Challenging Treatment Paradigms in HER2-Low and HER2-Ultralow MBC: Experts Examine The Evidence to Guide Individualized Clinical Decisions

 

[00:35:55]

 

HER2 Assessment and Testing in 2025: What HCPs Need to Know

 

So let's start with HER2 assessment and testing in 2025. What do we all need to know in order to help our patients in the best possible way?

 

[00:36:06]

 

Patient Case 1: 59-Yr-Old Patient With a Long History of Endocrine-Sensitive HER2-Low mBC

 

I'm going to start with a patient case. It's a 59-year-old lady with a long history of endocrine-sensitive HER2-low metastatic breast cancer. She had an initial diagnosis in 2010 with breast conservation surgery, radiotherapy and tamoxifen. Then 6 years later, she developed bone metastasis. There was a histology done with ERP, a positive HER2 1+ Ki-67. We get that routinely in our country 20%. And she received AI and bisphosphonate. She was not treated at our site, but she came about 2 years into that treatment just for second opinion and wanted to know whether we would have done anything different.

 

She just wanted to sort of know that we would take care of her once she progressed, because she knew we had clinical trials ongoing, so she was interested in changing to our center. So we left her on the therapy that was started because she was stable. She had a very good quality of life. And then 2 years later, bone metastasis progressed, and we started her on abemaciclib and fulvestrant.

 

And then 3 years later there was another disease progression in bone. And she was started on exemestane everolimus because she was wild-type for ESR1, PIK3CA and germline BRCA.

 

And then a year later. So you can see how that is sort of increasing and dynamic. She had a progression with first time visceral metastasis. And the question is, what to do now?

 

[00:37:39]

 

Pretest 1

 

So if you look at the latest approvals and information we have on HER2 status in patients with breast cancer and a long history of an endocrine sensitive disease, who would you consider for treatment with trastuzumab deruxtecan, T-DXd?

 

1. Would you think about it in newly diagnosed, previously untreated, asymptomatic HER2-ultralow disease;
2. Newly diagnosed, previously untreated asymptomatic, HER2-low disease;
3. Previously treated HER2-ultralow disease with several endocrine-based treatment options still available; or
4. Previously treated hormone receptor–positive HER2-low disease after several endocrine-based lines of therapy.

 

So please take your vote. The majority would certainly treat our patients, but one is tempted, given the efficacy. And Sarah is going to talk about this to sort of use the drug already earlier.

 

[00:39:04]

 

ESMO Living Guidelines: HR+/HER2- mBC With PD and Not a Candidate for ET ± Targeted Therapy

 

Can we move on? Okay. So in our recent ESMO guidelines, and for those of you who sort of have a look at the ESMO guidelines every once in a while, the most recent version can be found online, where we do living guidelines and we just change them from the hormone receptor–positive/HER2-negative, HER2-low, HER2-ultralow space, and that we always at every line of therapy ask the question, is the patient still a candidate for endocrine-based therapy? Yes or no? And if you go yes, then you will have other options. And if you go for no, then you will eventually come to this page, where we look at patients without previous chemotherapy for metastatic breast cancer.

 

And, if they are HER2 low or ultralow, we recommend T-DXd. And if they HER2 zero, so then we would recommend a chemotherapy. And in Europe, we still have an indication for bevacizumab in the first line. That's why this is on the slide as well. And if patients have had previous chemotherapy for metastatic breast cancer, then we also have an indication for T-DXd, but also for sacituzumab govitecan and datopotamab deruxtecan.

 

And then upon progression, you can use a different ADC, or you can eventually then go to a regular chemotherapy.

 

[00:40:33]

 

HER2 as a Biomarker in Breast Cancer

 

If we look at HER2 as a biomarker, I think this has evolved over the last 20 years or so. It's about HER2 overexpressing breast cancer with a gene amplification. It's about 15% to 20% of all breast cancers. And they come along with degrees of aggressiveness mutations. And we heard this afternoon a nice presentation on how if you target HER2 and PIK3CA pathway that you can also achieve some very good responses.

 

And HER2 obviously is the most important prognostic and predictive biomarker for HER2-targeted therapies. And we have a number of HER2-targeted therapies. We have the antibodies. In Europe, we don't have an approval for margetuximab. We have TKIs. Again, in Europe, we don't have neratinib approved in this setting. And we have ADCs, T-DM1 second-line, second-generation and T-DXd third-generation ADC. We'll hear more about the clinical efficacy in the next talk.

 

[00:41:39]

 

Overview of HER2 in Breast Cancer

 

So 15% of the breast cancers are HER2-positive. And then if you look at the hormone receptor status, and I think we'll see probably during this meeting as well, that we need to treat them separately the hormone receptor–positive/HER2-positive and hormone receptor–negative/HER2-positive at least when it comes to maintenance therapy, but also maybe in the future with different treatment approaches.

 

But hormone receptor–negative/HER2-positive is about a third of these cases.

 

[00:42:15]

 

Previous Binary Classification of HER2 in Breast Cancer

 

If you look at the previous classification of HER2 in breast cancer, we had 0, 1+, 2+ and 3+, and we were only interested in the 3+ and the 2+, ISH-positive. And you can see that we say HER2-negative and HER2-positive. And then we had this equivocal ISH test, which now is resolved as one of the last ASCO/CAP guideline modifications.

 

[00:42:42]

 

DESTINY Trials

 

And then the DESTINY trials came along. There was a large series of international trials investigating T-DXd, a third generation ADC as a treatment options for patients with breast, gastric, lung and additional cancer types. And for breast, I think the most important are DESTINY-Breast04 and 06 in the space of HER2-low disease and their phase III trials. And the patients always had T-DXd vs physician's choice of chemotherapy. And both of these trials reached the primary endpoint. We'll talk about some of the patient characteristics and the result later.

 

[00:43:21]

 

DESTINY-Breast04 and DESTINY-Breast06

 

So this is FDA-approved T-DXd for metastatic breast cancer with HER2-low or HER2-ultralow membrane staining in patients with 1 or more lines of endocrine therapy in the metastatic setting, and also in HER2-low disease for patients who previously received chemotherapy in the metastatic setting. That's the DESTINY-Breast04 study.

 

[00:43:50]

 

HER2 Expression Today

 

So if you look at the spectrum of HER2 staining, which we have today, we have the absolutely negative, which is called null or zero. Then we have ultralow, which is like 1 to 9% of cells with staining, which probably got overlooked a lot of times in the past just because it didn't have any relevance, and so did 1+, which also did not have any therapeutic relevance. And 1+ and 2+ we call HER2-low. If 2+ is ISH negative and then obviously we have the HER2-positives which qualify for anti-HER2 treatment if they are 2+ ISH positive or 3+.

 

[00:44:39]

 

Ongoing Challenges in Assessing HER2 Status

 

So how do we or rather our pathologists do that and evaluate the HER2 status. I think there's a lot of challenges, and we've gotten quite good at it for the upper part of the spectrum. which is the HER2 overexpressing tumors, where there is high concordance, as I will show you in a minute. But there's a lot of interlaboratory variability, standardization issues, tissue heterogeneity. I think that's a very important point.

 

It affected the efficacy of T-DM1 with T-DXd because it works across the spectrum of HER2 staining. That is not such an issue anymore. And then we have the implications of the changing HER2 status on treatment strategies.

 

[00:45:25]

 

ASCO/CAP Guidelines for HER2 Classification

 

So if you look at the ASCO/CAP guidelines, they have this group where we have sort of an equivocal ISH test. And then if you look at the copy number and do another immunohistochemistry and the guidelines clearly indicate that we should do another immunohistochemistry if there is an equivocal staining result, and then this can be resolved even if there is a second reviewer who needs to recount the ISH results. So we should not have equivocal, we should have negative or with additional comments or HER2 positive.

 

[00:46:06]

 

HER2-Low and HER2-Ultralow

 

And if you look at the HER2-low and ultralow, at least in our guidelines in Germany, the pathologist said they wouldn't put HER2-ultralow in the guidelines because it's very difficult to standardize. So I think they're now doing a lot of work on standardization of the HER2 testing with regard to the lower part of the spectrum because that's what we need today in order to give the indication for T-DXd therapy in the appropriate setting.

 

So we need to realize that some of these faint stains are important for patient care. And so we need to talk to our pathologists and make sure they understand that it does matter whether there is a little bit of staining, whether there is more than 10% of staining, or whether, obviously there is no staining at all.

 

[00:47:01]

 

Current HER2 Testing Recommendations and Anticipated Future Modifications

 

So what are the testing recommendations and how can we modify them in the future?

 

[00:47:09]

 

ASCO/CAP: Distinguishing 1+ From 0

 

So if you look at the ASCO/CAP’s guidelines, they give recommendations for distinguishing 1+ from zero. They tell you which objective lens the pathologist needs to look at. And they recommend a review by a second pathologist. And they also recommend appropriate controls. So we have controls that cover the lower end of the spectrum. And obviously, there needs to be attention paid to the preanalytical conditions of the sample. And there are challenges with metastasis, as you all know, if you have bone metastases for example.

 

[00:47:46]

 

ASCO/CAP Guidelines: Standardization of HER2 Testing

 

So the ASCO/CAP guidelines have developed over time. And each of these issues has a topic that they address specifically. So the first guidelines in 1998 sort of addressed the companion diagnostic test for HER2-directed therapy with trastuzumab. And then we had guidelines setting the standards for IHC and for ISH and address the false positive rates. The next ones addressed the false negative rates and retesting and discordant results.

 

Then the guidelines of 2018 looked at this equivocal staining I showed you before. And now the most recent guidelines address HER2-low. There is no changes in reporting. And we also need a semiquantitative score in order to differentiate the low spectrum.

 

[00:48:44]

 

Current HER2 Classifications

 

If you look at the current classifications about HER2-lows about 50% of all breast cancers. And then we have HER2-ultralow, where there is faint membrane staining in less than 10% of the tumor cells. And so HER2 is not longer a binary variable, although we sometimes use it when we talk about different subtypes of breast cancer. But it's actually a spectrum that we have to recognize.

 

[00:49:13]

 

Variables Affecting HER2 IHC Testing Results

 

If you look at the variables addressing the HER2 immunohistochemical results, I think we, as clinicians, may wonder, how can they ever get this right? But actually the concordance on the overexpressing tumors is very high. It's almost 100% because there have been round robins good quality control. So pathologist actually do this quite well. But there's obviously some variables like the tissue handling and fixation. It's easier to fixate a core biopsy than it is a complete tumor tissue where you have to give them time. So the fixation gets to the inside of the tissue as well. Then the tissue processing then obviously biopsy vs resection. And then we have analytical variables like the IHC variables or the reviewer experience. And obviously this is also going to change with the increased utilization of AI procedures.

 

[00:50:11]

 

HER2 IHC Assays

 

So the most widely applied HER2 assays are the Ventana PATHWAY 4B5 assay. And that column was used for the DESTINY-Breast04 and DESTINY-Breast06 trial eligibility. And then there's the trastuzumab. They are optimized for high levels of HER2 expression by immunohistochemistry. We have to realize that they were not developed to give us guidance for T-DXd treatment in the low and ultralow spectrum but for the overexpressing tumors.

 

And that's where we had round robins and good quality control. So there is no sensitivity or range to detect low levels of HER2. And I think it's very understandable that previously what was reported as 0 or 1+ may not be reported the same way today, because now we need attention to be paid to this. But in the past, if it was faint, who cares? Either way, it didn't really affect anything. So these older results may read out differently if the staining would have been done today.

 

[00:51:25]

 

HercepTest vs Ventana PATHWAY

 

So here's some studies looking at the concordance between the test. And as I said, there's high concordance for HER2-positive vs negative, like 98%. And we also see that in our own clinical trials. We have central pathology in a lot of our trials. And so what we see is that the concordance for HER2-positive results has been quite high.

 

There is complete agreement for the semiquantitative scores. Only in about 70% of the cases in the HercepTest detects HER2 expression with a higher sensitivity, and it's also more sensitive for HER2-low tumors.

 

[00:52:07]

 

Challenges With HER2 Assays

 

There are some challenges with the assays, and you can see here there's some CAP surveys and there is not so much concordance between 0 and 1+. And - and also with the experienced pathologist, they have a better concordance with 2+ or 3+ than with 0 to 1+. So this is not so easy to differentiate at the lower end of the spectrum.

 

[00:52:32]HER2 IHC Resources

 

And if you look at the rescoring, we have an interobserver concordance from 60% to about 86% and an intraobserver concordance from 84% to 88%. And if you look at 400 tissue samples that were scored at IHC 0, then a third of them came up as ultralow and 37% as IHC 1+.

 

[00:53:01]

 

Should Biopsy be Repeated (Re-testing) Over Time?

 

So the question for our patients is, should we do the biopsy repeat over time, or do we at least need to do the retesting over time?

 

[00:53:10]

 

HER2 Status Can Change Over Time

 

So there is some interesting studies here where the investigators saw that actually the HER2 status can change over time. And I think this is not just a biological phenomenon. This has - also has to do with staining depending on when the primary tumor was stained. Obviously, as I said before, in former days it really didn't matter whether it was 0 or 1+.

 

So here we have a sample of about 550 patients. So there is 38% discordance from primary tumor to metastasis, HER2-low vs zero, 15% going from zero to HER2-low and about the same amount going the other way around.

 

[00:53:52]

 

HER2 Status Can Change Over Time

 

We also have different work. This is by Dr Tarantino, published in 2022, where they looked at 232 patients and they saw that 44% went from zero to low and 22% went from HER2-low to HER2 zero. And there was an abstract a couple of years ago at the ASCO meeting where the investigators showed that if you have 5 different biopsies, you'll have 100% chance of having one HER2-low results. So it's sort of—I'm not asking everybody to do one biopsy after the other, but I'm just trying to get you awareness that there is some changes based on tumor heterogeneity but also based on different evaluation techniques over time.

 

[00:54:45]

 

HER2 Retesting: When to Do it?

 

So the recommendations of when to do retesting is obviously, if you have discordant results in metastatic disease, it makes sense to retest. But we also verify the metastasis by biopsy again. Then if the biopsy is very small not representative, there may be preanalytical concerns or fixation or staining. The weekend is always a good example when you sort of fixate longer than during the week, and the HER2-low status is needed for treatment.

 

And looking at biomarker data from the DESTINY trials, we know that if there's prior specimen was tested before 2023, it's advisable to retest again. And if there is HER2 heterogeneity between the samples. So we need to look at the primary tumor tissue, but we can also obviously go for other metastatic sites.

 

[00:55:43]

 

Global Analysis of HER2-Low Diagnosis in BC

 

So here's a global analysis of HER2-low diagnosis in breast cancer with 77 pathologists from 14 countries. They scored, they were trained, and they rescored. And the agreement rates post training was between 80% and 90%. So it's just a matter of training and being aware that this matters. And then you can get the concordance up quite substantially.

 

[00:56:12]

 

Augmented Interpretation of HER2, ER, and PgR in BC

 

And obviously, as I said before, there is also the use of AI now in pathology. And also AI is a big topic here at this ASCO meeting. And here's a data set where the pathologist had agreement of about 50%, and then the concordance after AI assisted revaluation went up to 75%. But it really doesn't matter so much whether it's 2+ or 1+ if the 2+ is ISH is negative. But it really matters whether it's zero or 1+ or zero or ultralow.

 

[00:56:49]

 

HER2 Reporting

 

And if you ask your pathologist and what - what to report. I think what we need to report is the immunohistochemical stain. But then also, go in the zeros to tell us whether there is a 10% or less membrane staining.

 

[00:57:08]

 

Panel Discussion 1

 

Before I close, let me just ask my colleagues, Sarah, how do your reports look like at Dana-Farber? Do you get the percentages? Do you get the immunohistochemical qualifier?

 

Dr Sarah Sammons (Dana-Farber Cancer Institute): Yeah. So we get immunohistochemistry on everyone. And actually our pathologists are routinely reporting HER2-ultralow as well. I know that that's not the case everywhere in the US and certainly nationally, but we get the semiquantitative score on everyone and ultralow at this time.

 

Dr Harbeck: Ian?

 

Dr Ian Krop (Yale Cancer Center): The same.

 

Dr Harbeck: Is there anything else you would like to know from your pathologist, or you're just happy with the percentage? Does that give you enough information?

 

Dr Krop: I think from the data you presented, it's hard enough to distinguish - in a semiquantitative way, null from 1, ultralow 1, 2 to try to parse that out even further with quantitation. You know that it can't be reproducible. So I wouldn't put too much faith in a number. I think it makes more sense given the difficulties in assessing this to try to at least just keep it in the groups.

 

Dr Harbeck: I mean, you're at Yale. David Rimm has always proposed to have another way of quantitative assessment of HER2. He has also given some discussions at this meeting in previous years, advocating for different assays. Do you think we need that, or do you think we have enough information to indicate T-DXd testing?

 

Dr Krop: Yeah. No, I think that's a great question. And, you know, some of the data that you showed in terms of the lack of concordance in the low range is from his group, and, you know, it's absolutely clear that the tests we have now were designed to distinguish, as you said, the very high from everything else. They weren't designed to distinguish between the low rates.

 

And if we think that that's important, at least right now, we do think HER2 zero is different than ultralow and low, at least in terms of the clinical trial data we have, with respect to sensitivity to T-DXd or benefit of T-DXd.

 

If we believe that, then we should get a test that distinguishes zero from everything else. And we don't have that now. He has developed some tests and he's trying to validate that. But I think there may be a—in the end, we may find out that even essentially zero cancers are sensitive to T-DXd. And we'll get some data from that with DESTINY-Breast15 and some other trials going on.

 

So I think right now it's a moving target. But theoretically it would be nice to have a test that we really could distinguish the zeros.

 

Dr Harbeck: Yeah. I mean, last year you gave a wonderful discussion of the DB06 data, and you asked the question, I think yourself and the discussion, do we really need to test? I mean, maybe not everybody saw the discussion. What do you think of your data? Do we need to test, or why don't we treat everybody?

 

Dr Sammons: That's a question on here too. So perfect.

 

Dr Harbeck: Okay. So.

 

Dr Krop: I don't think we have new data between when the DB06, a year ago, and now I think when we have data from the DAISY trial that looked at a small number of patients who had what was called HER2 zero, some of them actually were ultralow, where there was a 30% objective response rate. We're going to have data from DB15, which should give a bigger sample size to really look at that HER2 zero population.

 

If that shows significant response in the zeros, you know, validates what we saw in DAISY, then there shouldn't be a reason to test. But I think until we have that data right now, I feel like HER2 2, HER2 zeros shouldn't be treated.

 

Dr Harbeck: Okay. If there were any other comments or questions from online.

 

Dr Sammons: I think we adequately addressed the other one. There is one comment, that Ventana did validate the 4B5 HER2 pathway for HER2 low and HER2 ultralow, and it is approved as a CDx for ENHERTU. So there's just that comment that I think we addressed everything else.

 

Dr Harbeck: There's different ways of looking at companion diagnostic. For example, in our country we don't have that concept. So we rely more on quality assurance testing throughout the pathology community. But we're more flexible with regard to which individual test they're using. In the US, it's a bit different.

 

[01:02:10]

 

ASCO 2025 Abstracts

 

So for all of you who are interested in the HER2 testing, there is going to be a couple of disclosures. Two of them just online looking at AI-based algorithms, but also on the topic of reevaluation. But there is also one rapid oral abstract, which we saw today looking at the use of AI.

 

And with that, I could—

 

Dr Krop: I think there's a question.

 

Dr Harbeck: Okay. Sure. Do we have a mic? I can repeat it. Yes, please.

 

Speaker: [Inaudible].

 

Dr Harbeck: Okay. Thank you. Thank you so much. Let me just repeat. So I'll call you a pathologist, I take it. So she said it was okay. What I said, but probably a pathologist would have told you this story a little bit different. And the Ventana PATHWAY assay is approved as a companion diagnostic for treatment with T-DXd. And it's also approved for—has good quality assurance for the low and ultralow detection.

 

But as I said, not everywhere. We have a quite a diverse audience. We do have this concept of companion diagnostics.

 

[01:04:31]

 

Posttest 1

 

And with that, I would just like to come to my posttest question. Please don't be annoyed. Please answer the question one more time. Who do you think is the appropriate patient collective to be treated with T-DXd? Is it:

 

1. The asymptomatic patients that are newly diagnosed;
2. Patients with still several endocrine-based options; or
3. The patient after several endocrine-based lines of therapy.

 

Okay. There is still some of you who think that they're very interested in the data and say that we can also use this in newly diagnosed patients. But the majority says and this is, I think, the guideline conform indication that we should use T-DXd in those patients with HER2-low, ultralow disease who have no endocrine based lines of therapy anymore.

 

But I think Sarah and maybe we can discuss this after your talk. We can also get used to the idea of treating with chemotherapy if there is symptoms and then going back maybe to 1 line of endocrine-based therapy. We've also done that in some patients. But I don't want to steal any more of your time.

 

[01:06:01]

 

Posttest 1: Rationale

 

Could we move on? I think we discussed this. And Sarah is also going to talk a little bit more about the indications.

 

And with that, I hand over the podium to you. Thank you very much.

 

[01:06:15]

 

Clinical Application: Selecting Treatment for HR+/HER2- mBC Following Multiple Lines of Endocrine Therapy

 

Dr Sammons: Great. I feel like a HER2 expert pathologist myself now. And so we've talked a lot about HER2-low and HER2-ultralow testing. But now let's talk about why we care so much and the data for how this has evolved as a biomarker for our patients.

 

[01:06:37]

 

Patient Case 2: 67-Yr-Old With HR+/HER2-Ultralow mBC Recurring on Endocrine Therapy + CDK4/6 Inhibitor

 

And we'll start with a case. Case number 2 is a 67-year-old with hormone receptor–positive/HER2-ultralow metastatic breast cancer, who's recurring on her endocrine therapy and CDK4/6 inhibitor. She is now on everolimus and fulvestrant. She's already progressed on CDK4/6 and AI. And now after everolimus and fulvestrant, her PET CT shows an asymptomatic disease progression with 2 new liver lesions and some mild bone progression.

 

You do a liver biopsy to check her receptors, and she is still hormone receptor–positive/HER2-ultralow, and she has an excellent performance status.

 

[01:07:23]

 

Poll 3

 

Based on her HER2-ultralow status and the latest guidelines and expert recommendations, which are the following therapies would you offer this patient?

 

1. Sacituzumab govitecan;
2. Capecitabine;
3. Taxane; or
4. Trastuzumab deruxtecan.

 

Okay, so 81% of you would give her trastuzumab deruxtecan, 4% would consider capecitabine, which I honestly think is reasonable, given that she's asymptomatic and 15% would give sacituzumab. So let's talk a little bit more about that.

 

[01:08:14]

 

Patient Case 3: 54-Yr-Old Math Teacher With HR+/HER2-Low Unresectable Breast Cancer

 

So next we're going to do another case. This is a 54-year-old math teacher. We all loved math. So she is now endeared to us. With hormone receptor–positive/HER2-low unresectable locally advanced breast cancer. She was prescribed endocrine therapy plus CDK4/6 inhibitor as her adjuvant therapy. And then at her 6-month follow up visit on her adjuvant therapy, she actually presents with new visual disturbances, dizziness and disorientation. And very unfortunately, you perform a brain MRI, and she has multiple brain metastasis.

 

She has one 2-centimeter parietal lesion and one 1-centimeter temporal lobe lesion. You do a CT of her chest, abdomen, pelvis, which reveals innumerable liver lesions and a bone scan that shows bone metastasis. And you do a biopsy of the liver and she's ER 30% and she is HER2-low 1+ by immunohistochemistry.

 

[01:09:28]

 

Pretest 2

 

So which of the following systemic therapy options would be optimal for this patient with CNS lesions, several liver lesions, a bone scan showing bone metastasis and progression while she's on her adjuvant CDK4/6 endocrine therapy. This is a patient that we're obviously very worried about. Would you:

 

1. Switch her endocrine therapy in CDK4/6 inhibitor;
2. Maybe give her abemaciclib and fulvestrant;
3. Give her single-agent chemotherapy with capecitabine;
4. Give her sacituzumab govitecan or trastuzumab deruxtecan.

 

Okay, so 88% of the crowd is going to give her T-DXd, 6% are going to give single agent chemo, and 6% are going to switch our endocrine therapy in CDK.

 

[01:10:28]

 

Disease Prognosis and Goals of Care

 

Prognostic Significance of HER2-Low Disease

 

So let's talk about the prognostic significance of HER2-low disease. So HER2-low is what I would call a new biomarker in metastatic breast cancer. We do not think of it as a new disease entity. We still have 3 buckets in the way we treat breast cancer. There's hormone receptor–positive, HER2-negative, actually, now I would say HER2-positive is now adequately split by hormone receptor status. So maybe we have 4. And then triple negative disease.

 

And I would not say based on the body of evidence that we have that HER2-low is a new category of breast cancer. It is simply a biomarker. And we have a multitude of studies that have shown us that HER2-low that there is no difference in metastatic breast cancer patients overall survival, whether or not they are HER2-low or HER2 zero.

 

When you group them into their respective hormone receptor statuses. So we don't feel like this HER2-low biomarker indicates a distinct biology or a prognosis. And we do know from previous studies, we have looked at HER2-targeted therapies such as trastuzumab, T-DM1 for HER2-low. And that has not been effective for that class. So it wasn't until these new next-generation ADCs where we start to see a benefit and this new biomarker emerging.

 

[01:12:01]

 

Unmet Need For Effective Therapies in HR+/HER2- mBC Following CDK4/6i Therapy

 

So let's talk a little bit about the unmet need for effective therapies for hormone receptor–positive/HER2-negative metastatic breast cancer after progression on a CDK4/6 inhibitor.

 

[01:12:12]

 

Limited Median PFS in Patients With HR+/HER2-Low mBC Post-CDK4/6i Therapy

 

You know, we have options. But you know, in general, we'll usually try another line of endocrine therapy for these patients. We usually track their mutational testing. We see if they have a PIK3CA, AKT, PTEN, ESR1 alteration. Oftentimes we'll give them a second-line of endocrine therapy.

 

But the median progression-free survival of endocrine therapy regimens post CDK is rather short. You know, for endocrine and targeted therapies, we're not, you know, pushing much past 5-7 months. For endocrine monotherapy, a lot of those trials showed, you know, a 2% to 3% median PFS. For the ESR1 mutant patients who have long exposure on their CDK, we might get up to 8 months, but really, there's a high unmet need here for effective therapies that really prolong progression. You know, and then we get in the third and fourth line therapies.

 

Usually by then, we're considering most patients to be endocrine resistant. And we're switching to chemotherapies, single-agent chemotherapy post endocrine therapy as a median PFS, you know, between the 6- and 7-month range. And now we have ADCs that are outperforming these therapies. And we'll go over that data.

 

[01:13:31]

 

Endocrine-Resistant HR+/HER2-Low mBC Options: Chemotherapy or ADCs   

 

So let's talk about our options for antibody–drug conjugates in our endocrine-resistant patients, which is really at this time where we are using antibody–drug conjugates and chemotherapy after we maximize our endocrine therapy options.

 

[01:13:44]

 

ADCs in HR+/HER2-Low mBC

 

So we have 3 different approved antibody–drug conjugates for hormone receptor–positive/HER2-low or HER2-negative metastatic breast cancer. We have trastuzumab deruxtecan, which targets anti-HER2. It has a highly potent topoisomerase payload.

 

The vast majority of our patients, I would say about 85% of them, are going to be HER2-low or HER2-ultralow if we're in a country where we can do that testing.

 

Sacituzumab govitecan is an anti TROP2 ADC that has a SN38 payload, which is also in the same class of these topoisomerase inhibitor drugs. There is no biomarker for this class of drugs. We have done studies looking at TROP2 expression and seen some signals, but in general it works vs chemotherapy regardless of biomarkers.

 

The newest kid on the block is datopotamab deruxtecan, which is another anti-TROP2 ADC which has the same topoisomerase payload as trastuzumab deruxtecan. So the main problem here is that they all have the same payload. And hopefully in a couple of years from now we'll be sitting here talking about newer ADCs with different payloads. But for now, they're all topoisomerase inhibitor payloads.

 

[01:14:59]

 

Low HER2 Expression: New ADC Target in mBC

 

And so the way we decide which patient might benefit from which ADC at this time, the only biomarker that we have in our determination is by looking at HER2-low and HER2-ultralow. You can see 60% to 65% of patients will be low. Another 20% will be ultralow and about 15% are truly null. And I do see these patients in the clinic where you have 3 different biopsies from primary to metastatic and another metastatic, and they are truly null. They have no expression. And those patients do exist.

 

[01:15:35]

 

DESTINY-Breast04: T-DXd vs Chemotherapy for Previously Treated HER2-Low ABC

 

And so based off of understanding what their HER2 status is, we now have 2 clinical trials that showed efficacy in the HER2-ultralow and low populations for T-DXd. The first being DESTINY-Breast04. This was a randomized, phase III, open-label clinical trial that took patients with HER2-low breast cancer. So 1+ or 2+, ISH not amplified. They had to have metastatic breast cancer.

 

The vast majority of them were hormone receptor–positive. However, there were some triple-negative patients in this patient population. They could have had 1-2 prior lines of chemotherapy in the metastatic setting, or a recurrence 1 prior line if they had a recurrence less than 6 months after their adjuvant endocrine therapy.

 

If they were hormone receptor–positive, they had to have at least 1 line of endocrine therapy, and patients were randomized 2-to-1 to either trastuzumab deruxtecan or physician's choice chemotherapy, which could have been either capecitabine, eribulin, gemcitabine or a taxane.

 

The primary endpoint was PFS in the hormone receptor–positive population. Key secondary endpoints were the PFS in all patients overall survival and overall response rate.

 

[01:16:57]

 

DESTINY-Breast04: T-DXd Improves PFS and OS in HR+/HER2-Low mBC

 

So we see here the progression-free survival on the left in the patients with hormone receptor–positive disease. Trastuzumab deruxtecan led to a median PFS of 10 months vs 5.4 months with chemotherapy for a hazard ratio of 0.51, which was very statistically significant.

 

You can also see that the overall survival in this population, was improved with T-DXd vs chemotherapy at 24 months vs 17.5 months for a hazard ratio of 0.64. That was statistically significant. So this really solidified T-DXd as a standard option for these patients after 1 line of chemotherapy in the metastatic setting.

 

[01:17:42]

 

DESTINY-Breast04: Efficacy in Patients With Stable CNS Metastases

 

We also looked at a sub analysis in the DESTINY-Breast04 clinical trial of the patients that had a history of stable brain metastasis. Brain metastasis are one of our main problems in the clinic. They're very difficult to treat. Patients have, in general, poor outcomes. And patients with HER2-negative brain metastasis have very few systemic therapy options.

 

And what they were able to see. There were 24 patients in the T-DXd arm that had a history of stable brain mets and 11 on the chemotherapy arm. So a small subset, but nonetheless helpful to look at.

 

The intracranial confirmed overall response rate was 25% with T-DXd vs 0% with chemotherapy. So not the intracranial response rate we see in our HER2-positive patients, which is more like 70%, but we're still seeing some intracranial responses here. The intracranial clinical benefit rate was around 60%. So a somewhat promising and certainly better than chemotherapy in our patients with CNS disease.

 

[01:18:55]

 

DESTINY-Breast04: Exploratory Analysis of PFS and OS in HR- Patients

 

They also did an exploratory analysis of DESTINY-Breast04, looking at the essentially triple-negative HER2-low patients. And the progression-free survival with T-DXd was 8.5 vs 2.9 months, which was statistically significant. And the overall survival in this population was improved as well. So it can still be an option for our triple-negative HER2-low patients.

 

[01:19:23]

 

DESTINY-Breast06: T-DXd in Chemotherapy Naïve and HER2-Ultralow Advanced/Metastatic Breast Cancer

 

We last year saw the results of the DESTINY-Breast06 clinical trial, which essentially moved T-DXd into the first-line as a first-line cytotoxic. So this was a multicenter, open-label, phase III trial. All of the patients in this trial were actually hormone receptor–positive. They could have progressive disease on greater than or equal to 2 lines of endocrine therapy plus targeted therapy. They had to be HER2-low. But this trial also included those HER2-ultralow patients that we talked about.

 

And patients could have no prior chemotherapy in the advanced setting. They were randomized 1-to-1 to either T-DXd or physician's choice chemotherapy, which was capecitabine or a taxane. The primary endpoint was PFS in the HER2-low population. Key secondary endpoints were PFS in the overall population and the HER2-ultralow population, as well as overall response rate overall survival.

 

[01:20:27]

 

DESTINY-Breast06: Baseline Characteristics

 

So just getting into—this is the newer trials. So we're going to learn a little bit more about these patients. You can see that patients were relatively young with a median age of 58. You can see that most patients were HER2-low. However, there were about 150 patients in the trial that were HER2-ultralow.

 

You can see that about 66% of the patients were HER2 IHC 1+, 32% 2+ out of the HER2-low patients. And you can see that they were essentially all estrogen receptor-positive. 30% of them were primary endocrine resistant. About 31% of them had de novo metastatic disease. Very few of these patients had bone-only disease; 86% had visceral disease, which is kind of rare for a first-line chemotherapy population; 67% of them had liver metastasis.

 

So these were kind of patients that I would say that the PIs were worried about with a lot of visceral disease, very little bone-only disease and a lot of liver disease.

 

[01:21:43]

 

DESTINY-Breast06: Prior Treatment

 

The median prior lines of endocrine therapy were 2 in terms of prior CDK4/6 inhibitor. About 90% of them had a prior CDK4/6 inhibitor. In terms of prior adjuvant or neoadjuvant cytotoxic chemotherapy, about 50% of them had prior chemotherapy in the adjuvant or neoadjuvant setting.

 

[01:22:08]

 

DESTINY-Breast06: Efficacy

 

In terms of the efficacy, in the top left, you can see that the progression-free survival in the HER2-low population was 13.2 months with T-DXd, vs 8 months with chemotherapy for a hazard ratio of 0.62, which was statistically significant.

 

The PFS in the intention to treat population was almost identical. And the progression-free survival in the HER2-ultralow population was also nearly identical, though the hazard ratio is higher at 0.78. Likely because it's a smaller sample size.

 

[01:22:46]

 

DESTINY-Breast06: Survival in HER2-Ultralow Disease

 

In terms of survival in the HER2-ultralow population, we can see here that there appears to be a trend towards improved survival, with 84% with T-DXd and 78.7% with physician's choice chemotherapy. But I will say that the overall survival data is immature at this time and not fully reported.

 

[01:23:16]

 

DESTINY-Breast06: PFS Subgroups in HER2-Low by BICR

 

Here is the DESTINY-Breast06 progression-free survival subgroups for the HER2-low, which was the primary endpoint. You can really see across the board there was benefit regardless of their endocrine resistance pattern, their prior chemotherapy, whether or not they had liver metastasis, whether or not they had prior CDK4/6 inhibitor.

 

So the FDA did approve the indication based on this study, adults that have metastatic hormone receptor–positive/HER2-low or ultralow breast cancer, as determined by an FDA approved test that has progressed on 1 or more prior lines of endocrine therapy in the advanced setting.

 

[01:23:56]

 

DESTINY-Breast06: Efficacy by Pace of Disease Progression on Previous Endocrine-Based Therapy

 

We also saw data this past year at San Antonio looking at the efficacy by pace of disease, of progression on their prior endocrine therapy-based regimen. Approximately 90% of patients received at least 1 line of endocrine therapy with a CDK4/6 inhibitor.

 

One of the new sort of parameters that we look at in the metastatic setting is how fast a patient has relapsed on their first-line CDK4/6 inhibitor. We really worry about the patients who relapse within 6 months of their first-line CDK4/6 inhibitor. We are very worried that those are not endocrine-sensitive patients anymore. And those are patients that I often rebiopsy and think about a line of chemotherapy as the next line.

 

And what was pretty striking here was that those patients who have very aggressive endocrine-resistant disease had a median PFS of 14 months vs 6.5 months with chemotherapy. We also saw, you know, respectable PFS in those that had 6 to 12 months on their CDK4/6 inhibitor, and also on greater than 12 months. But for the patients that relapse less than 12 months after their CDK, we see pretty good activity, which is nice because we worry about those patients.

 

[01:25:17]

 

ADC After ADC (A3) Study: Sequencing ADCs in HR+/HER2- mBC

 

Another thing that I wanted to point out is, you know, we now have these 3 ADCs that are approved for hormone receptor–positive patients. And so there's been a lot of retrospective studies looking at do ADCs work one after the other? What if I use first-line T-DXd? Can I then use sacituzumab in the next line or vice versa?

 

One study that was presented by my colleague, Ana Garrido-Castro, looked at 68 patients from academic medical centers who received greater than or equal to 2 ADCs for metastatic breast cancer. 30 of them were hormone receptor–positive, 38 were triple negative, and 50 of them were HER2-low.

 

And they looked at the median PFS on ADC1 vs ADC2. And you can see the median PFS on ADC1 was 7.5 months. The median PFS on ADC2 was 2.5 months. So you're really not getting very much benefit with your second topoisomerase inhibitor ADC.

 

She looked at whether or not the antibody target change HER2 vs TROP2. No target change mattered. The second ADC really seems just not to perform well across the board, indicating that there could be some cross resistance. There are some ongoing trials to kind of tease out which patients might benefit from a second ADC.

 

[01:26:43]

 

DEBBRAH: T-DXd in HER2+ or HER2-Low Breast Cancer With Leptomeningeal Carcinomatosis

 

One other thing that I wanted to point out, one of the most—actually, I would say the most challenging clinical scenario in metastatic breast cancer is the development of leptomeningeal disease. It's incredibly challenging to treat. Patients have very poor survival. We saw some data from the DEBBRAH trial looking at a very small number of patients, only 7 treated with T-DXd with leptomeningeal disease.

 

[01:27:11]

 

DEBBRAH: PFS

 

But the patients had a median overall survival of 13 months. This included HER2-low and HER2-positive patients. A median OS of 13 months is pretty respectable. We need more data here. This is a very small subset, but I do think T-DXd could be promising for our LMD patients.

 

[01:27:33]

 

Treatment Algorithm for HR+/HER2- mBC

 

So this is a treatment algorithm that we look at for hormone receptor–positive/HER2-negative or low patients. We’re generally treating them with a CDK4/6 inhibitor in the first-line. In the second-line, we're using biomarker strategies. And then in the third-line and beyond at this time, you know, we're looking at the HER2-low vs ultralow status, their pace of disease, patient preference when we're trying to determine whether or not to use a line of chemotherapy vs T-DXd.

 

I can say for me, the patients that I'm really worried about rapid disease progression, highly symptomatic, I'll use T-DXd if they're HER2-low—if they're endocrine-resistant but have a slow pace of progression, it's rather asymptomatic. I will still use capecitabine and save T-DXd as the second-line cytotoxic.

 

If they're truly, truly HER2 null, then they're going to get a line of chemotherapy. And then we can either use datopotamab or sacituzumab.

 

[01:28:33]

 

Posttest 2

 

So as a posttest, which of the following systemic therapies would be optimal for a patient with CNS lesions, several liver lesions and a bone scan showing bone metastasis? Would you:

 

1. Switch the endocrine therapy and CDK4/6;
2. Give them single agent chemotherapy which had an intracranial response rate of zero;
3. Give them sacituzumab; or
4. Give them T-DXd after they had radiation to the brain.

 

This patient was HER2-low.

 

Okay. Well, the same ones are going to give the same things, but at least 90% of us maybe chose what I would choose.

 

[01:29:23]

 

Posttest 2: Rationale

 

For this patient, this patient was HER2-low. We're very worried about them. They are endocrine resistant. They have liver mets. They have symptomatic bone mets, and now they have brain metastasis.

 

I would use T-DXd for this patient, you know, after I treated their brain lesions with radiation. We do know that at least has some CNS penetration. And certainly, the median PFS as first-line chemo favors chemotherapy and also the overall response rate is much higher. And I would want a response for this patient. They had asymptomatic disease. Didn't have CNS disease. Totally fine to reach for capecitabine.

 

All right. Any questions from the audience?

 

Dr Harbeck: Yeah, it's quite busy here on the iPad. So thank you very much for sending them in. Whether it's from the room or from online. There's 2 questions about the biomarkers in addition to HER2-low, ultralow, the ESR1 mutations, or if the patient was a PIK3CA positive, what would be the best treatment sequence?

 

Dr Sammons: Yes, absolutely. So when I think about ADCs and chemotherapy, I'm really thinking about an endocrine-resistant patient. So where I'm going to worry about biomarkers like ESR1 or PIK3CA is more when I'm choosing a second-line endocrine therapy. I absolutely am going to look at those biomarkers, for a second-line, you know, choice.

 

If a patient has an ESR1 mutation, they have low volume disease. They've had a long time on their first-line CDK4/6. Then elacestrant is, you know, certainly a great option. If they have a PIK3CA mutation, then fulvestrant and capivasertib would be a nice option there.

 

Dr Harbeck: I mean but we all have patients like from before elacestrant was approved, for example. And I remember one patient where we sort of exhausted at that time the endocrine lines of therapy. Then we gave her T-DXd. We gave her sacituzumab. And then we tested for ESR1, and she had a mutation, and we put her on elacestrant.

 

Dr Sammons: Okay.

 

Dr Harbeck: The disease was progressing slowly. She had a wonderful year. She came to me and said that was the best year during her treatment period.

 

Dr Sammons: That's great.

 

Dr Harbeck: Because the quality of life was there. So I don't think when the disease isn't really that aggressive at the moment, that we couldn't go back to an endocrine-based option that we hadn't the chance to use before.

 

Dr Sammons: That's a great point. Yeah, that's a great point.

 

Dr Harbeck: So I think we need to individualize this a little. So this is one set of the questions about the biomarkers. The other set is does it really matter whether it's HER2-low or ultralow.

 

Dr Sammons: I don't know. I don't know. I mean, all we have is the DESTINY-Breast06 data and the median PFS and the response rates for HER2-low and HER2-ultralow were nearly identical. And we now have an FDA approval for both of them. And so I do use T-DXd in the ultralow patients at this time. I do not use T-DXd for the truly null patients if they've been null on all of their biopsies.

 

Dr Harbeck: And what would you do like in the ultralow setting in second-line?

 

Dr Sammons: If they've gotten T-DXd or if they hadn't?

 

Dr Harbeck: If they hadn't.

 

Dr Sammons: If they had not?

 

Dr Harbeck: Yeah.

 

Dr Sammons: Yeah, yeah. I mean, I think, if they got capecitabine in the first-line and then their ultralow, I think T-DXd in the second-line is perfectly reasonable.

 

Dr Harbeck: Okay, so one last question is about the local therapy in your patient. Gamma Knife or anything stereotactic? Or would you just rely on the ADC?

 

Dr Sammons: That's a good question. So for a brain metastasis patient, if they were truly HER2-positive and we were very inclined to avoid radiation therapy and they had asymptomatic brain metastasis, we might consider holding off on radiation because the intracranial response rates for HER2-positive disease with T-DXd are in the 70% to 80% range.

 

I would not feel comfortable doing that for a HER2-low patient. I would recommend local therapy with stereotactic radiosurgery, because I'm just not comfortable enough with an intracranial response rate of 25% to hold off on radiation. That's my personal preference. I don't know if you feel the same.

 

Dr Harbeck: Probably should have amended DESTINY-Breast12 to capture that as well. One last question and I'll let you go. Looking at the other side of the spectrum and we talked about T-DXd, and I had the question in my talk about the exhaustion of endocrine-based therapy options. How about using T-DXd earlier, like after the CDK when there was a good response just because it's such a powerful medication? Or would you always go the endocrine route first?

 

Dr Sammons: Yeah. I mean, I think at the end of the day, these patients still have metastatic breast cancer, and we're sequencing their therapies, and we're trying to maximize the amount of therapies that we can give them. Unless I have a reason to put them on early IV chemotherapy, where they're going to lose their hair and be subjected to, you know, the side effects that T-DXd has. I mean, it still has a decent number of side effects. It's chemotherapy. I'm going to maximize my endocrine therapy options.

 

Now, if I have a patient who has rapid progression within 6 months of their CDK4/6 6 inhibitor and symptomatic progression, and I really need a response. Sure, I might use T-DXd in that case. Or if I—you know, sometimes when I have these rapid relapses on first-line CDK4/6, you biopsy them and they've almost lost a lot of their ER, you know, their estrogen receptors, 20%.

 

I'm not sure I'm going to give that patient a second-line of endocrine therapy. Might use T-DXd at that point.

 

Dr Harbeck: Okay. So there is no clear cut pathway. But there's very many individualized options for our patients.

 

Dr Sammons: I think we're still going to have to use our brains until AI is, you know.

 

Dr Harbeck: It’s the art of oncology, you know. Thank you very much.

 

Dr Krop: Nice job.

 

Dr Sammons: Thanks.

 

Dr Harbeck: And I think talking about individualizing according to quality of life and safety is a very nice transition to Ian Krop. And he's now going to talk about how we maximize safety and efficacy of our ADCs.

 

[01:36:36]

 

Maximizing Safety and Efficacy of ADCs

 

Dr Krop: Yeah. No, I think that is a very nice transition because I think as we all know, you know, there are guidelines for managing toxicities, but every patient is different. And you have to, you know, take all those factors into account that's the true art of oncology particularly, you know, choosing the treatment is a one-time thing, but then you have to manage patients on it to try to optimize their quality of life and their effectiveness while on the treatments. And that takes a lot of work.

 

[01:37:13]

 

Patient Awareness of Potential AEs With ADCs Is Key

 

So let's talk about some of the facts about toxicities. And then hopefully we can have more of a discussion about how we manage specific situations.

 

So you know, I think we all grew up managing side effects of chemotherapy and got used to, you know, the common side effects of chemotherapy. But now we have this whole new class of drug, each of 4 ADCs that are approved and each of them has pretty, you know, unique toxicity profiles. And we're all learning how to deal with that in the clinic.

 

This is a list of, you know, all the common AEs. But you know, it's pretty clear that there's a few of these for each of these drugs that are most noticeable and the ones we pay the most attention to. So with T-DXd, nausea is very common. And you know, one of the principal things we have to manage in most patients, fatigue, alopecia, all can happen. And then there's ILD pneumonitis, which we'll talk extensively about, you know, which is potentially the most serious side effect of T-DXd.

 

And we need to always need to be vigilant about that. With T-DM1 in general, the best tolerated of the ADCs. But thrombocytopenia can definitely occur, as can transaminase elevations. And then in rare cases, you can have more serious long-term hepatotoxicity.

 

With sacituzumab, you know, the TROP2 ADC, nausea, certainly common, diarrhea is common. And those are things that we have to pay attention to. But I think neutropenia is the one of these toxicities that often requires the most management with sacituzumab, and then datopotamab, which, you know, is so interesting, the fact that it has virtually the same target antibody. It has virtually a very similar payload class as sacituzumab, but it has drastically different toxicities. Virtually no hematologic toxicity, but stomatitis is common.

 

Ocular toxicity is something that we have to pay attention to. And nausea also can happen. And the real difference between saci and datopotamab is the linker. And it just shows you how multifactorial the actual clinical impact of these different drugs are based on the payload target and linker.

 

[01:39:48]

 

DESTINY-Breast04: T-DXd-Related AEs

 

So just talking a little bit more about DESTINY-Breast04 more granularly since we've talked about that a lot in the previous discussion. So again, nausea is quite common, but as you can see, it's almost all grade 1 and 2, fatigue, alopecia. But again, in terms of what are the adverse events that require you to lead to treatment discontinue - treatment discontinuation. It's ILD pneumonitis in more than half of the discontinuations.

 

[01:40:19]

 

DESTINY-Breast04: Drug-Related TEAEs by Age

 

There was actually an interesting—there's now been several interesting comparisons of adverse event profile of T-DXd by age. And this is the one from DESTINY-Breast04. We also did one looking at the other DESTINY trials in aggregate. And I think the interesting finding is that, for most of the toxicities, there really wasn't a big difference between the prevalence of toxicities between ages under 65 and those patients 65 or older. It's remarkably similar if you look down those columns, if anything, in the older patients, there's actually fewer of some of these toxicities.

 

The 1 major difference is ILD where we saw both in DB04 and in DB 01, 02 and 03, there was substantially greater prevalence of ILD in the older patients. Most—almost all of these were lower grade events, but still something that's quite noticeable.

 

[01:41:27]

 

Pretest 3

 

So here's our first pretest question. So in addition to discussing the potential for ILD with T-DXd, with our patients, which of the following strategies would you implement to overcome clinical challenges regarding nausea and vomiting when a patient is starting this drug? Would you consider:

 

1. Prophylactic 5-HT3 and NK;
2. Antagonist along with dex and olanzapine;
3. Just use the prophylactic 5-HT3 and NK1;
4. Prophylactic 5-HT3 with dex only; or
5. Not prophylaxis and just respond if a patient has nausea and vomiting.

 

So go ahead and answer. Yeah. That's great. And this is kind of the one of the guidelines that I think has changed the most recently from when we first started using T-DXd. And we can talk about this in a little bit.

 

[01:42:41]

 

Summary of AEs of Interest With T-DXd From Phase III Trials

 

So again, just kind of going over the aggregate ease of interest with T-DXd, we've already talked about these are pretty constant or consistent across the large, randomized phase III trials in breast cancer. Again, nausea is the most common, mostly grade 1 and 2.

 

[01:43:01]

 

NCCN Guidelines and Emesis Risk for Anticancer Drugs

 

And just going back to what we were talking about with the pretest question in terms of managing the emetogenic risk for anticancer drugs, you know, originally trastuzumab deruxtecan was listed as a moderate emetogenic drug. But with more experience all of us have had with the drug, the NCCN guidelines were recently amended to now moving into the high emetogenic category. And that's why also the guidelines for prophylaxis have changed.

 

[01:43:42]

 

ASCO Antiemetic Guidelines Update 2020

 

And so now the recommendation for these high emetic risk drugs, which now includes T-DXd, include basically a 4-drug combination of an NK receptor antagonist such as aprepitant, a 5-HT3 receptor antagonist dex and olanzapine for Day 1 and then Day 2 and 4. I think it's a little less clear for T-DXd, how much whether you want to continue any of these drugs in further days of treatment. Certainly, there's also chronic nausea associated with T-DXd, and I think many of us have had very good experience with olanzapine for that problem as well, you know.

 

So I think this 4-drug regimen really has become the standard recommendation for T-DXd. It's certainly not needed for all patients. But I think the general sense is there's not a downside to starting out with all 4 drugs, to really make sure that patients don't have a problem with their first cycle and then potentially develop anticipatory nausea. You always can back off with subsequent cycles.

 

[01:44:50]

 

Posttest 3

 

Well, we've already got to the posttest. Okay. So going over this question again, what's your answer for 4 drugs, 2 drugs? Different 2 drugs and no prophylaxis for T-DXd first cycle.

 

Yeah. As I said, I mean, my practice has transitioned as well. Just typically would use 5-HT3 and dex originally and then just because of people having breakthrough and because this kind of change in the guidelines, I'm starting out with oftentimes with 4 drugs, and then backing off as patients to kind of declare how well they're doing.

 

[01:45:53]

 

Posttest 3: Rationale

 

And we talked about the rationale from the new guidelines.

 

[01:45:58]

 

Interstitial Lung Disease/Pneumonitis

 

ADCs: Interstitial Lung Disease

 

So pneumonitis. Again, this is toxicity that is certainly not new. We've had it with multiple chemotherapy drugs. It was also associated with T-DM1 in about 1% or so of patients. Certainly can happen with everolimus. But with T-DXd it kind of became something that we really had to address more directly because of the potential for fatal ILD that was seen in some of the early trials.

 

Now, what causes this from a mechanistic standpoint is really still unknown. There is HER2 expression in the lung, but it's mostly on the epithelium. It's not in the alveoli where interstitial lung disease occurs. So it's thought at least from the animal models, that it’s probably predominantly a target independent uptake of the drug, potentially in macrophages. There's also potential for this as a bystander effect from cleavage of the drug and other places. But again the real underlying mechanism is still not completely defined.

 

[01:47:17]

 

T-DXd: Occurrence of Treatment-Related ILD/Pneumonitis in Phase III Trials for Advanced Breast Cancer

 

But what is defined is that this is something that happens in all of the T-DXd trials. It's been 10% to 15%, fairly consistently. Most of them are grades 1 and 2. But there are grade 3. And in some trials, we've seen fatalities from ILD.

 

[01:47:36]

 

ILD Risk Factors: Pooled Analysis From 9 Phase I/II Trials of T-DXd Monotherapy

 

It's interesting that this is not so much of a cumulative toxicity. The majority of these toxicity of ILD happens within the first year of treatment. There are some additional events later on. But - the slope of the curve, as you can see here, is really most steep in the first year of therapy. And the median onset is somewhere in the 150 day range, depending on which study you look at.

 

We have tried to identify risk factors for ILD. They're shown in this plot here. There's some that clearly have stood out. Patients from Japan have clearly have a higher risk. They have a higher risk of ILD from other drugs as well. Patients with preexisting lung comorbidities are higher risk. We already talked about older patients, and dose, which doesn't really apply to breast cancer since we have 1 dose for breast cancer. But in other diseases where there's a higher dose used, there's also a higher incidence of pneumonitis.

 

[01:48:50]

 

Strategies to Manage ILD Associated With T-DXd

 

So I think, I hope you've seen this type of slide before. These are the guidelines for managing ILD with T-DXd. I think there's a pretty good consensus that this is an effective approach. You know, the number 1 thing to do when you're starting a patient on this drug is to make sure they are aware of this potential toxicity, because certainly one way that people have gotten into trouble, especially early on in the use of T-DXd was that they would develop pulmonary symptoms. They would go to an emergency room. They were, you know, felt to have some type of infectious process and put on antibiotics and sent home, and then, you know, the ILD progresses.

 

The same as, you know, making sure your staff know about this so that when a patient calls, calls the office, who's on T-DXd that they're—you know, they know that this is something that we need to watch out for.

 

So if you do suspect somebody is having pulmonary symptoms and or has findings on a CT scan or a chest x-ray, the workup is very clear. You need a high resolution CT scan. It's recommended to get a pulmonologist involved, “if indicated.” But I would certainly strongly advocate that you find a pulmonologist that you establish a relationship with and involve them, especially with your first few cases of suspected ILD, because I think they can be incredibly helpful.

 

So, you know, the major workup is to try to exclude other causes. But once you have made the diagnosis of ILD, clearly you stop the T-DXd. It's recommended if it's grade 1. So that is asymptomatic. That in addition to holding the T-DXd, you consider using steroids. I typically do start steroids in a patient with grade 1 ILD because I'm trying to get the ILD to resolve as quickly as possible so that it can get patients back on their T-DXd.

 

The current guidelines are, if it resolves within a month, essentially for 4 weeks, that you can restart at the same dose. If it resolves in greater than 28 days, then you should dose reduce 1 dose level before restarting. And then very importantly, if it's symptomatic ILD grades 2-4, the drug should not be restarted. The drug should be stopped, steroids started and should not be restarted at the time that the toxicity resolves.

 

[01:51:45]

 

Pooled Analysis of T-DXd Retreatment After Recovery From Grade 1 ILD/Pneumonitis

 

As I mentioned, the guidelines are that it's okay to restart rechallenge patients with T-DXd after someone has recovered from grade 1, again asymptomatic pneumonitis.

 

[01:52:03]

 

Pooled Analysis of T-DXd After Recovery From Grade 1 ILD: Treatment Characteristics

 

We have a pretty good now aggregate data from all of the DESTINY trials across multiple disease types that was reported at ESMO last year, which showed that you can effectively treat patients.

 

[01:52:24]

 

Pooled Analysis of T-DXd After Recovery From Grade 1 ILD: Outcome of Recurrent ILD

 

You know, essentially 45 patients were restarted with their ILD, and the average time that they were able to stay on therapy was about 85 days. I'm trying to find it on the slide. And about a third of the patients developed a second incident or reincidence of ILD. Those were low grade events and - and did not progress further than that. So this definitely can be done.

 

[01:53:02]

 

Pooled Analysis of T-DXd After Recovery From Gr 1 ILD: Individual Outcomes/Characteristics in Each Patient

 

There were patients—as you can see in this relatively complicated graph, the 3 patients who were underlined here all had multiple rounds of ILD and were rechallenged effect successfully and they develop ILD again and they were rechallenged again. So there were patients on these studies who were able to continue on drug, even through multiple lines of grade 1 ILD, and overall, about 17% of patients were able to stay on T-DXd for more than a year after restarting the T-DXd.

 

So we know this is an effective drug. It's in the patient's best interest. And these data support rechallenging patients with asymptomatic ILD.

 

[01:53:55]

 

Cardiotoxicity

 

So, quickly, just switching gears to talk about cardiotoxicity.

 

[01:54:00]

 

Occurrence of Left Ventricular Dysfunction: Summary of Events in Phase III Trials of T-DXd in Breast Cancer

 

Fortunately, this is not a substantial problem for the vast majority of patients with these drugs. You can see from all of the DESTINY-Breast02, 03 and 04 trials here that the rates of cardiotoxicity were low in the 2 to 4% range. And almost all of them were low-grade events. And very few patients had to stop a HER2 ADC because of cardiotoxicity.

 

So on this slide at the bottom there, there's a question of why there is higher incidence of all grade ventricular dysfunction in DESTINY 02 and 04 compared to DESTINY 03. I don't have an answer for that. Either of you guys have an answer for that? You know, it makes sense that that we'd see more cardiotoxicity in DESTINY-Breast04. Because that's generally the patient's first exposure to a HER2-directed drug.

 

And so, you know, they haven't had that trastuzumab stress test, since most of the time patients develop cardiotoxicity, it's with their first exposure. But that doesn't explain why it's a little higher in DESTINY-Breast02 as well. So it's a mystery. May just be chance.

 

[01:55:28]

 

Cardiac Safety of HER2 Therapy in Patients With Reduced Left Ventricular Function: SAFE-HEaRt Study

 

So, you know, we all have had patients who have underlying mild cardiac dysfunction when they present to us and if they have HER2-positive disease or HER2 now low or ultralow disease, and you're considering using HER2-directed therapy. How do you proceed with that?

 

Most of the trials required an EF of 50% or more. There is this study that was reported prior to the ADCs where it looked at patients who had ejection fractions with mild dysfunction and basically 40 to 50 and were given a HER2-directed antibody or T-DM1, and 90% of those patients did not have any significant cardiac events or further decline in their EF.

 

The 3 out of 30 patients who did have a cardiac event, one of them was an asymptomatic decline, and the other 2 were more significant but it was not fatal. So, you know, again, these are very effective drugs. Even though we don't have specific data on using them in patients who have ejection fractions that are mildly depressed, I think you have to, you know, weigh the risks and benefits.

 

And at least these data and some similar data would suggest that it's worth considering as long as the patient's informed about the potential.

 

[01:57:08]

 

Cardiotoxicity

 

So we talked about this for the most part.

 

[01:57:15]

 

Managing Mucositis With Datopotamab Deruxtecan

 

And I just wanted to briefly mention about mucositis with datopotamab. This is, again, a drug that we're all just getting used to using in the clinic. It was just approved in January.

 

[01:57:24]   

 

Stomatitis/Mucositis With Dato-DXd

 

It's, you know, salient toxicity is that patients can get stomatitis or mucositis. Most cases are low grade, grade 1 or 2, prophylactic mouthwash with a steroid, dexamethasone or other steroid mouthwash has been quite effective, particularly again, if you use it prophylactically rather than starting it after patients develop the toxicity. There's mixed data on using cryotherapy in the mouth, but it's also something to consider.

 

[01:58:04]

 

Managing Neutropenia With Sacituzumab Deruxtecan

 

Sacituzumab Govitecan: Key Adverse Events

 

And then lastly, sacituzumab govitecan, again, similar drug, but has much more hematologic toxicity than datopotamab. Neutropenia is definitely something that we have to monitor for closely. It obviously can be life threatening. Diarrhea also is a potential problem with this drug.

 

[01:58:26]

 

Neutropenia with Sacituzumab Govitecan

 

In terms of the neutropenia, again, it really should be monitored with each dose. So both days 1 and day 8 of treatment and the guidelines suggest holding the drug if the ANC at Day 1 is less than 1500 or less than 1000 on Day 8. I think many of us end up having a pretty low threshold for using growth factor and/or dose reductions. Both of those measures can definitely help. And again, the key is to keep the patients on a drug if they're benefiting from it.

 

[01:59:04]

 

Clinical Application: What’s Next? A Look to the Future in HER2-Low mBC     

 

So we theoretically have some questions to talk about. I know we're kind of at time though because I think this is supposed to stop at 8:30. I don't know if rather than take kind of general things, are there specific questions we want to take a minute or 2 to go over?

 

Dr Harbeck: Yeah. I think there's one last question. We talked about the sequencing of the ADCs, I think quite extensively before. But there is a question about patients with concomitant lung diseases like asthma or COPD. Do they have an increased risk of ILD or pneumonitis. Or maybe take this one step further. Do you have any contraindications for T-DXd?

 

Dr Krop: So, you know, just like patients with low ejection fraction were not, you know, enrolled or were not eligible for any of the trials. Patients with substantial histories of pneumonitis in the past, particularly pneumonitis requiring treatment, you know, were often excluded from many of the trials. As I mentioned in the—so we don't have great data on the whether there's increased risk of pneumonitis in patients who previously had pneumonitis for another cause. It comes up a lot with patients who had radiation pneumonitis. I think that's something that I pretty much ignore.

 

But if you had pneumonitis from another drug like everolimus, gives me pause. Again, we don't have a lot of data because those kind of patients often were excluded from the trials. But I think, you know, prior pneumonitis is something that definitely makes me concerned.

 

In terms of things like asthma. you know, the data we have on predictors of ILD does show a modest increase in incidence in patients who have lung comorbidities, which include including those kinds of things, but it's not a dramatic increase. And again, you have to weigh the risks and benefits in a drug that can be, you know, really beneficial for many of our patients.