treatment without delay based on the severity is only grade 2;

2. Delay Dato-DXd until improvements and start as a reduced dose, of course mouthwashes;

3. Delay the use of dato and reinitiate after grade 0 or grade 1 at the same doses, of course, mouthwashes; or

4. Discontinue treatment, observe the patient for 2 weeks to see if the symptoms are worse or not, because the patient received prophylaxis, then we do not need to go for mouth washes;

Please vote. Let us see. Okay. Let us see the results. One second. It has more delay. First, always when we have grade 2 we have to stop the treatment. That is always when we have grade 2. But the patient did receive prophylaxis. We should reduce the dose. If the patient did not receive prophylaxis we could restart at the same dose. This is very important which this is an exception with other adverse events. If prophylaxis, reduce the dose. If no prophylaxis, maintain the dose. Always mouthwashes. Let us go for the next slide.

[00:59:36]

Roundtable Discussion Points

We have some discussion points. Sara, when do you use a primary prophylaxis with G-CSF to prevent neutropenia with sacituzumab in the clinical practice?

Dr Tolaney: That is a good question. I will say that I have started using prophylaxis a lot more commonly. There was new guidance that had come out to consider using primary prophylaxis in patients who may be at risk for neutropenia. For example, someone who is previously had neutropenia, someone who previously had febrile neutropenia, someone who may be older and have comorbidities, and those are all patients you really, really should be using primary prophylaxis upfront. I will usually give either 3 days of G-CSF after Day 1 and then use a long acting pegfilgrastim after Day 8. I find that that works quite well.

Dr Cortes: Yeah. One quick question. You have a patient who is doing really great with sacituzumab govitecan or with datopotamab whatever, and the patient experiencing some delays because of neutropenia. Would you consider G-CSF to avoid the decrease of the dose, or do you prefer to decrease the dose and try to continue without the use of G-CSF? Toxicity profile or toxicity otherwise is very, very good.

Dr Tolaney: Usually, with at least with sacituzumab, I find that if I use growth factor, I can easily maintain dose and I tend to just do that. So I usually use a growth factor and do not dose reduce because I find that that works well.

Dr Cortes: Sara, what is coming next?

[01:01:06]

Novel and Emerging Agents Key Ongoing Clinical Trials

Dr Tolaney: I think it is an exciting time. I wish we had more time to discuss because it would be fun.

[01:01:13]

Key Ongoing Phase III Trials of TROP-2-Directed ADCs Early Breast Cancer

There is so many trials that are coming where these drugs are now moving into the early breast cancer space. You can see, for example, in triple negative disease and the residual disease space, there are trials that are ongoing evaluating either sacituzumab or Dato-DXd or sacituzumab govitecan. I think this will be really exciting as these patients do have high risk of recurrence, and an ADC here would be particularly important. There is also further work being done in the metastatic setting. For example, we talked about ACSENT-04 which looked at sacituzumab, and pembrolizumab, and the PD-L1 positive for triple negative setting. There is also TROPION-Breast05 which is ongoing evaluating Dato-DXd and durvalumab upfront. There is other novel studies being done. I think TroFuse-011 is a very cool study because it is trying to see if immunotherapy could work even in PD-L1 negative disease, so adding pembrolizumab to Sac TMT vs Sac TMT alone vs chemo. You can see again, a lot of really exciting trials that are ongoing.

[01:02:20]

Roundtable Points

Given our limited time, maybe I will just pick your brain, Javier, with 1 of these questions. But if you are looking to the future, what do you think we are likely to see change compared to where we are now? If you were to say, look, a year from now, what do you think will be different with the use of ADCs?

Dr Cortes: Well, I think that you are totally right. I think the time is exciting. I think that we will see these drugs in the early breast cancer setting. In my opinion that is very clear. I think that we are going to see in the very near future how these drugs could be combined with other ones. Now we are exploring maybe different these bispecific antibodies, anti-PD-1 plus anti-angiogenic drugs. Maybe we will combine between them. I think that for sure these drugs will be in the early breast cancer setting and I think that we will be able to combine with other drugs in the future.

[01:03:16]

A Final Survey

Dr Tolaney: Yeah. It is a really exciting time. Thank you very much, Javier, for the really fun discussion about all that is going on. Maybe we can pick the audience's brain with a couple quick polling questions.

[01:03:29]

Poll 3

Do you plan to make any changes in your clinical practice based on what you have learned in today's program?

A. Yes;

B. No; or

C. Uncertain;

[01:03:44]

Poll 4

Then, if you do not mind, if you could just take a moment to text in 1 key change that you do plan to make in your practice based on this education from today. That would be great and super helpful to us.

[01:04:00]

Q&A

We are just about at time but I do not know if there is 1 final question, Javier, that you would like to address. I think 1 of them that I think comes up a lot, particularly post-ESMO, was really based on the data that you presented, which is what would you do if you were seeing a patient who had metastatic triple negative breast cancer and had a tumor that was PD-L1 negative? What drug are you going to give? Obviously, beautifully presented the data for Sacituzumab. We also saw great data for Dato-DXd. If the audience had access to both of these drugs, what are they supposed to actually do in clinic and how do you make a decision?

Dr Cortes: Well, I think that I want to be very honest, that I think that both of them are basically identical, in my opinion, very, very similar in terms of activity. I think that PFS was identical 0.62, 0.57. Patient characteristics were some different between both trials in terms of overall survival. We have to acknowledge the point of crossover. According to the trial in the TROPION-03, it was not obviously in the TROPION. But when you look at, for example, what happened the Western countries in the TROPion-Breast02 for the overall survival, the hazard ratio was 1.2. What does it mean? That when you are able to cross into sacituzumab this will have an impact in survival. My key message here is that in my opinion the activity is very similar. We have to take into account other aspects. We have to discuss toxicity, neutropenia, diarrhea, compared with eye disorders, and stomatitis mucositis. What about Days 1 and 8 every 3 weeks compared with every 3 weeks, which is an advantage in my opinion, for dato but maybe the toxicity profile is not that clear? Eye disorders for me is much more uncomfortable than neutropenia. I think that God thinks we will have patients for all of these drugs, I think that the point here, and I think that you will agree, I would like to hear your thoughts also, is that we have to use these drugs, if available before chemotherapy, because clearly we will be able to control the disease a little bit more time and time in triple-negative breast cancer is gold, unfortunately.

Dr Tolaney: I think that is very well said, Javier. I think both data sets, I think, were very exciting because I do think it is a big deal to see improvements in outcomes for triple negative breast cancer patients and really important to have choices. Sometimes a patient may have a contraindication to 1 of those drugs and so it is nice to be able to choose between the 2, as you alluded to, given differences in toxicity profiles. It is just such a nice thing to see that outcomes are improving for this really difficult to treat disease, and hopefully again, we will see more of these agents move into the early disease space and help us cure more of our patients as well.