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Integrating HER2-Directed ADCs Across Early and Metastatic Breast Cancer: Practical Strategies for Testing, Sequencing, and Patient-Centered Care

This is, of course, an ADC symposium, but there was this very important piece of news that does not relate to ADCs in HER2-positive early breast cancer over the past year or so, which is that we now have very clear evidence that carboplatin does not improve PCR rates in HER2-positive early breast cancer, at least in a largely stage 2 population, which is where these trials have been done.

We saw randomized data come out from the HELEN-006 trial and the neoCARHP trials, which are shown here. Those were two randomized Phase 3 trials that compared taxane HP for 18 weeks versus taxane carbo HP for 18 weeks, in these head-to-head comparisons. They both concluded that PCR rates with or without carboplatin were basically the same.

At the same time, we saw the PCR rates come out from the Compass HER2 PCR trial. Over 2000 patients who were treated with 12 weeks of neoadjuvant THP on that very far left of the slide, and we saw good, respectable, robust PCR rates in a huge cohort of patients treated with that 12-week regimen as well.

You can see visually on the slide that it does look like the PCR rates with the 12 weeks look somewhat lower than the 18 weeks, although we do not actually have a trial that is told us that in a randomized fashion.

That is really important data. At the same time, what we do not have from any of these three trials is long-term outcome data yet. Again, they did all largely enroll somewhat lower risk populations, more stage 2 than stage 3. There are some caveats here for sure, but in the randomized settings where we have tested it at this point, we know that for PCR, carbo does not help us.

DESTINY-Breast11: Neoadjuvant T-DXd With or Without THP vs ddAC-THP in Patients With High-Risk HER2-Positive EBC

Then we had neoadjuvant T-DXd come to the party. We saw the results of the DESTINY-Breast11 trial. This is the randomized Phase 3 trial of neoadjuvant T-DXd. This took a population of stage 2 and 3 HER2-positive breast cancer patients - although again, I will point out they were especially high-risk, so clinical T2N0 patients were not eligible for this trial. This was an all-comers stage 2 and stage 3. This was especially high-risk stage 2 and stage 3.

The patients were randomized to T-DXd THP, four cycles each, T-DXd for eight cycles, or a control regimen of ACTHP. The primary endpoint here was PCR. Very interestingly, that arm of T-DXd times eight in the neoadjuvant setting, enrolment was stopped early for a couple of different reasons. The PCR rate in that arm actually looked significantly lower than in either of the other two arms. More is not necessarily better. Even when you have a really good drug like T-DXd, there is still value in addressing cross-resistance with different mechanisms, like adding THP.

In addition, there were, as I understand it, some concerns with patients getting to surgery on time in that arm. You will not hear me talk more about T-DXd times eight here this evening, but the ultimate comparison that we saw was T-DXd THP versus ACTHP. Importantly, as you can see in the top right of the slide, we also, as of exactly two weeks ago today, have FDA approval for this regimen in the neoadjuvant setting, T-DXd THP, so we really have to figure out who are we giving this to, which is, of course, a good thing, a good option.

DESTINY-Breast11:pCR in Each Arm (Primary Endpoint)

As you can surmise from the FDA approval, this trial met its primary endpoint, which is shown here. There was a significantly higher PCR rate for T-DXd THP, 67% versus 56% with the ACTHP, so a delta of 11% there.

DESTINY-Breast11 Safety Summary

In terms of the safety, summary, the CliffsNotes version here is that, fortunately, pretty much no matter what metric you looked at, high-grade AEs, SAs, AEs leading to treatment interruptions, LV dysfunction, patient-reported outcomes, T-DXd THP was more safe and more tolerable than the ACTH comparator. This was getting us a better PCR rate, and it was better tolerated by pretty much every metric.

DESTINY-Breast11: Adjudicated Drug-Related ILD/Pneumonitis: Events by Cycle

Obviously, we zoom in on ILD for this drug. Here we saw pretty low rates of ILD in both arms, basically 5%, and very rare, just one event of fatal ILD on each arm. Obviously, that is still something that we really want to avoid for all patients, especially these early-stage patients, so this is an important signal, but it did not look to be increased in the T-DXd arm here.

DESTINY-Breast05: Adjuvant Trastuzumab Deruxtecan (T-DXd) in HER2-Positive High-Risk EBC

That is neoadjuvant T-DXd, very briefly. What about adjuvant T-DXd? We also saw the DESTINY-Breast05 trial read out over the past year. This was the trial that for patients with residual disease after HER2-directed therapy and chemotherapy, were randomized to either 14 cycles of T-DXd or our old historical standard, the KATHERINE regimen, 14 cycles of T-DM1.

Again, important to remember this was a particularly high-risk population. This was a higher risk population, actually, than the KATHERINE trial had enrolled, so in order to get into this trial, you had to not just have residual disease, but have residual nodal disease, or if you had residual disease just in your breast, you had to at the beginning, based on your clinical staging before you got your neoadjuvant therapy, have a particularly high burden of disease, what the study deemed inoperable at baseline, if you did not end up with residual disease in the nodes.

This is not just all comers with residual disease. This is a particularly high-risk population. Again, basically, clinical T2N0 patients were left out of this trial. The primary endpoint here is IDFS, which is, of course, a stronger endpoint than PCR. Again, the important key news on the right side of the trial here is that we also got FDA approval for this agent in the adjuvant setting two weeks ago.

DESTINY-Breast05 Primary Endpoint: IDFS

Here is the primary endpoint of the trial that led to its FDA approval. There was an absolute improvement of about 9% in three-year IDFS in this high-risk population in favor of the T-DXd arm. This is great news, of course, for our higher-risk patients. Looking at that hazard ratio, you can see 0.47, so we divided about in half the risk of an IDFS event, and the absolute numbers, you can see one from 83.7% three year IDFS with T-DM1. Not that great, honestly, these are HER2-positive patients. We like to cure as many of these patients as we possibly can, and we expect to versus 92.4, so a 9% bump up with the T-DXd.

DESTINY-Breast05: First IDFS Event Type

I always like to zoom in on this data just to look at the CNS recurrences, also in the T-DM1 versus the T-DXd arms. As expected and as we hope, not just all events were reduced with T-DXd, but distant recurrence events were reduced with T-DXd, as you can see in that red box.

Then, if you look at the numbers of the CNS events specifically between those two boxes, you can also see that, at least numerically, these are small numbers, the CNS events are also going down for the patients who got the T-DXd, and that is reflected as well in the BMFI, the brain free interval data that is on the top right of this slide.

Caveat here is that these are all numerically interesting and consistent data, but none of this is statistically significant because these are small numbers. We know preventing CNS events is so important in all breast cancer patients, but especially HER2-positive patients. I think it was really nice to see that the numbers were going in the right direction for T-DXd.

I will remind you, they did not go in the right direction when we looked at trastuzumab versus T-DM1 in the KATHERINE trial. There, the recurrence rate and the event rate was clearly lower in the T-DM1 arm. The CNS event specifically actually did not look differently, and numerically were a little worse in the T-DM1 arm. I think it was nice that we see this agent potentially acting in the CNS. In about 40 minutes or so, we will talk about the CNS data for this agent specifically.

DESTINY-Breast05: TEAEs in ≥20% of Patients

However, of course, as anybody who is given T-DM1 or T-DXd knows, for any prolonged period of time, T-DXd for 14 cycles is more toxic than T-DM1 for 14 cycles. That came out in the A, E and the PRO data here as well. GI side effects, cytopenias, fatigue tended to be worse with the T-DXd. The only things that were worse here with T-DM1 were lab abnormalities, transaminitis and thrombocytopenia.

DESTINY-Breast05: Adjudicated Drug-Related ILD by Adjuvant RT

Also, we saw that the rates of pneumonitis in this trial, where we are giving 14 cycles of T-DXd, were higher in the T-DXd arm versus the T-DM1 arm. You can see a rate of 9.6% all grade pneumonitis for T-DXd, versus 1.6% for T-DM1. If you look at that boxed area on the bottom there, there were still, unfortunately, two events of fatal or grade five pneumonitis in the T-DXd arm here out of about 750 patients total.

Then lastly, and I think very clinically relevant, the investigators thankfully did a really careful job of trying to figure out, for these patients on adjuvant T-DXd who were also getting adjuvant radiation, did it matter if the radiation was sequential with or concurrent with the adjuvant T-DXd? You can see there was a cohort of patients, a little less than half who got sequential radiation, a little more than half who got concurrent radiation with their adjuvant T-DXd. Thankfully, there was no signal that concurrent radiation with T-DXd increased the risk of drug-related pneumonitis. That is reassuring. When we give this in the adjuvant setting, it does not have to delay our radiation plans.

NCCN 2026 Guidelines for HER2 + Perioperative/Adjuvant Therapy

This entered into the NCCN guidelines adjuvant T-DXd as of January of this year, and again now is FDA approved.

Should T-DXd Be Used in the Neoadjuvant or Adjuvant Setting?

Now, we have to figure out, and this is, of course, a great problem to have, should T-DXd be used in the neoadjuvant or in the adjuvant setting? Just to sum this up, we saw that neoadjuvant T-DXd times four clearly improves pretty much every metric of safety and tolerability compared to neoadjuvant dose dense ACTHP. I would say by the transitive property that probably means it is also better tolerated than TCHP, although we do not actually have that comparison.

A drawback of these data, though, is that PCR was the primary endpoint. PFS will only be a secondary endpoint. PCR is not the strongest primary endpoint. Not that this is a reason not to do it, but if we give T-DXd in the neoadjuvant setting, we are going to have to figure out what do we do with residual disease post T-DXd.

On the flip side, if we give adjuvant T-DXd times 14, we know that that worsens safety and tolerability compared to T-DM1. This trial had DFS as its primary endpoint and showed a very meaningful halving of the event rate, and the CNS recurrence data, which are so important, did look to favor T-DXd in this comparison.

Again, a few caveats. Clinical T2N0 tumors, remember, were not basically were not represented in any of the Phase 3 data that I just showed you. I certainly predict - I am curious if my co-faculty agree - that neoadjuvant THP is sufficient for some patients. We have to await compass HER2 PCR results to confirm that we want to see longer-term follow-up from HELEN-006 and neoCARHP confirm that, but that would definitely be my prediction. Obviously, we have this expanding menu of options, and we need biomarkers here that are actually clinically useful.

Posttest 2

Let us go now to our post-test. We still have some time. Same question that we asked in one of the pre-test. We have a 55-year-old patient with HER2-positive stage 3 breast cancer. She gets neoadjuvant TCHP, she gets residual invasive disease. She is considering adjuvant T-DXd, so these are the DB05 data. Which of the following is the most appropriate way to counsel her about what DB05 showed? A, B, C, D.

I am taking a minute to take this in. 100% with the right answer. That is exactly right. The hazard ratio is 0.47. It was a halving of the event rate, and the absolute benefit was 9%, not 20%.

Patient Case: Selecting Neoadjuvant Therapy in HER2+EBC

We have 30 more seconds, and I just thought this was so clinically relevant. There is so much room for debate that I wanted to take 10 seconds each to give our answers to this first patient case. This was again the 38-year-old woman she presented with extremely high-risk disease. She is young, she is healthy. She is a candidate for whatever therapy you want to give her. Are you going to give her a T-DXd THP? Are you going to give her TCHP? Are you going to give her THP?

My answer in three seconds is I would give her T-DXd THP. I think TCHP is just - I do not feel comfortable with THP here, honestly, just because of the caveats I said about the carboplatin dropping data so far. It is more stage 2. We do not have long-term outcomes, so I would not probably give THP, but it is just such a toxic regimen. I am so ambivalent about the actual efficacy benefit of the carboplatin. I would give her T-DXd THP, what about you guys?

Dr. Ian Krop (Yale Cancer Center): I would as well. I think, the very appropriately, both DB11 and DB05 enrolled specifically enrolled high-risk people. This person certainly would have would have been eligible. I think the data are very strong. I think again, the only caveat is the one you had brought up relative to this, is if she does not have a PCR, what do you do? I do not think that is a reason not to use it.

Dr. Sara Hurvitz (University of Washington): It is an area of controversy. We do not really know. You showed 83% PCR for ER, PR negative HER2 positive with T-DXd and I think TRYPHAENA was about 80% PCR with TCHP. The study did not have a TCHP control arm. I think in the US, we all think that was a mistake. I am concerned that four cycles of T-DXd is not adequate. I would really like to use it in the adjuvant setting for somebody who does not benefit.

I could not agree more with you, THP is not appropriate here, nor is T-DXd appropriate for lower risks. Those are really the highest risk patients. I think we just have to present the data as they are and decide whether we will use it in that neoadjuvant setting. The ILD rates were acceptable, but there was a death. But TCP is no walk in the park. I think we have to face these data with equipoise and have a nuanced discussion.

Dr. Waks: Thank you. There is no right answer. All right, Dr. Krop, you are up.

First-line Treatment Evolution: Applying Emerging Evidence to Optimize Initial Management of HER2-Positive Metastatic Disease

Dr. Krop: Good evening. We are going to continue on that theme. Actually, I did not even realize the parallels of this, as you will maybe you will notice as well. We just heard some very exciting new changes in how we are approaching neoadjuvant or early-stage disease. We have very similar new data in patients with metastatic, newly diagnosed metastatic disease. Let us talk about that.

Patient Case: Selecting 1L Maintenance Therapy in ER+/HER2 + MBC

We will start out with this case of a 62-year-old woman who has triple-positive disease, metastasized to the liver and the bones, but not to the brain. Previously, she had presented a number of years ago with stage 1. Her triple-positive disease treated with TH and endocrine therapy, but somewhat surprisingly, eventually developed metastatic disease to the liver that remained triple positive on biopsy, wild type for PIK3CA.

She gets standard induction therapy with a taxane and HP, and now is asking what is next. Her goal is to delay her disease progression as long as possible. Based on the latest evidence which we will talk about, which of the following approaches would you recommend for maintenance therapy for this patient?

1. Trastuzumab/pertuzumab;
2. Trastuzumab/pertuzumab plus endocrine therapy;
3. HP endocrine therapy plus palbociclib; or
4. HP with tucatinib, the HER2 kinase inhibitor, plus or minus endocrine therapy.

Again, not a right answer here.

A nice mix, as you guys did for the first one. Let us go through some of the data.

Guideline Recommendations for HER2+MBC: 1L Therapy

Just to level set, these are the guidelines right now from NCCN for patients with newly diagnosed HER2-positive advanced disease. The preferred regimen is to do induction taxane HP, with then maintenance either HP or HP plus endocrine therapy and palbociclib if patients are triple positive. Another recommended regimen is trastuzumab deruxtecan plus pertuzumab.

CLEOPATRA: Trastuzumab + Docetaxel ± Pertuzumab in Untreated HER2 + MBC

To remind everyone, this standard of induction THP was based on the CLEOPATRA regimen trial, which looked at newly diagnosed HER2-positive patients and randomized them to docetaxel plus trastuzumab with or without pertuzumab.

CLEOPATRA: Survival With Pertuzumab, Trastuzumab, and Docetaxel as 1L Therapy in HER2+MBC

These data were very clear that the addition of pertuzumab led to about a 16-month improvement in overall survival, as shown on the left, and on the right, about a six-month improvement in progression-free survival. I am just highlighting in that bottom box on the right there. Interestingly, 16% of those patients on the THP arm were still progression-free more than eight years out from their initial therapy. These patients are probably cured. An example of, with really effective therapy, it does look like we can cure some subset of patients with HER2-positive disease. We will talk about that in a little bit more.

DESTINY-Breast09: T-DXd ± Pertuzumab vs THP as 1L Treatment for HER2 + MBC

That regimen of THP has been our standard for well over a decade. Just as in early-stage disease, we have this disrupter of T-DXd, which, in this case, was evaluated in a study called DB09, which again looked at newly diagnosed HER2-positive metastatic patients and randomized them to either T-DXd plus placebo, T-DXd plus pertuzumab, or the standard induction THP followed by maintenance HP. In this case, the data at the initial presentation at ESMO, I am sorry, at last year, was only of the T-DXd plus pertuzumab arm. The T-DXd alone arm has not yet reached its analysis point.

DESTINY-Breast09: PFS by BICR (Primary Endpoint)

What they found was that T-DXd plus pertuzumab was associated with a substantially improved progression-free survival compared to the THP control. The median PFS was over 40 months with the T-DXd plus pertuzumab, compared to about 27 months with THP. This was highly significant. Objective response rates actually were quite high in both arms, as expected. Complete response rates were higher with the T-DXd pertuzumab arm, 15% versus about 8.5% with THP. There are some data to suggest that those patients who have a complete response are more likely to have these very long disease control than patients who have lesser responses.

DESTINY-Breast09: Overall Safety Summary

In terms of safety, overall, rates of grade 3 and see adverse events were similar between the arms. I did highlight on the right there that the duration of cytotoxic therapy with the T-DXd pertuzumab arm was about 22 months. Because there is no built-in maintenance phase with the THP regimen, as you would expect, the length of duration of the taxane, the cytotoxic regimen, was about 4 to 5 months.

DESTINY-Breast09: Conclusions

The conclusions from this study, I think, were quite clear. T-DXd plus pertuzumab really has shown unprecedented activity in the first-line setting, but we also know that T-DXd is very effective in the second-line setting from DB03 with a PFS median of about 30 months.

The question is not whether we should be using T-DXd in the metastatic setting for HER2-positive patients. It is whether we should use it in the first line, or consider using the standard induction THP regimen and saving T-DXd for second-line therapy. The question is, should you to do one or the other?

PATINA: Palbociclib + Anti-HER2 + Endocrine Therapy in Previously Treated HR+/HER2+MBC

Before you answer that, we have to appreciate the fact that our maintenance therapy options have increased over the last couple of years for those patients who get induction THP. We have data from the PATINA trial, which looked at patients who had triple-positive cancers, who received standard taxane HP, and at the time that they finished their cytotoxic regimen and were starting maintenance, they were randomized to either HP plus endocrine therapy, or HP plus endocrine therapy plus the CDK4/6 inhibitor palbociclib, based on preclinical and some clinical data showing significant efficacy of CDK4/6 inhibitors in HER2 positive disease.

What this study showed was that those patients who were randomized to the palbociclib arm had a substantially longer PFS, as shown on the left, with a median PFS of over 44 months with that regimen, compared to about 29 months with the regimen without the palbociclib. Overall survival data were immature but trending in the right direction.

PATINA: Safety

In terms of safety, as you would expect, there was substantially more neutropenia with the addition of palbociclib, diarrhea also was increased, but overall, this was a pretty well-tolerated regimen, and the rate of discontinuation of palbociclib was only about 8%.

HER2CLIMB-05: Tucatinib vs Placebo Added to HP as 1L Maintenance for HER2 + MBC

Another maintenance option came from the HER2CLIMB-05 study. This looked at the use of tucatinib in the maintenance setting. Again, this was in patients who had either ER positive or ER negative HER2-positive disease. Again, patients who were started on standard taxane HP. If they did not have progression, in switching to the maintenance phase, they were randomized to HP with placebo or HP plus tucatinib in both arms. Endocrine therapy was allowed for the ER-positive patients.

HER2CLIMB-05: Investigator-Assessed PFS (Primary Endpoint)

Again, what was seen with the addition of this additional HER2 targeted agent, in this case, tucatinib, was a substantial improvement in progression-free survival compared to HP maintenance alone. In this case, the median PFS was 25 months compared to 16 months without tucatinib.

HER2CLIMB-05: PFS by Hormone Receptor Status

Interestingly, if you break it down by hormone receptor status, there was benefit in both subtypes, but the relative and absolute benefits were greater in the hormone receptor-negative HER2-positive patients with the addition of tucatinib.

DESTINY-Breast09: Conclusions

Getting back to our question of should we use T-DXd in the first or second line setting, we now have these additional induction maintenance regimens, either with tucatinib or with palbociclib, that clearly improve the duration of benefit in the maintenance setting. Now, factoring that in, balancing efficacy versus toxicity, in my mind, it is unlikely that really one approach, first line or second line T-DXd, is going to be optimal for all patients. If you believe that, how do you decide who might be better for first versus second line?

Should T-DXd Be Used in the 1L or 2L Setting?

I think there is a number of characteristics that we can talk about. Certainly, if you have a subset of patients who have characteristics that are going to make them less likely to do well with induction THP, that would be a patient who you much more likely to consider using first line T-DXd.

DESTINY-Breast09: PFS by PIK3CAm Status

We have some of these. We have molecular features like PIK3CA mutation status, as shown here in the data from DB09. You can see in the blue for the patients who were on the THP control arm, those patients who had a PI3 kinase mutation detected on the left there have a median PFS of only 18 months, compared to those patients who received THP and who did not have a PI3 kinase mutation. On the right, PFS of almost 33 months. A pretty big difference there. Whereas in the patients on the T-DXd arm, it did not really matter very much whether or not you had a PI3 kinase mutation. I think patients who have a PI3 kinase mutation you might consider using upfront T-DXd more strongly, T-DXd, pertuzumab.

Should T-DXd Be Used in the 1L or 2L Setting?

There are other molecular features that you could consider looking at. There is also clinical features, such as brain metastases, as you will hear a little bit more about later tonight, having the presence of significant disease burden and a lot of visceral disease, recent progression after receiving adjuvant or neoadjuvant cytotoxic therapy HP, all reasons to think that perhaps you want the T-DXd regimen first.

Of course, patient preference should also be strongly considered. Some patients are really going to want to maximize their PFS and worry less about toxicity. Some patients very strongly want to stop receiving infusional therapy and prefer orals. There are those patients who I mentioned earlier who are really striving for that very long-term disease control, which may be associated with a higher complete response rate that is seen with T-DXd pertuzumab compared to THP. We do not have data to demonstrate that that is true, but it is certainly something that can be considered.

DEMETHER: 1L T-DXd Induction Followed by SC Pertuzumab + Trastuzumab Maintenance in HER2+MBC

I think, personally, a hybrid approach where we use a T-DXd induction followed by a maintenance phase, seems like it would be very appealing. We do not have any real data, prospective data, on that approach of using T-DXd followed by a maintenance phase. There is the Demeter study, which is looking at six cycles of induction T-DXd, followed by HP plus or minus endocrine therapy. We do not have data for this, it is enrolling now. There are a number of other studies like this getting underway. I think we definitely will have more data in the future to help guide this question of what is the most appropriate induction first-line therapy for our patients.

Advanced Sequencing Strategies: Personalizing Treatment Pathways for Relapsed or Refractory HER2-Positive Disease

I will stop there and hand it over to my colleague.

Dr. Hurvitz: Now we are going to talk about what to do after frontline therapy.

Patient Case: Selecting 2L Therapy in ER-/HER2+MBC

We have a case, a 51-year-old postmenopausal woman with ER-negative, HER2-positive metastatic breast cancer involving the liver and lung. No brain mets. She had de novo stage 4 breast cancer treated with first-line THP. She had a complete response in the liver and lungs after three cycles and transitioned to cycle six to HP maintenance, and after two years experienced disease progression in her liver and bone.

Poll 5

Based on the latest evidence, which of the following approaches would you recommend for the next line of therapy?

1. T-DXd;
2. T-DM1;
3. The HER2CLIMB, tucatinib, tras, capecitabine regimen; or
4. Continue HP maintenance, but add tucatinib.

Please vote.

DESTINY-Breast03: Updated PFS and OS

Most people are choosing T-DXd. Let us look at some data post THP. DESTINY-Breast03, of course, looked at T-DXd versus T-DM1 as the second line regimen or regimen after taxane trastuzumab and showed a significant improvement in progression-free survival and overall survival, with a PFS of 29 months for T-DXd versus 7.2 months. A more than quadrupling of PFS, leading to T-DXd moving up into that second line setting.

The Art of Medicine: Evolving Standard for HER2+MBC

The art of medicine is really keeping up with the data as it comes out. We are trying to figure out now, if Ian’s T-DXd pertuzumab regimen from DESTINY-Breast09 is the one that is used in the frontline setting, what do we do in a second-line setting now? How relevant are the DESTINY-Breast03 study data in the second-line setting? It really is a data-free zone.

Paucity of Post-T-DXd Outcome Data

We are relying on data like these, which are looking at outcomes after T-DXd for patients treated with therapy. It is real-world data because all of the clinical trials that we have now, that are prospective to date, are in patients who are T-DXd naive. The median real-world objective response rate for patients after receiving T-DXd in this particular analysis was 14.5%, and the PFS was 4.1 to 4.6 months. I am hoping the data are not this abysmal. I am optimistic, like most oncologists. I think it looks better than this, but these are the data as they are right now.

Exploratory Analysis of DESTINY-Breast02 and -03: Outcomes on Next Line of Therapy

There was an exploratory analysis of DESTINY-Breast02 and 03, looking at outcomes of next line of therapy for patients who went on to receive T-DXd therapy. You can see at the top, patients receiving a tyrosine kinase inhibitor-based regimen. DESTINY-Breast01 is in red, and DESTINY-Breast03 is in grey, and 03 is, of course, for the most part doing better because it is an earlier line setting.

You can see that the PFS is somewhere hovering around five months for the majority of these patients. There was this weird blip with trastuzumab monotherapy in eight patients, having a PFS of 18.6 months. I do not think any of us expect to see that. I think there is probably 1 or 2 patients pushing that out. The point is post T-DXd is an unexplored frontier that really needs more data.

Patient Case: Selecting 2L Therapy in ER-/HER2 + MBC

Let us talk more about this patient. She is 51. She had liver and lung mets, no brain mets. Let us say she was treated with T-DXd pertuzumab in the frontline setting, and she has a complete response after three cycles. After 12 months, she throws in the towel and says, "I am not doing this anymore. I am nauseous all the time. I am tired, I have anorexia. Please switch me to a maintenance HP regimen," and after six months, her disease progresses on the HP. Now, what would you recommend for this patient?

For me, I think I would not rechallenge after six months with T-DXd, given that. But what if she experienced progression after 18 months on HP really quick? Would you rechallenge a patient like this, Ada, with T-DXd, pertuzumab?

Dr. Waks: I would at that point.

Dr. Hurvitz: What is your cut-off? Six months, 12 months?

Dr. Waks: Yeah, somewhere between 6 and 12, greater than 12, I would definitely rechallenge. Less than or equal to six, I definitely would not. In the middle, I would think about it.

Dr. Hurvitz: You would think about how they tolerate it. What about you, Ian? This will be relevant even for patients who are getting it in the adjuvant setting. What would your cut-off be?

Dr. Krop: I agree. I think a year because it is the time it takes the earth to go around the sun. It seems like a good reason, a good number to pick. It is a good cut-off both in the post-adjuvant and in this stage.

Dr. Hurvitz: I totally agree.

The Art of Medicine: Evolving Standard for HER2 + MBC

We are going to be facing this in a clinical setting now or soon if not now. We have a data-free zone. The rechallenge is a big question that we will all have to decide.

NCCN Guidelines for HR-Positive or HR-Negative and HER2-Positive Recurrent Unresectable or stage IV Disease

Looking to our NCCN guidelines for hormone receptor-positive or hormone receptor-negative HER2-positive breast cancer, you can see in the first line setting it is now lots of options available. THP, where the T is docetaxel or paclitaxel, and now T-DXd is another recommended with pertuzumab. Of course, we do not yet know the single-agent T-DXd results. I think we are all eagerly awaiting those results. Do we even need pertuzumab in that frontline setting? Then we have second line is the HER2CLIMB in T-DM1, and then fourth line, as Bill Gradishar says, is the Wild Wild West. Pick your poison literally. There are so many options that you can use, and not a lot of data about how they work post-T-DXd.

HER2CLIMB: Tucatinib + Trastuzumab + Capecitabine in Previously Treated HER2 + MBC

Going through these data pretty quickly, HER2CLIMB, I think most of you are aware looked at adding tucatinib to trastuzumab capecitabine. This study was very uniquely designed, allowing patients with active, untreated, or progressive or stable brain metastases, and 48% of patients enrolled had brain metastases. PFS was the primary end point.

HER2CLIMB: PFS (Primary Endpoint Population)

As you can see, it was met with an almost three-month improvement in progression-free survival and a hazard ratio of 0.57. So, adding the TKI to trastuzumab capecitabine improved outcomes and led to its FDA approval.

HER2CLIMB: OS (Total Population)

Overall survival, similarly was, significantly improved in the overall population, 27% reduction in the risk of death. This represented about a five and a half month improvement in overall survival.

HER2CLIMB-02: Tucatinib + T-DM1 in Previously Treated HER2 + MBC

Then along came HER2CLIMB02, because at the time, T-DM1 was the standard of care after taxane trastuzumab. DESTINY-Breast03 had not yet come out. This study was designed with looking at adding tucatinib to T-DM1 to see if we could improve progression-free survival, but specifically improve outcomes for patients who had CNS metastases, given tucatinib is blood-brain barrier penetrant. In this study, primary endpoint was again PFS, and again, patients with brain metastases were allowed.

HER2CLIMB-02: PFS, All Patients

Here are the results showing a significant improvement, but only 2.1-month improvement in progression-free survival in the overall patient population. You can see that improvement was pretty much seen in all of these subgroups, but really seen more for those patients who had brain metastases at baseline. Overall survival was not yet seen in this clinical trial. It has not been established, but this is an option. One thing we will talk about is toxicity of this regimen a little bit later.

NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+MBC With ≥2 Prior Lines of HER2-Targeted Agents

Of course, we always have neratinib - remember neratinib and lapatinib, these other TKIs? The NALA study did look at neratinib versus lapatinib cape and did establish an improved mean progression-free survival, not median, but mean PFS with neratinib. Of course, diarrhea is fairly substantial, and I think for the most part, tucatinib has replaced neratinib.

SOPHIA: Margetuximab vs Trastuzumab in Pretreated HER2 + ABC

Margetuximab, which is an engineered HER2-targeted monoclonal antibody, to engage more tightly with the FC receptor. Looked at margetuximab chemo versus chemo, looking at PFS.

SOPHIA: PFS

The PFS was better with margetuximab, but OS was not better. When you slice and dice the data based on patients FC gamma receptor single nucleotide polymorphism genotype, there seemed to be benefit in the genotype that binds the immune cells less tightly, the FF subgroup, but it did not meet statistical significance. This is approved and available, but have you used it in the last three years, margetuximab?

Dr. Waks: I have used it maybe twice in a patient where I did-

Dr. Hurvitz: You do the genotyping.

Dr. Waks: - you do the genotype

Dr. Hurvitz: What about you, Ian?

Dr. Krop: I have not used it since I have moved to Yale. In a previous institution I did.

HER2 Positivity Confers Resistance to Endocrine Therapy

Dr. Hurvitz: We know that there are a number of studies looking at hormone-targeted therapy in ER-positive HER2-positive breast cancer. There is good data showing that HER2 amplification confers resistance to endocrine therapy. As you can see here, HER2-positive patients in red versus HER2 negative, in terms of the responses seen with endocrine therapy.

Mono-HER2 Therapy + ET Vs ET Alone in ER+/HER2 + MBC

We have a number of studies - this is now history but keep in mind the tandem study, the EGF3008, and the CALGB4302 all looked at using endocrine therapy with HER2-directed therapy and showed the HER2-directed therapy is important.

Dual- vs Mono-HER2 Therapy + ET in ER+/HER2 + MBC

There have also been studies looking at dual versus mono HER2 therapy with endocrine therapy, the PERTAIN study and the ALTERNATIVE study. PERTAIN looking at pertuzumab trastuzumab and alternative, looking at lapatinib trastuzumab

Dual vs Mono-HER2 Therapy Combined With Endocrine Therapy in ER + HER2 + MBC

You can see here that the dual HER2 targeted therapy with endocrine therapy and PERTAIN improved outcomes. In the alternative study using lapatinib with trastuzumab and aromatase inhibitor improved outcomes. So, hitting both pathways hard is an option for patients, but I think with the PATINA data, many of us are doing this in the front-line setting. We are doing it earlier. We are adding it to that HP maintenance.

MonarchHER: Abemaciclib + Trastuzumab ± Fulvestrant in ER + HER2+ MBC

MonarchHER which is such a great study, looking at CDK4/6 inhibition. Sara Tolaney designed and presented these results showing that a chemo-free approach with fulvestrant, abemaciclib and trastuzumab yielded an improvement in progression-free survival for the first time, I think showing it was better than chemo trastuzumab in terms of objective response rate and PFS. Elegant, wonderful data. I have used this clinically. Have you? This was before PATINA. This was the OG PATINA type regimen.

Summary: Evolving Standard for HER2 + MBC

We have a really rapidly evolving standard. We are all getting whiplash, keeping track of all the approvals, the way T-DXd keeps moving up earlier and earlier, we are having to react and interpret those data. In the first line setting, we do have T-DXd pertuzumab available. Maybe T-DXd will be just as good without pertuzumab. We do not know if we can use that as an induction strategy followed by HP maintenance. These are unknown questions. Then we, of course, have THP, which remains a standard.

I did recently try to get T-DXd pertuzumab approved for a patient of mine who was just riddled with mets everywhere in her body and brain mets, and I thought T-DXd would be better than THP. It was denied, because it is a preferred, but it is not level one, like right up there. Second line, if you have not used T-DXd, I think we would all agree we should. There is survival benefit there. We have not yet seen survival with DB09. We also have tucatinib. We have T-DM1. That is something maybe we can talk about later. Where are we using TDM one? Where has that gone?

Late Line Options for HER2 + MBC: “Dealer's Choice”

Then the fourth line setting, a number of options, including some of these other ones we have talked about Margetuximab.

Posttest 1

Post-test. Patient with de novo HER2-positive breast cancer disease progression after THP. Which of the following statements is most accurate regarding next line of treatment for this patient, based on available evidence? Please vote.

I love it. You guys are listening. You are small but mighty, I love it. T-DXd has improved PFS and OS compared with T-DM1 in the DESTINY-Breast03 trial. That is the correct answer. It is never been compared to the HER2CLIMB regimen, so well done. I will pass the mic now to Ada.

Managing CNS Metastases: Practical Strategies for Systemic and Local Therapy Integration in HER2- Positive Breast Cancer

Dr. Waks: We have touched on brain mets peripherally a number of times already. I will take just 10 minutes or so and try to dive more specifically into the CNS metastatic disease data that we have here.

Patient Case: Managing HER2 + Breast Cancer Brain Metastases

Let us start with a case. This is a 58-year-old woman who presents to the ED with a seizure. Two years ago, she was diagnosed with a stage 3 hormone receptor-negative HER2-positive breast cancer. She was treated with neoadjuvant TCHP. She had significant residual disease, so you know this is a very high-risk even then. She completed a year of adjuvant T-DM1 - of course, now we would give her T-DXd - and she completed that seven months ago.

Now, she is in the ED with her seizure. She has imaging that shows a three-centimeter left frontal brain met and an eight millimeter cerebellar metastasis. She undergoes resection of the frontal, the dominant three-centimeter large left frontal brain met, and the pathology shows the same ER, negative HER2, positive breast cancer.

She gets radiation to the post op cavity and to this unresected eight millimeter cerebellar lesion. She has body staging that shows multiple liver metastases. What systemic therapy in this first-line setting, but very risky disease, would you start for this patient?

Poll 6

Would you give her

1. T-DXd + P;
2. HER2CLIMB;
3. HER2CLIMB-05; or
4. T-DM1 neratinib.

100% consensus. T-DXd plus P. Although it sounds like you just tried to get this insurance approved and you could not, well, it was maybe a different situation, but wow. Okay, so we are all on board with T-DXd plus P here.

Brain Metastases in HER2 + BC: An Unmet Need

Just setting the stage, why do we talk about CNS disease, especially in HER2-positive breast cancer? We know it is particularly prevalent. We know it is an area of unmet need. If you look at these data for patients from the real world, Flatiron huge database, metastatic patients with HER2-positive breast cancer, by the time this large cohort was getting third-line therapy and beyond, 22% to 36% of them had brain metastases.

You can see that is consistently at all lines of therapy. A little bit of a higher proportion in the hormone receptor negative patients who are on the right, and a little bit lower, but still prevalent in the hormone receptor positive HER2-positive patients.

Brain Metastasis Management Is Multidisciplinary

Very importantly, brain metastasis management, of course, is multidisciplinary. Here is a place where we cannot just rely on our great systemic therapies. Surgery is something that should be considered like it was in this patient, especially in patients who have a newly diagnosed single or dominant lesion, especially if it is large, usually with a cut-off of about three centimeters. Especially if it is symptomatic, and especially if the patient is a good surgical candidate because they have either good systemic control or good systemic options going forward. Of course, it is your best option if you need a histologic diagnosis.

Virtually all of these patients are getting brain radiation with either whole brain or more targeted SRS. In our randomized trials of SRS versus whole brain, there is no difference in overall survival, but we clearly know and see that the cognitive outcomes are better with SRS. SRS is preferred over whole-brain for a limited number of metastases. Of course, the operative word here is limited, and what do you and your radiation oncology colleagues think is a limited number of metastases? Then we have some very effective systemic therapy options for our HER2-positive patients.

DESTINY-Breast12: T-DXd in Previously Treated HER2 + mBC With and Without Brain Mets

Let us dive into the data we have here for systemic therapy. We have the DESTINY-Breast12 trial, which looked at T-DXd specifically in patients either with or without brain metastases. This is an interesting trial. It was a stage 3B/4 trial, so there is no randomization here. It is two single-arm parallel cohorts, one with brain mets, one without.

Both cohorts are getting T-DXd. They have different primary endpoints. One was PFS, one was overall response rate. Importantly, this is not a first-line population. This is basically the DESTINY-Breast03 population, but here again, they have brain mets or no brain mets.

DESTINY-Breast12: PFS in Patients With Baseline Brain Metastases

This is second/third line-ish.

If you look at the PFS data for patients just with baseline brain metastases, this was about 240 patients, you can see that whether you looked at the overall PFS, which is on the left of the slide, or you looked specifically at the CNS PFS, essentially these are indistinguishable. The 12-month PFS was 60-ish percent. Essentially, in these brain metastases patients, the drug was working just as well in the CNS compartment as outside it.

DESTINY- Breast12: ORR in Patients ± Baseline Brain Metastases

Same message if you look at the overall response rate data, which is what is shown here, if you look at the overall response rate in the body for the patients on the top left who had no baseline CNS mets, or you look at the overall response rate for the patients who, in the overall body, for the patients who did have brain metastases or on the bottom, you look specifically at the CNS overall response rate just at the brain compartment for those who had measurable disease in the brain, all those numbers are somewhere around 65% to 70%. Again, we are just seeing this drug work equally well in the body. The brain is the take-home message here, not showing it on the slide, but also, there were some patients with active brain mets, some patients with stable brain mets. Again, the numbers look largely similar for those two populations as well.

DESTINY-Breast12: OS in Patients ± Baseline Brain Metastases

Then, in terms of overall survival for the patients with and without brain metastases, this also looked pretty much the same between both of those two groups. I keep putting these figures up next to each other. Again, of course, the overarching message here is that the drug looks just as good in the brain and outside of it, although it was not actually a comparative trial.

Posttest 5

With that review, let us go back to the post-test version of our pre-test question. We have a patient with HER2-positive metastatic disease. She has newly diagnosed brain metastases. She asks you how T-DXd performs in patients with and without brain metastases based on DB 12. How would you counsel this patient?

You guys are rocking it. 100% have the right answer that the CNS PFS was the same as the overall PFS for the patients with brain metastases.

HER2CLIMB: Tucatinib + Trastuzumab + Capecitabine in Previously Treated HER2 + mBC

We already saw Dr. Hurvitz tell us about the HER2CLIMB trial, adding tucatinib to trastuzumab capecitabine.

HER2CLIMB: Patients With Brain Metastases

As she highlighted, a really unique and important thing about this trial, this trial really was a trailblazer in that about half of the patients had brain metastases. About two-thirds of those actually had active brain mets. A third had stable brain mets.

HER2CLIMB: OS for All Patients With Brain Metastases

We saw comparing these, the OS outcomes specifically in the brain metastasis patients, we saw a substantial improvement in overall survival for the brain metastases patients of nine months.

HER2CLIMB: Continuation of Systematic Therapy After Isolated CNS Progression

A really important, I think, clinical nugget that I always come back to from this trial is highlighted here. There were a small number of patients on this trial who had this clinical scenario, where they had isolated CNS progression while they were on whatever therapy they were on, without systemic progression. The trial allowed those patients to get local therapy to the brain and then continue on whatever systemic therapy they were on. You can see for the patients who took that approach, which was 21 patients, not a huge number in the tucatinib trastuzumab capecitabine triplet arm, they still got 7.6 months of median PFS after they had this local therapy for their isolated CNS progression, which was longer compared to 3.1 months in the placebo arm.

HER2CLIMB-05: Study Design

HER2CLIMB-05, we talked about already. This is the trial that added tucatinib to the HP maintenance in the first-line setting. Brain metastases were not very well represented in this trial, unlike the original HER2CLIMB. Patients could have asymptomatic brain metastases or stable brain metastases, treated brain metastases.

HER2CLIMB-05 Secondary Endpoint: CNS-PFS

There is not a lot to see here in terms of CNS PFS, but you can see, in general, in the overall and the brain met population here, it looks numerically and visually like we are seeing slightly fewer CNS PFS events with the addition of tucatinib, which makes sense.

PATINA: Cumulative Incidence of CNS Progression/Death

Then lastly, Ian talk to us about the PATINA trial and the PATINA. Investigators also have tried to look at the CNS events on seen on PATINA, and also, reassuringly, have shown that the incidence of CNS progression or death in the palbociclib arm does look to be lower than in the non-palbociclib arm. All of these optimized maintenance strategies look to have some CNS activity and hopefully prevention as well.

NCCN Guidelines 2026: Breast Cancer Brain Metastases

The final thing I will point out is that this always trips me up. If you are looking for the NCCN guidelines on breast cancer brain metastases, you cannot find them in the NCCN guidelines for breast cancer, but you can find them in the NCCN guidelines for CNS cancer. If you want to find this table, look in a totally different NCCN guideline, which is for brain metastases, and you will find this very helpful reminder table of regimens to use in patients with breast cancer brain metastases.

These are the options there for patients with HER2-positive brain metastases. HER2CLIMB and T-DXd are in the preferred category for reasons that we saw. T-DM1 with or without neratinib. Then the other HER2 TKIs. We did not talk about high-dose trastuzumab, but high-dose trastuzumab, as well as intrathecal trastuzumab, are also options with small amounts of data, but interesting support in the literature.

Ensuring Safe and Effective Care: Multidisciplinary Management of Toxicities Across HER2-targeted Therapies

With that, I will turn it back over to Doctor Hurvitz.

Dr. Hurvitz: Let us talk about safety.

DESTINY-Breast09: Most Frequent TEAEs and AESIs

From the DESTINY-Breast09, I think Ian already talked a little bit about this, but just looking at the difference between T-DXd pertuzumab and THP, you are seeing more nausea. Just keeping in mind the 70% of patients will experience some nausea. We have to be really aggressive with our antiemetic therapy. More GI side effects and a little bit more in terms of neutropenia as well.

NCCN Guidelines and Emesis Risk for Anticancer Therapies

NCCN guidelines do categorize trastuzumab deruxtecan as a high emetogenic risk, meaning greater than 90%, and so retrospective data show that if you add an NK1 receptor antagonist, that is going to be very helpful for patients who are treated with this. We are using a lot of olanzapine in our patients, even just a microdose, just a little bit at bedtime, to help our patients through this.

The 5 “S” Rules: Detecting and Managing T-DXd-Related ILD

In terms of ILD, of course, this can be life-threatening. It is very important that we are watching our patients, especially if you are using T-DXd for years, which some of our patients may be on. If you do not adopt a maintenance strategy, I think you have to be ever watchful and remember that you stop it if there is asymptomatic ILD seen with ground glass opacities on imaging, and that you do not resume until that is totally gone away. If it takes more than a month to go away, you need to dose reduce. Working with our multidisciplinary team is really important and using steroids, I will even use it in grade 1 ILD that is asymptomatic.

HER2CLIMB Safety: It's Mostly the Capecitabine

In terms of HER2CLIMB, the HER2CLIMB regimen, the toxicity that you see with an increased rate of hand-foot syndrome and diarrhea, it is mostly the capecitabine. We are seeing, augmented capecitabine-type side effects. Diarrhea can occur. 82% of patients with tucatinib, which is higher than seen in the capecitabine trastuzumab alone at 54%, tends to be grade 1 or 2, but you really do have to monitor patients, especially those first few cycles. Nausea can also be seen, and you have to monitor the liver transaminases when you are treating with tucatinib.

HER2CLIMB-02: TEAEs

Again, here are HER2CLIMB02 treatment emergent adverse events, which again reflect what we saw in HER2CLIMB. Perhaps less diarrhea because we are not using capecitabine, but you do need to monitor those ALT AST, if this is used. It is not yet an approved regimen to use Tucatinib with T-DM1, but if it is ever approved, watching the ALT and AST is really important because 16% of patients will have higher-grade ALT AST elevation.

HER2CLIMB-05: Safety Summary

Then from the HER2CLIMB-05 study, adding Tucatinib to maintenance HP again, you are seeing, in my opinion, lower risk in terms of side effects, but you do see that patients have to have tucatinib or placebo dose held. Half the patients treated with tucatinib did have to have their doses held, and about 30% had to have dose reduction. Those TEAEs leading to discontinuation tended to be hepatic or diarrhea events.

Neratinib: Toxicity and NCCN Guidance

Neratinib again, diarrhea, that is the main thing we see. In the adjuvant setting, the extended adjuvant setting, we use an escalation strategy over the course of several weeks, starting at a low dose and going up. I think most of us, if we are using neratinib in the metastatic setting, are also using that dose escalation strategy. Although in my opinion, I think neratinib has for the most part been replaced by tucatinib, except in those patients with CNS progression, where we have run out of options.

Multidisciplinary Pearls: What Nurses and Pharmacists Can Operationalize Early in Treatment

We have to be multidisciplinary in our approach to taking care of our patients. We are a team. Nurses and pharmacists can certainly be really important in helping our patients adhere to therapy, and helping us know when our patients are running into trouble. It is very important for all patients to look at the label status, the treatment goals, monitor heart function, reinforce when patients should be calling or reaching out, or going to the emergency room.

With T-DXd pertuzumab, we have to educate our patients about respiratory symptoms and really underscore the importance of calling us with that T-DM1-containing therapy. Pay attention. You need to be monitoring CBC and LFTs, and dose interruption education for, especially for low platelets, and monitor for neuropathy. Keep in mind that T-DM1 guidance there for monitoring. Then following patients for early diarrhea with tucatinib and monitoring them closely.

Posttest 4

Our post-test patient with HER2-positive metastatic breast cancer is starting tucatinib with trastuzumab capecitabine, the HER2CLIMB regimen. Which monitoring strategy is most important to implement during treatment? Go ahead and vote.

Almost there. Very close. Yes. ALT, AST, and bilirubin every three weeks is really important with tucatinib, but you guys did better, and you are almost all right. Yes, tucatinib can be associated with hepatotoxicity, so it is important to monitor patients.

Precision in Practice: Optimizing HER2 Testing and Pathology Interpretation Across the Expression Spectrum

With that, I will turn it back over to Dr. Krop.

Dr. Krop: We have talked a lot about HER2 in the last five lectures. We thought we would close with a session on how we identify HER2 on cancers.

Rationale for ASCO/CAP HER2 Effort (Circa 2005)

Even though it is been a long time since the first HER2 therapy was developed in 1998 with trastuzumab, back then, HER2 testing really was not great. There was a lot of patients who had false positive results, and there was very poor concordance between local testing and central testing. It really caused a lot of problems in terms of not only patients not getting the right treatment for their particular cancer, but also it hindered drug development. Fortunately, ASCO and the College of American Pathologists got together and really over the last 20 years or so, have firmed up how we test for HER2.

Revised ASCO/CAP HER2 Testing Guidelines: Initial Approach

I think now we are in a place that to identify HER2-positive cancers, we have a pretty good and clear-cut set of guidelines. So, by FISH, if the cancer has a ratio more than two and at least four copies of the HER2 chromosome, HER2 gene, that is a positive FISH test, and if the rate is less than two, and the HER2 copy number is less than four, then that is negative. Very clear. That encompasses the vast majority of cases.

Revised ASCO/CAP HER2 Testing Guidelines: Summary

There are some outlier situations. We now have good guidelines for dealing with those. If you have a cancer that is IHC 2 plus and has aneuploidy, that means that the ratio is greater than two, but there is less than four copies of HER2, the plan is to retest the FISH, and if that is negative or if that fits that same criteria, if it again shows up as aneuploid, then that is a HER2 negative cancer. If you have an equivocal test, which is a ratio less than two, but there is four to six copies of HER2, again, guidelines say you should repeat that FISH. If it shows the same range of HER2, then again, that is a HER2-negative cancer.

Really, the only in contrast here is in Polysomy. That means if you have a ratio less than two, but more than six copies of HER2, then again, you should be repeating it. If it again shows more than six copies of HER2, that is considered a HER2-positive cancer. That is the only one of those groups that you think of that.

It used to be thought that if you have one of these outlier cases, that you should go back and ask the lab to do a different CEP17 probe. That is now not recommended. If your pathologist just follow these rules, it is very clear cut, and everybody, I think, has an answer, whether it is positive or negative, which is what we, of course, we need in the clinic to decide therapy. I think we made a lot of progress in defining the HER2-positive cancers.

DESTINY-Breast04 Phase III Trial: T-DXd Improves Outcomes in HER2-Low MBC

The DESTINY-Breast04 trial really added some complication to HER2 testing that we thought we had figured out, which is that you do not actually need to have a HER2-positive cancer to benefit from a very powerful HER2-directed therapy like trastuzumab deruxtecan.

HER2 Expression Varies Widely in HR + Breast Cancer

It brought in this concept of HER2 low since in the DB04 trial, patients who had HER2 one plus or two plus nonamplified cancers seemed to benefit substantially from T-DXd compared to chemotherapy. Subsequently, we had the DB06 trial, which now added an even slower level of HER2. This ultra-low cancer HER2 level, which is less than one plus but not completely negative. HER2 zero by the conventional definition, but there is at least some low-level staining.

DESTINY-Breast06: Response in HER2-Ultralow MBC

Of course, again, that became relevant because in DB06 the HER2 ultra-low cancers, as shown in the very far right, you can see the ultra-low cancers had a response rate of over 61%, similar to what you saw with HER2 low cancers in terms of response rate.

HER2 Low Is Unstable

Great news for patients. Much expanded the range of patients who can benefit from T-DXd. These data really pointed out that the HER2 low group and now ultra-low group is really hard to pin down using our current testing. We saw that from studies like this that showed that HER2 low was very unstable, that if you look at paired biopsies between primary and metastasis or one metastasis and other metastasis, there was a lot of variation. Cancers went from low to negative and vice versa, negative meaning zero.

Impact of Repeated Biopsies on Probability of Detecting HER2-Low Disease

We saw really concerning and consistent studies like this from Mass General Hospital, which showed that if you repeat biopsy on patients who were initially are HER2 zero, the more you test, the more likely you are going to get to be at least one of the biopsies being HER2 low. In fact, if you tested five times, every single patient had at least one that was HER2 low.

Current HER2 IHC Assay has Poor Concordance Distinguishing HER2-low Vs HER2 IHC 0 Cancers

Really trying to dig down to why we are seeing this, is it really that the cancer is changing its HER2 level from time point to time point? Probably not. Although there might be some of that. I think the bigger concern is just the test was not designed to look at these very low levels of HER2. You can see in this really nice study by David Rimm, a pathologist who is worked in this area for a long time. He got a bunch of his friends together and they tested each one of them looked at 170 cases. You can see on the left there the test for HER2 IHC, is very good at distinguishing the HER2 zero, one, and two, so the low group from the positive group from the three plus. You can see the low group here, you got very good concordance. Almost all the pathologists agree. If you look at the high group, so the tans or the HER2 positive cancers, in this group, you can see pretty good concordance there. There is only this really small group of cancers where there was some discordance in how they were judging. The test very good distinguishing the really highs from everybody else.

If you look at the opposite situation on the right here, when you are trying to distinguish the zeros, the very essentially the absent HER2 from all other levels, it is really bad. You can see that there is a huge amount of cases that were felt to be discordant for that distinguishing zero from everything else. The reason is because the test was designed back in the day when all we cared about was HER2-positive three-plus cancers. It was really good at distinguishing that really high level from everything else, but not the opposite.

“Using the Current, Now FDA-Approved, HER2 Assay for T-DXd Is Like Weighing Mice on a Scale Made for Elephants”

Dr. Rimm [?] often likes to quote this that essentially trying to use the current test for looking at very low levels of HER2, therefore, T-DXd sensitivity is really like weighing mice on a scale made for elephants. It was not designed to do that. It cannot do that, and that is why we are seeing all of this discordance.

Practical Definition of HER2 Low

From a practical standpoint, what we do in the clinic right now is from a really nice consensus conference from ESMO, was that any patient who had any biopsy throughout their course that ever had HER2 low, so HER2 one plus two plus, can be considered a patient who is HER2 low disease, even if their most recent test came back as HER2 zero. Again, taking into account the fact that these levels really are not reliable at these low levels. If you have a patient who ever had a HER2 low cancer diagnosis, then you can use T-DXd for that patient.

What Is HER2 Ultralow? “Splitting the Zeros...”

Of course, it gets even more complicated now that we are talking about these ultra lows, these minuscule levels of HER2. If we cannot distinguish low from zero, we certainly cannot distinguish ultra-low from zeros. So that is really a problem.

NCCN Guidelines Distinguish HER2 0, Low, and Ultralow Cancers

The NCCN guidelines now do separate the HER2-negative HER2-zero cancers with no membrane staining versus the HER2-negative with some membrane staining. That is the ultra-low. Again, in the clinic, it is really hard to rely on that test.

Need for Improved HER2 Testing

Just to summarize, the current testing for HER2 low and ultra-low is really suboptimal. There are some new assays in development that are more quantitative and focus on these ultra-low levels of HER2, but we need trials to validate these new assays to predict T-DXd benefit.

TBCRC066: Quantitative IF for Measuring HER2 in HER2-Low MBC (QuantifyHER)

In the Translational Breast Cancer Research Consortium, there is a trial going on now that is prospectively collecting samples from patients treated with T-DXd and using some of these new assays to try to identify the patients who do and do not benefit from T-DXd.

Key Question Related to T-DXd in Advanced Breast Cancer

I think hopefully this whole question is going to be moot because are we really sure that T-DXd does not have activity in cancers that really are completely HER2 zero or null, not below levels of the ultra-low?

Phase II DAISY Study Suggests T-DXd Has Activity Even in Cancers Without Detectable Levels of HER2 Expression

The reason that question, which seems silly on the face of it, comes up is because we have trials like this Phase 2 DAISY trial, which showed that even in cancers that were HER2 zero, there was a 30% response rate to T-DXd.

Key Question Related to T-DXd in Advanced Breast Cancer

If that is borne out, it really means that we do not we really need to test anymore. Just like we do not test TROP2 levels to gauge whether we should be using datopotamab or sacituzumab govitecan.

DESTINY-Breast15: T-DXd in HER2-Low or HER2 IHC 0 MBC

We will have a hopefully definitive trial, DESTINY-Breast04, which is enrolling now, that actually is looking specifically prospectively at these HER2 zero cancers, both hormone receptor negative and hormone receptor positive. Hopefully, we will get an answer from this that will answer this question.

Summary

Until then, you really, I think, need to talk to your pathologist when you have a HER2 zero cancer to say, can you go back? If no other sample shows any HER2 staining, can you go back and look at that sample that you have? Is there ultra-low levels? Do you see any trace staining, because that would allow you to consider using T-DXd?

Posttest 3

With that, we have a quick post-test. We have our 58-year-old patient who has a hormone receptor-negative HER2 one plus cancer previously treated with endocrine therapy. Develops metastatic disease after progression on multiple lines of therapy. Another liver biopsy is done again shows ER-positive disease, but now it is HER2 IHC 0. Based on currently available evidence, which of the following most accurately interprets these results when considering the use of trastuzumab deruxtecan?

Yes, that is that is perfect. It supports classification as this is a patient you can treat as HER2 low.

Dr. Waks: Of course, the bottom one is true too honestly, like you showed in DAISY, so.

Dr. Krop: Right. Although we will wait for the DV15 data to confirm that-

Dr. Waks: I see why 20% of people said.

Poll 7

Dr. Krop: Yes. Just a couple last housekeeping things. Do you plan to make any changes in your clinical practice based on what we talked about today? Yes or no?

Poll 8

If you do not mind taking a moment to text any change that you are planning to make in your clinical practice, I think there is a free text box there.

Q&A

We have five minutes for questions. Fortunately, we have a number of questions that just popped up. Thank you. This is a good question for all of us. How do DESTINY-Breast09, PATINA, HER2CLIMB-05 fit together when choosing first-line induction and maintenance therapy for HER2-positive metastatic disease?

We saw that all three of those studies show very good progression-free survival. Again, as I have tried to make the point, that I do not think there is one perfect answer for any specific overall, and you have to really ask what the patient wants and, and other characteristics. I do not know, how do you guys - so for like a HER2 positive hormone receptor positive patient, if you had to choose without any additional information, what are you guys doing for that patient?

Dr. Hurvitz: I am concerned we are overtreating in the frontline setting. I am old enough to have seen patients go 10 years on maintenance HP and quality of life is fabulous. You can now give it subcutaneously. I really think, especially in hormone receptor positive, where patients can go a really long time, and we can add in and use the PATINA regimen, add in endocrine therapy. I am not convinced. I am really eager to see the T-DXd alone data from DB09 and the survival data, because we can use T-DXd in those patients whose disease progresses. If, however, DB09 shows a survival advantage, then I think I will be more compelled to use it more broadly. I think your discussion regarding PIK3CA and the HER2 DX and these assays, they may help make us smarter in terms of stratifying patients.

Dr. Waks: I agree. I feel like, in a de novo hormone receptor-positive, HER2-positive patient at this point, I would virtually always use PATINA, because I know I can use T-DXd with a good PFS and OS benefit in the second-line setting. I think PATINA gives me the best opportunity to get that patient benefit of endocrine therapy, which is so important in an ER, positive HER2-positive patient, and CDK4/6 inhibitor, which we now know is so important. I can fit those in the second and the third, and the seventh line. I do not really know how to do that. I would rather use those incredibly important therapies in a first-line maintenance setting. That is de novo, not recurrent ER-positive disease. I think otherwise, you get into much higher risk, more individualized situations, PIK3CA mutation, hormone receptor negative brain metastases. All of those would make me much more likely to use T-DXd plus p at this point. Maybe without p when we see those data.

Dr. Hurvitz: It is interesting like over 40% of our metastatic patients are de novo. It has really gone up because we are doing so much better in the early stage setting.

Dr. Krop: Now that we are using T-DXd, at least at some point in the early disease setting, you expect that the recurrences are really going to go down. Of course, how we are going to deal with those patients who - the rare patient who does recur - is going to be maybe more challenging. Yes, I completely agree. I think the PATINA regimen for the triple positives is just the data are quite compelling.

Then just to finish that up, because there is actually several questions about this. For the ER-negative HER2-positive group you cannot use the PATINA regimen. We have the HER2CLIMB-05 regimen, which also showed efficacy. Do you think about it differently for the ER negatives than you do for the ER positives in terms of the T-DXd, THP?

Dr. Hurvitz: I am a little more compelled to use it in that particular instance - ys, T-DXd.

Dr. Waks: I agree. I think it is hard to find a hormone receptor-negative, HER2-positive patient where I would not start with T-DXd plus p at this point. We know we are overtreating some of them. Some of them would be cured with THP alone, so that stinks. We got to use Pik3 CA status, HER2 DX, things like that, as they get validated, but I would largely use T-DXd plus p. We have HER2CLIMB in the second-line setting with an OS benefit.

Dr. Hurvitz: Would you do it as an induction strategy and then do maintenance HP with tucatinib? Because I think with the patient sitting with you, we have all treated patients with T-DXd a long time, and they slowly lose weight, they slowly lose their hair. It is not easy to be on in perpetuity.

Dr. Waks: My answer, and I am so curious what your answer and Ian's answer is, that I do not intend, in the absence of data, to say at the outset, for every patient, this is my plan. I am giving you X cycles of T-DXd, and then we are going to stop, and it is going to be an induction, and we are going to transition to whatever maintenance.

I do not plan to do that, but I certainly plan to have a very low threshold to say, I do not think you are tolerating this, that well. What do you think about transitioning to maintenance at this point? I call that stopping for toxicity, but with a different threshold than we would stop a different drug for toxicity. That is what I think I am going to do.

Dr. Krop: We did not really have time to go through this, but in the trial in DB09, patients were allowed to come off the T-DXd pertuzumab arm, stop their T-DXd if they had toxicity, and they were then able to continue on HP. There was a maintenance option for those patients, but based on toxicity, not based on a predefined, “we are going to stop after six to eight cycles of a taxane”. Those patients were included in that group. As I said, the median duration of therapy was about 21 months for the T-DXd in that T-DXd arm.

One last question, which is up your alley, which is in early breast cancer, how do you discuss T-DXd-related ILD and pneumonitis risk when you are with patients, particularly when radiation therapy is planned?

Dr. Hurvitz: I just really underscore the risk, and I think we should be monitoring with CTs of the chest, the way they did in the study, which was really intense monitoring. I do not know how they got CTs scheduled every six weeks, but it was done, and because there are fatalities and these are patients who are potentially cured with non-ILD-inducing therapies, it is really important to make sure we are monitoring closely and that they are aware of it.

Dr. Krop: I think in the adjuvant trial, it was not every six - I think it was only every six weeks for the first two, and then they spaced it out a little bit. Yes, it is important. I think when we talk about monitoring, it is absolutely important and critical to be doing the chest CT scans. You also have to tell your patient, hey, be aware, if you start noticing dyspnea, cough, then that is something to call in because there is definitely been instances where patients had those symptoms, did not tell their provider, went to an emergency room, emergency room doctor does not know about T-DXd, thought it was pneumonia get treated, and then their ILD worsens. It is both incumbent upon us to be aware of it, but also to communicate that to patients, so they know to reach out with this.