Advancing Precision Care and Shared Decision-Making in First-Line HER2-positive Metastatic Breast Cancer Management: Expert Insights, Patient Resources, and Adaptive Decision Support

[00:11:16]

DrAditya Bardia (University of California): We will review first-line therapy selection in HER2-positive metastatic breast cancer.

Next slide.

[00:15:58]

Clinical Factors Influencing Therapy Selection

If we look at clinical factors that influence therapy selection, there are 4 broad factors one needs to think about:

• First one is the level of HER2 expression;
• Second is the prior HER2-directed therapy, the disease-free interval, the site and extent of metastasis;
• Third, the availability of different treatment options; and then
• Finally, patient preference and comorbid conditions.

I will review all these 4 options.

[00:16:32]

Level of HER2 Expression

Let us start with the level of HER2 expression.

[00:16:39]

Previous Binary Classification of HER2 in Breast Cancer

Traditionally, the classification of breast cancer in terms of HER2 has been a binary classification: HER2-positive and HER2-negative.

What is HER2-positive? HER2-positive essentially refers to tumor that has HER2 expression of IHC 3+. That is complete membrane staining of the cells with HER2, or if it is 2+ tumors that also have FISH amplification. HER2 2+ with FISH amplification or HER2 IHC 3+ is considered HER2-positive and that is what we will focus on today. Review treatment options related to this group.

[00:17:21]

HER2 Expression Today

There is also this classification of HER2-low and ultralow that would not be the focus today. That is essentially HER2-negative, but negative does have some HER2 expression, and that is why we have this new classification of HER2-low, HER2-ultralow and HER2-null. But that would not be the focus today. Today, we will focus on HER2-positive positive breast cancer, which is HER2 IHC 3+ or 2+ with FISH amplification.

[00:17:51]

HER2-Low and HER2-Ultralow

The reason we have HER2-low and HER2-ultralow is because there is some HER2 expression in these cells which can make these patients a candidate for HER2-directed antibody drug conjugate-based therapy like trastuzumab deruxtecan.

[00:18:09]

ASCO/CAP: Distinguishing 1+ from 0

Now at low levels of HER2 distinguishing 1+ from zero can be difficult, but this is important because if there is some expression of HER2 that can be sufficient for antibody drug conjugates to bind to the cell and deliver the payload. That is why we have this classification of HER2-low and HER2-ultralow.

If it is unclear, it is reasonable to have a review by a second pathologist when things are very close to the threshold of zero from 1+, appropriate controls are needed. The preanalytical conditions are really important because you can have antigen loss if the specimen is not processed appropriately. At low levels, it is really important to ensure that the analytical considerations are maintained.

[00:19:00]

ASCO/CAP Guidelines: Standardization of HER2 Testing

These are the standard ASCO/CAP guidelines for HER2 testing. This all started with trastuzumab. With trastuzumab, there was a companion diagnostic, which was HER2 testing that was required. ASCO and CAP had their guidelines for IHC and ISH testing, and this has been revised over time. The latest guidelines being in 2023. They also include 1+ or 2+ without FISH amplification as those patients could be candidates for trastuzumab deruxtecan. So you have the HER2-low addressed in the ASCO/CAP guidelines as well.

[00:19:43]

Prior HER2-negativedirected therapy

We talked about HER2 expression, how identification of HER2-positive is important because that is actionable. Now let us talk about prior HER2-directed therapy, the site extent of metastasis, the disease-free interval.

[00:20:00]

Targeted Therapies for HER2-positive Breast Cancer

If you look at the different therapies that are approved for HER2-positive breast cancer, they can broadly be divided into:

• Antibodies;
• Tyrosine kinase inhibitors; and
• Antibody drug conjugates.

Antibodies are monoclonal antibodies that bind to HER2, example being trastuzumab, margetuximab and pertuzumab. Antibody drug conjugates are antibodies with payload linked to it. The antibody binds to the cancer cell, then delivers the payload. Example being T-DM1, the first ADC approved for HER2-positive breast cancer; T-DXd, another HER2-positive ADC approved for breast cancer, and then there are others in clinical development.

The third category is tyrosine kinase inhibitors. These are small molecule inhibitors of HER2 tyrosine kinase and essentially inhibit the signaling of HER2. Examples include lapatinib, neratinib and tucatinib. These are 3 HER2-targeted tyrosine kinase inhibitors that are FDA approved.

[00:21:13]

Other Considerations for Selecting First-line Therapy

Now if we have multiple options, how do we select the different therapies? It is based on the efficacy of these drugs obviously. Besides that the symptomology of disease, the disease-free interval. If a patient has received, say, taxane plus trastuzumab plus pertuzumab in the neoadjuvant setting or adjuvant setting and then has recurrence quickly on the regimen or shortly thereafter, one would be hesitant in using the same regimen again.

The disease-free interval does guide what to do next. Similarly, we often use T-DM1 in the adjuvant setting. If a patient has recurrence on adjuvant T-DM1 or shortly thereafter, that will influence what to do next in the metastatic setting.

The extent of metastasis whether patients have bone-only mets vs bone plus visceral metastasis such as liver metastasis can also influence the choice of HER2-directed therapy.

Then finally, sequence considerations. As I mentioned, if a patient has been on T-DM1 previously, which is an ADC, that could influence what to do next.

[00:22:31]

Local Availability of Treatment Options

The third thing to consider is the local availability of treatment options.

[00:22:36]

Efficacy of Standard of Care and Emerging Novel Therapies for First-line Treatment of HER2-positive mBC

Let us now review the different treatment options that are available. I will start with first-line and then I will talk about subsequent lines of treatment options. Then we always have to consider patient preference.

[00:22:52]

Pretest 1

I will start with the pre-test case. Based on current FDA approvals and clinical practice guidelines, which of the following patients with HER2-positive breast cancer would be a candidate for frontline T-DXd?

1. A newly diagnosed patient with CNS and systemic metastasis;
2. Patient with disease progression on neoadjuvant or adjuvant pertuzumab containing regimen within 6 months; or
3. Patients who are intolerant or ineligible for T-DM1.

Please send in your answers.

Okay, so we see a mix of all the 3 options. Majority would consider T-DXd for patients with progression on neoadjuvant/adjuvant pertuzumab containing regimen. That would be my preferred choice as well. We will review this from the clinical trials. If a patient has already received prior neoadjuvant/adjuvant pertuzumab, that is usually in combination with the taxane, so I would be hesitant in using the THP regimen again and consider T-DXd.

For a patient with CNS metastasis, that is certainly an option to consider as well, given the activity we have seen with T-DXd.

[00:24:27]

Pretest 2

Okay, let us go to the next question. Which of the following were reported in the randomized, open-label, phase III PATINA study that evaluated efficacy and safety of palbociclib in combination of standard of care anti-HER2 therapy plus endocrine therapy vs was anti-HER2 therapy plus endocrine therapy without a CDK4/6 inhibitor in patients with HER2-positive, hormone receptor-positive metastatic breast cancer?

1. Improved PFS but lower five-year overall survival;
2. Improved PFS and five-year overall survival;
3. Similar PFS and five-year overall survival;
4. Similar PFS but improved five-year overall survival.

Please send in your answers.

Okay, we will review the PATINA study as well in terms of the impact it had. It was a study that showed improvement in the median progression-free survival, overall survival as well as we will see.

[00:25:45]

Guideline-Based Systemic Therapy for Unresectable or HER2+ mBC

If you look at the guidelines, the current guidelines for management of HER2-positive metastatic breast cancer at this time, the first-line recommended therapy includes a taxane in combination with trastuzumab and pertuzumab. The taxane can either be docetaxel or paclitaxel usually give 6 to 8 cycles of this regimen followed by maintenance HP. Then you can stop the chemotherapy but just continue the antibody-based treatment.

For patients with hormone receptor-positive, HER2-positive metastatic breast cancer, you can also add endocrine therapy when you are in the maintenance phase with HP. After first-line in the second-line setting, we generally recommend T-DXd based on the DESTINY-Breast03 trial. After T-DXd, one could consider T-DM1, or there are other options as well like tucatinib, trastuzumab, capecitabine, trastuzumab docetaxel, trastuzumab vinorelbine, trastuzumab carboplatin, margetuximab plus chemotherapy, neratinib-capecitabine. So lot of treatment options one could consider in the third-line plus setting.

Usually, tucatinib plus trastuzumab plus capecitabine is the preferred third-line and then after that you have other options as well.

This is the current guideline-based systemic therapy. This might change over time as we have newer drugs and some of these drugs might move to the first-line setting based on clinical trials. But at this time, this is the current guideline-based systemic therapy.

[00:27:27]

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

Trastuzumab docetaxel with pertuzumab was based on the CLEOPATRA study. It was a pivotal trial that looked at the triplet of pertuzumab trastuzumab docetaxel vs doublet of trastuzumab docetaxel. There was improvement in progression-free survival as well as overall survival.

Overall survival of 57.1 months, which was clinically meaningful, statistically significant as well. This was practice changing.

[00:27:57]

PATINA: Addition of Palbociclib to Anti-HER2 Therapy + ET vs Anti-HER2 Therapy + ET in HR+/HER2+ mBC

More recently at SABCS 2024, we saw the results of the PATINA trial. This was an interesting study that looked at palbociclib in combination with trastuzumab pertuzumab when patients were in the maintenance phase. Patients had already received 6 to 8 cycles of trastuzumab plus/minus pertuzumab with the taxane, and if they had disease control after 6 to 8 cycles and moving to the maintenance phase, randomized to continue the maintenance phase with endocrine therapy or continue the maintenance phase with endocrine therapy plus palbociclib. So the addition of a CDK4/6 inhibitor in this setting.

[00:28:42]

PATINA: PFS and Interim OS

The trial showed an improvement in progression-free survival that was quite impressive with a median progression-free survival of 44.3 months. That is close to 4 years in the first-line setting with the addition of palbociclib and also showed a trend towards improvement in overall survival as well.

Five-year overall survival of 74.3% vs 69.8%. Trend towards improvement in OS and close to doubling of progression-free survival, something that is clinically meaningful and statistically significant as well.

[00:29:22]

DESTINY-Breast07: T-DXd ± Pertuzumab for Previously Untreated HER2+ mBC

In terms of other therapies, DESTINY-Breast07 is looking at T-DXd plus/minus pertuzumab, also has an arm of T-DXd plus durvalumab. We saw the results at ASCO 2024, a very high response rate with T-DXd monotherapy and an even response rate with T-DXd plus pertuzumab. A confirmed objective response rate of 84% with this doublet therapy.

[00:29:50]

DESTINY-Breast07: Safety Summary

In terms of side effects, side effects that we have seen with T-DXd including rare but known side effect of pneumonitis but there were no surprises and no major overlapping side effects with T-DXd and pertuzumab.

[00:30:06]

Other Foundational Studies

DESTINY-Breast07: T-DXd vs T-DM1 in Previously Treated HER2+ mBC

In terms of other foundational studies, DESTINY-Breast03 essentially established T-DXd in the second-line setting. This was patients who had received prior trastuzumab taxane head-to-head comparison of T-DXd vs T-DM1.

[00:30:20]

DESTINY-Breast03: Updated PFS and OS

We saw very significant improvement in PFS with a hazard ratio of 0.33 and improvement in overall survival as well. This has been a practice changing study that established T-DXd as the preferred second-line therapy.

[00:30:39]

PERTAIN: Addition of Pertuzumab to Trastuzumab + AI ± CT in Previously Untreated HR+/HER2+ mBC

The PERTAIN study looked at pertuzumab to trastuzumab plus AI with/without chemotherapy in patients with untreated hormone receptor-positive, HER2-negative metastatic breast cancer.

[00:30:51]

PERTAIN: PFS (Primary Endpoint) and OS in ITT Population

Essentially also confirmed the addition of pertuzumab to trastuzumab in terms of improving progression-free survival. You could see a trend in terms of improvement of overall survival as well.

[00:31:05]

PERTAIN: Safety Summary

In terms of safety, no major surprises, side effects that we have seen with pertuzumab, including diarrhea as well. But otherwise no major surprises with the addition of pertuzumab.

[00:31:18]

Posttest 1

We will now move on to the post-test questions. Based on current FDA approval clinical practice guidelines, which of the following patients with HER2-positive breast cancer would be a candidate for front-line T-DXd?

1. Patient with CNS systemic metastasis;
2. Patient with disease progression on neoadjuvant pertuzumab containing regimen; or
3. Patient who is intolerant to T-DM1.

Great. Majority are correct. As we reviewed, patients who have disease progression on prior pertuzumab taxane-based regimen, we would not use THP again, T-DXd would be the preferred treatment option.

[00:32:16]

Posttest 1: Rationale

This is as per NCCN guidelines. It is a category 1 recommendation to consider T-DXd in this setting.

[00:32:27]

Posttest 2

Second question. Which of the following was reported in the PATINA trial, the addition of palbociclib combined with anti-HER2 therapy with endocrine therapy vs the same without palbociclib for patients with hormone receptor-positive, HER2-positive mBC?

1. Improved median progression-free survival but lower five-year overall survival;
2. Improved progression-free survival, overall survival;
3. Similar progression-free survival, overall survival;
4. Similar progression-free survival but improved overall survival.

Please send in your answers. That is correct. Majority are correct.

[00:33:16]

Posttest 2: Rationale

As we reviewed, the PATINA trial showed a significant improvement in progression-free survival, progression-free survival that was getting close to 4 years as well as a trend towards improvement in overall survival.

Before we go to the next section, would like to ask DrWaks as well. Your thoughts about the PATINA study and the role of CDK4/6 inhibitor?

DrAdrienne Waks (Harvard Medical School): Yeah. I mean I think this was a really interesting, important and basically immediately practice changing study. I have started based on these really impressive PFS results, the OS results that are preliminary but look like they are trending in the right direction so far considering the addition of palbociclib as a standard of care basically for all ER-positive, HER2-positive metastatic breast cancer patients.

I have a few patients who are incredibly far out on their aromatase inhibitor plus HP, their maintenance regimen years into it. For example, I have not called up those patients and told them now I am going to add palbociclib for you. Thought about it but I did not. But for patients who were within their first 6 months or so on the maintenance HP with aromatase inhibitor, I have called them up and said I want to bring you in sooner and I want to add this new agent to your regimen.

DrBardia: Yeah. No, absolutely, the results were very impressive. Thanks for reviewing when you would consider palbociclib based on the PATINA trial and when you would not in terms of patients who are already on HP and endocrine therapy. I have a similar practice as well. Look forward to seeing the publication. Right now we have seen the presentation, we have not seen the publication yet. But I would anticipate sometime this year we will see the publication as well.

How about T-DXd in the case we had previously, where a patient has disease progression on prior pertuzumab-based therapy, say, either HP or just after surgery, after neoadjuvant therapy patient has disease progression. Do you consider T-DXd? What is your disease-free interval when you would consider T-DXd vs reusing THP? Then we can talk about the upcoming DESTINY-Breast09 as well.

DrWaks: Yes, I have DESTINY-Breast09 in the next 2 slides coming up, so it will be coming. Yeah, I think for sure a patient who is less than 6 months out from their trastuzumab, pertuzumab-based neoadjuvant or adjuvant therapy, I would move them over to T-DXd and consider that it is their first-line metastatic regimen if they have progressed to metastatic disease at that point, but really very much a second-line regimen. I think that is within the spirit of DB03.

I think honestly even 6 to 12 months, I would do the same and say if they are 11, 12 months out from neoadjuvant or adjuvant HP that I would want to move on to T-DXd at that point. I think it is when you get to 13 months and 18 months and things like that, that it gets a little bit dicier and technically generally when more than 12 months have elapsed. Now we have reconsidered, we look at the way that the trials were conducted and we reconsider that as a first-line metastatic paradigm if more than 12 months have elapsed from the early stage therapy.

But I certainly get nervous at the 13-month mark going back to something like THP, that is for sure. At that 12 to 18 month, 12 to 24-month timeframe, I think I would look at patient factors and burden of disease and symptoms and things like that. How they tolerated the first taxane and HP therapy and things like that.

By the time I am past probably 24 months from prior HER2-directed therapy exposure, I would consider that. I would go back to THP at that point. Again, the answer to this is entirely going to change when we talk about DB09, but what about you? What do you do?

DrBardia: Similar practice. You very nicely summarized. If it is less than 6 months, I feel very comfortable with T-DXd. If it is more than 2 years, I feel comfortable recycling THP. Between 6 months to 2 years, that is where you have to look at all these factors.

As you said, this might all change with DESTINY-Breast09. That is a good segue. I will hand it to DrWaks, who will talk about different studies and ongoing trials including first-line therapy for HER2-positive mBC.

[00:38:02]

Ongoing Trails of Interest in First-line Treatment of HER2+ mBC

DrWaks: Thanks. All right. Hi, everybody. I have a couple of different things to cover today. We will talk about emerging and changing paradigms in the first-line following up on DrBardia’s discussion of our established options at this point. We will talk about brain metastases and then we will finish out talking about management of common side effects.

What do we have in the pipeline that is up and coming in the first-line treatment of HER2-positive metastatic disease.

[00:38:37]

DESTINY-Breast09: T-DXd ± Pertuzumab vs Pertuzumab + Trastuzumab + Taxane in HER2 + mBC

The biggest headline grabber here is the DESTINY-Breast09 trial. This is a randomized phase III trial of comparing the old standard in first-line metastatic HER2-positive breast cancer of THP, which is that orange box on the bottom there, to T-DXd by itself, which is the top box there or T-DXd plus pertuzumab.

The primary endpoint here is the comparison of each of those T-DXd containing arms back to the THP. This is a trial that has completed accrual and we know from a press release that was just within the last week or 2 that T-DXd plus pertuzumab has demonstrated a “highly statistically significant and clinically meaningful improvement in PFS compared to THP”.

There has been no report at all so far in the data about T-DXd by itself compared to THP, which is a separate comparison in the trial. But this press release did tell us that T-DXd plus pertuzumab compared to THP met its primary endpoint in terms of PFS.

We will see more of those data at ASCO in just about 2 weeks. That will be very exciting. I think there is a lot of thinking that all of us will have to do. We will have to see these data. How great is the magnitude of benefit for the T-DXd plus pertuzumab over the THP? What is the tolerability look like for these 2 regimens comparatively? This is going to answer some questions and then bring up a lot of others, but very interesting press release and data to come at ASCO about potentially moving T-DXd. We will see with or without pertuzumab but here with pertuzumab into the first-line.

[00:40:35]

DEMETHER: Maintenance HP Following T-DXd Induction Therapy for HER2+ mBC

I think as I alluded to on that last slide, a concern of course that we have about moving T-DXd to the first-line is that it is more toxic on average than THP. A nice thing about THP is that generally, as DrBardia said, we do an induction chemo phase about 6 to 8 cycles of the taxane and then the patients get this potentially very long period on quite tolerable every-3-week HP. That is not the way that DESTINY-Breast09 was conducted. In that trial, patients were on T-DXd indefinitely. There was not an induction phase.

There are trials going on like this trial, DEMETHER, which is run out of Spain, that is looking at trying to bring that induction and maintenance strategy up alongside T-DXd in the first-line. This is not going to be a registrational trial. This is an international single arm phase III trial, where patients in the first-line with metastatic HER2-positive breast cancer get 6 cycles of induction T-DXd and then stop the T-DXd and just move on to HP maintenance.

You can see the sample size there is 165 patient study. Again, this is not going to be a registrational trial, but I think it will be very interesting to understand how patients do with this induction and then maintenance strategy with T-DXd as the induction. I think in terms of tolerability, this strategy makes a lot of sense, and so it will be interesting to have this relatively small study that can tell us a bit about the efficacy here as well.

[00:42:07]

SAPPHO: Sequential Therapy With Curative Intent in Newly Diagnosed HER2+ mBC

Moving it to something completely different. The SAPPHO study, again, not a practice changing study, but I think a very interesting concept in HER2-positive breast cancer. This is a 72-patient trial that is being run through the Translational Breast Cancer Research Consortium. It is a national study, single-arm, phase II study.

It is looking at the question of basically do we now have good enough drugs that we can treat HER2-positive metastatic breast cancer with curative intent? It is trying to bring paradigms that are used in hematologic malignancies like lymphomas and leukemias, where you have all these effective drugs, you use them in really quick succession and in combination upfront and you try to induce a long-term remission in a patient.

Basically this trial is based on the premise of asking can we do that in HER2-positive breast cancer now that we have so many good HER2-targeted therapies.

In this trial looking at potentially curative intent therapy for metastatic HER2-positive disease, patients basically get 2 years of therapy. They get a 1-year induction phase where they first get THP, they then get T-DXd. They then get T-DM1 tucatinib. We try to get a space in that first year all of our really good anti-HER2 treatments. Then they enter a maintenance phase of just HP with tucatinib. By the way, they are also getting endocrine therapy if they are ER-positive and then they actually stop their HER2-directed therapy.

The question is, if we have selected the patients carefully and given such effective drugs in this relatively aggressive fashion upfront, could we potentially cure these patients?

I think it is an interesting paradigm and we will see how these data look. The trial is currently accruing.

[00:44:01]

STOP-HER2: Trastuzumab Cessation in HER2+ mBC

On the flip side of that question of can we cure a subset of HER2-positive metastatic breast cancer is the STOP-HER2 trial. This trial I think is just responding to what we all very commonly see in clinic in a handful of patients that there are patients who you start on their THP first-line. These are typically de novo metastatic patients, not recurrent metastatic patients.

You start them on their THP first-line. There are some patients, I have them at 5 years, 7 years who are just still on their HP maintenance. We do not know, have we cured their metastatic breast cancer, can they stop their HP maintenance at this point or do they need this? Is it playing some suppressive role and we can keep going.

STOP-HER2 is just a observational, again, phase II study looking at if a patient in that situation with a prolonged response to maintenance first-line HP stops their maintenance HER2-directed therapy, what will happen to them? Will they experience a recurrence or potentially and hopefully will they not?

[00:45:05]

Impact of Brain Metastases in Selecting Anti-HER2+ Therapy for mBC

That is sort of what is your appetite for some of the exciting things to come in HER2-positive metastatic breast cancer therapy.

Let us move on to brain metastases and how these affect our selection for anti-HER2 therapy in metastatic patients.

[00:45:21]

Patient Case 2: 41-Yr-Old Woman With Newly Diagnosed HR-/HER+ mBC

Our patient case is a 41-year-old woman. She has a newly diagnosed hormone receptor-negative, HER2-positive metastatic breast cancer, liver mets and bone metastases. She received first-line treatment with THP, had a partial response for 2.5 years and then had progression in liver metastases. She began T-DXd that would be standard as we heard from DrBardia, but actually has a PFS of only 10 months unfortunately. Then new liver lesions appear.

At that same time, she reports new headaches and so undergoes a brain MRI with 3 relatively small brain metastases and undergoes SRS to those 3 brain lesions.

[00:46:06]

Poll 3

The question for the audience is, at this point, what systemic therapy would you recommend that she start next? Would you recommend:

1. Capecitabine/neratinib;
2. Intrathecal trastuzumab;
3. Tucatinib/trastuzumab and capecitabine called the HER2CLIMB regimen; or
4. T-DM1.

Excellent. The majority of participants say T-DM1, a few ideas for capecitabine-neratinib, trastuzumab or T-DM1 - sorry, the majority say HER2CLIMB tucatinib-based regimen.

Let us look at the data for HER2CLIMB and other regimens.

[00:46:58]

Incidence of Brain Metastases per Line of Therapy

As we all know, if we treat patients in clinic, the incidence of brain metastases for HER2-positive breast cancer patients is relatively high, and this is a real clinical need for our HER2-positive metastatic patients. If you look here at data from about 18,000 patients in the real world Flatiron database, if you look at patients on the left are hormone receptor-positive and HER2-positive disease.

On the right are hormone receptor-negative and HER2-positive. If you look at the third-line and beyond, you can see that for those who are hormone receptor and HER2-positive, there is about a 25% rate of brain metastases. In the hormone receptor-negative in HER2-positive patients, it is more like 36%. There are actually other cohorts that would suggest that this can get as high as 50% in later line metastatic setting. This is a prevalent problem for our patient population.

[00:47:52]

Therapy Options for HER2+ mBC and CNS Disease

When we are treating HER2-positive metastatic disease that involves the CNS, we know that we have to consider not just systemic therapy and select the correct systemic therapy for the patient, but also consider local approaches with either surgery or radiation.

To go down this flow chart briefly here, assuming that your patient has a fairly good prognosis and are a candidate for some local or systemic therapy. In terms of local approaches, the spectrum of options is anywhere from on the left surgery followed by SRS to the resection cavity. That is generally something that we reserve for patients who have 1 dominant, usually relatively large brain lesion, not necessarily absent but certainly well controlled extracranial disease and generally somebody who we feel we have the potential to get good long-term systemic control to make it worthwhile to put that patient through a neurosurgery.

If you move to the right through the flow chart, if somebody has a single small lesion, maybe it is inaccessible surgically, maybe they have a limited number of small lesions, those are patients who we take to generally radiation with a targeted approach, SRS.

If we have patients who just have multifocal brain metastases, many, many different sites and lesions involved, then typically those are patients who proceed to whole brain radiation therapy.

Then if you look in the coral colored section of the flow chart, we of course have to think about systemic approaches that we will use in addition to these local approaches. In some cases, like a patient who has had an isolated CNS recurrence while on their, say, maintenance first-line HP, we sometimes will just do local therapy and then continue with the HER2-directed regimen that we had them on if they have had good sustained systemic control and a CNS problem only.

On the other side of this flow chart, a patient who has had repetitive CNS progression events, then we are going to want to use 1 of our systemic regimens that has very good evidence for HER2-positive brain metastases such as the HER2CLIMB regimen or T-DXd and we will look at those in a moment.

[00:50:16]

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

HER2CLIMB was a randomized phase III registrational trial for patients with HER2-positive metastatic breast cancer. This was approximately a third-line patient population. These had all gotten H and p and T-DM1. All the patients got trastuzumab and capecitabine and then they were randomized either tucatinib, a very selective anti-HER2 TKI or placebo.

[00:50:42]

HER2CLIMB: PFS and OS

The primary results of this trial were published a couple of years ago now in The New England Journal of Medicine. This trial met its primary endpoint. It showed a PFS advantage for the addition of tucatinib and a significant OS advantage for the addition of tucatinib in the overall study population. This has been FDA approved for about 5 years now.

[00:51:01]

HER2CLIMB Intracranial Activity: Brain Metastasis Status

But what was really unique and impactful about this trial, and I think teaches us lessons about how we should design trials for HER2-positive metastatic breast cancer in general going forward because this is really an important demonstration of how much we can do when we include brain met patients in our clinical trials.

What was really important here is that about half the patients in the trial, almost 300 patients who were enrolled had brain metastases and many of those patients had active brain metastases, meaning they were completely untreated or they were previously treated and now progressing.

Then about the other half or third of the patients with brain metastases had previously treated and stable brain metastases, but CNS disease nonetheless.

[00:51:49]

HER2CLIMB: OS in All Patients With Brain Metastases  

The most important figure for the brain metastasis population in this trial is shown here. When the investigators looked at the overall survival specifically in those 300 or so patients enrolled with brain metastases, you can see the tucatinib containing triplet, which is the blue line, was substantially better than doublet therapy. There was a significant and clinically relevant improvement in overall survival, specifically in the brain metastasis population shown here.

The improvement was from about 12 months to about 21 months. A 9-month improvement in overall survival, specifically in a brain metastasis population in this trial.

[00:52:36]

HER2CLIMB Intracranial Activity: CNS-PFS and OS in Patients With Active Brain Metastases

If you looked specifically at the patients with active brain metastases, you might be especially worried about. The same improvements were seen essentially PFS and the CNS, OS, both improved the tucatinib containing regimen.

[00:52:50]

HER2CLIMB Intracranial Activity: CNS-PFS and OS in Patients With Stable Brain Metastases

Very similar data for those with stable brain metastasis.

[00:52:54]

HER2CLIMB Regimen After T-DXd: Retrospective Data From France

I always like to show this slide because I think in practice a lot of the time we do end up using this regimen after T-DXd, and so there is a paucity of data for how anything is going to be effective after T-DXd. But these were some helpful retrospective data from France, 100 patients who got the HER2CLIMB regimen after T-DXd and there was some evidence of activity here, which was very good and important to see.

Median PFS of 4.7 months, 6 month PFS of 33%. I think this gives us some reassurance that this regimen can work well after T-DXd, which is often where it ends up getting placed.

[00:53:35]

DESTINY-Breast12: T-DXd in HER2+ mBC ± Brain Metastases

More recently, just at ESMO last fall, we saw the DESTINY-Breast12 trial presented, which finally gave us some really good data for T-DXd and HER2-positive metastatic breast cancer with brain metastases.

In this trial, this was basically a single arm trial. All the patients on the trial got T-DXd and you could enroll if you had brain metastasis at baseline or if you did not. Then the trial just treated you with the T-DXd and followed you for outcomes.

[00:54:05]

DESTINY-Breast12: PFS in Patients ± Baseline Brain Metastases

In this trial, the overall PFS in the overall population at 12-month PFS was about 60%. You can see reassuringly in the right panel that if you looked at the CNS PFS specifically in the patients with baseline brain mets, it was virtually the same about 60%. I think what you are seeing in this slide here and what you will see resonating throughout the results of this trial over the next couple of slides is that this agent really looked like it was performing the same whether you had disease in your CNS or not.

[00:54:39]

DESTINY-Breast12: ORR in Patients ± Baseline Brain Metastases

Again, that is shown here. The overall response rate in patients who had no baseline CNS metastasis was about 70%. The overall response rate within the CNS for patients who had CNS metastases was basically 70%. Again, this agent just looks like it is working equally well in the brain and outside of the brain.

[00:55:00]

DESTINY-Breast12: OS in Patients ± Baseline Brain Metastases

Same theme for overall survival. This looked the same whether you had brain metastases present or not.

[00:55:10]

Improving Patient Adherence: Identifying/Mitigating Factors Contributing to ADC Therapy Attrition

Let us wrap up in the final 5 minutes or so by talking about some adverse events that we very commonly run into on these different drugs, especially trastuzumab deruxtecan and how we can address them in clinic.

[00:55:27]

Patient Case 3: 48-Yr-Old Woman With mBC Receiving T-DXd

We will start off with a case. This is a 48-year-old woman who has metastatic breast cancer and she is on T-DXd. Again, she has a history of HER2-positive metastatic disease. Her cancer recently progressed on adjuvant HP. She starts on T-DXd based on our discussion earlier and the results of DESTINY-Breast03.

As she is starting on T-DXd, she is an educated patient and she asks you about what potential side effects should she be looking out for watching out for on this new therapy.

[00:56:03]

Pretest 3

In addition to explaining the potential for ILD and pneumonitis, which of the following strategies should you implement to combat nausea with this agent?

1. Should you consider what we think of as a 4-drug regimen of 5-HT3 antagonist and an NK1 antagonist and dexamethasone and olanzapine; or
2. Just the first two; or
3. Just a different mix; or
4. Just no prophylaxis for nausea vomiting with T-DXd.

Give you a couple seconds to put in your answers. Excellent. Good. I am happy there is a little bit of a split here so we can have a good discussion and hopefully show you where the guidelines fall anyway here.

55% chose the first answer, which is the most aggressive antiemetic regimen, a 4-drug regimen. But there is a considerable proportion who answered B or C as well, which is a 2-drug antiemetic regimen.

[00:57:13]

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

In terms of how frequently we see various AEs in general, for patients treated with T-DXd across different phase III trials, rates of nausea overall are about 70% to 80%, some are around 10% or less with higher than or equal to grade 3 nausea. Diarrhea seems like it can happen but is less frequent, about 20% to 30% all grade and very, very low single-digit percent who have high grade diarrhea.

Neutropenia can happen about 10% to 20% any grade as you can see on that bottom line there. Very uncommon for that to be high grade. Though, we do see it occasionally.

[00:57:54]

NCCN Guidelines and Emesis Risk for Anticancer Drugs

ASCO and the NCCN actually initially did not put T-DXd in the highly emetogenic chemotherapy category. However, with more uptake of the drug over the past few years, it has been re-categorized as highly emetogenic as I certainly have had, and I think many of us have had in clinic, these patients sometimes who just have really significant nausea with T-DXd. I personally find it difficult to predict who they will be, but it can absolutely be clinically significant.

This has been re-categorized from the moderately emetogenic to the highly emetogenic category in NCCN and ASCO guidelines.

[00:58:36]

Managing Emetogenic Risk: ASCO Antiemetic Guidelines

What the ASCO guidelines recommend if you are giving a highly emetogenic agent, which is on the left of this slide here, is actually on Day 1 of treatment to give that full 4-drug regimen. So a 5-HT3 receptor antagonist, which is something like ondansetron, palonosetron, you can see them listed on the bottom here, granisetron, as well as an NK1 receptor antagonist, which is like aprepitant, fosaprepitant, as well as dexamethasone and olanzapine.

The ASCO antiemetic recommendations for T-DXd are all 4 of those drugs on the first day of treatment and then Days 2 through 4 to continue the steroid and the olanzapine. So essentially similar to something like AC with respect to antiemetic management.

[00:59:30]

Posttest 3

Let us talk in these last few minutes about ILD. At this point, same question, same patient. Which of these antiemetic strategies would you want?

1. Would you do a 4-drug regimen, which is the first option;
2. More paired down two drug regimen, that is options two or three; or
3. Potentially you would give no prophylaxis.

What do you think? Good. Okay, excellent. 70%-plus of patients said the 4-drug regimen, which is what the ASCO guidelines would recommend now that this is categorized as highly emetogenic.

[01:00:28]

Interstitial Lung Disease/Pneumonitis

Now let us finish out with ILD and pneumonitis, a very important adverse event we see with T-DXd. We know across many different phase III trials of this drug that the rate of any grade pneumonitis is about 10% to 15% and just under a 1% rate of fatal ILD has been seen pretty consistently on these trials as well.

[01:00:52]

Strategies to Manage ILD Associated With T-DXd

In order to manage ILD associated with T-DXD, it is really important to monitor patients for this to be very upfront and proactive about telling them that they need to alert you immediately about respiratory symptoms, cough, dyspnea, etc.

I think confirming ILD as it turns out to be really hard in clinical practice. Sometimes it is a slam dunk and radiographically and clinically it all fits perfectly together. But there are always other things on the differential diagnosis. There are other inflammatory causes. There are viral illnesses, and so I do think often having definitely need a high resolution chest CT, having a discussion with pulmonology colleagues can certainly also be helpful because in clinical practice this is not always clear cut.

In terms of the management of ILD. If you decide that the patient has a grade 1 ILD, meaning it is radiographically apparent, but they have absolutely no symptoms, then this is the only scenario where a patient could have ILD and then you would consider rechallenging them with the drug. Again, this patient is asymptomatic from their ILD.

In the case of a grade 1 ILD, you can consider treating them with steroids. In practice I usually do this because I am wanting to improve their radiographic findings more quickly so I can get them back on the drug. But the guidelines do not say you have to treat with steroids if they are asymptomatic.

If those radiographic changes resolve within a month, then you can rechallenge with T-DXd and you can maintain the dose per guidelines. If those radiographic changes resolve, but it takes more than a month, then you can rechallenge with T-DXd but reduce by 1 dose level. Again, this often drives me to give the patient the steroids because I am trying to resolve these radiographic findings sooner rather than later. Although you do not necessarily have to do that.

For any higher grade ILD, meaning any symptoms whatsoever, you permanently discontinue the agent, you do not re-challenge and you initiate steroid therapy.

[01:02:57]

Takeaways

To sum this up. In the management of HER2-positive breast cancer with brain metastases, we know that we need to consider both local therapies, surgery and radiation and systemic therapies.

I showed you that tucatinib, capecitabine and trastuzumab, the HER2CLIMB regimen is associated with an OS benefit in HER2-positive breast cancer with brain metastases. However, we also now see the data from the DESTINY-Breast12 trial, which shows that T-DXd has a benefit regardless of baseline CNS metastases and that its activity really appears to be equivalent extracranial and intracranially.

The ongoing and soon-to-report DESTINY-Breast09 trial will further define the role of T-DXd in the first-line management of HER2-positive disease. This will be an evolving discussion at ASCO later this month.

[01:03:50]

Question and Answer Session

Dr Waks: Let me kick off the Q&A and A session by asking DrBardia for what you are totally unplanned, a question that I am curious about, about brain metastases.

Now that we have HER2CLIMB, but we also have DESTINY-Breast12. When you have a patient with a HER2-positive breast cancer that involves the brain, are you choosing T-DXd or HER2CLIMB? Do you have a preference between those two? Are you swayed by the OS data, you like T-DXd better? How do you think about that?

Dr Bardia: It is a great question. Our traditional answer had been that if a patient has brain mets and they are also having disease progression elsewhere, so progression in the liver plus progression in the brain, we would lean towards T-DXd. But if the progression was just in the brain and everywhere else, the disease is under control, we would prioritize tucatinib. But that has changed after DESTINY-Breast12.

I was quite impressed by DESTINY-Breast12 in terms of the responses that were seen in the brain. With cross-trial comparisons and their caveats, you do see that T-DXd does have impressive activity. I have moved to T-DXd for patients with brain mets including leptomeningeal disease with the understanding that I can use tucatinib after that. It is a matter of using these drugs in sequence, but I have moved to T-DXd.

Now sometimes patients just have 1 or 2 lesions, so you can do SRS or you can control the brain metastasis by some local treatment. But if there is extensive brain mets, I generally move to T-DXd. I am curious to hear your thoughts as well.

Nancy Lin at your institution led the study. How has that influenced the practice of T-DXd?

Dr Waks: I think we would give the same answer. Up until DESTINY-Breast12 came out, I think we were really favoring the HER2CLIMB regimen and tucatinib triplet for intracranial predominant disease.

Now just given how generally strong the T-DXd data has evolved to be over the years with this recent update that it really looks like it is just as good inside the brain as outside the brain. I think it generally gets placed before the HER2CLIMB regimen, even though Nancy Lin led that charge. They are both great, but I think in the end of the day, that is usually our order at this point.

I see a couple of different questions in the chat here. Yeah, I think to me the hottest topic, which is going to be even more important once we see the DB09 in two weeks is how are we going to incorporate T-DXd into the first-line? I do not know. Have you talked about this among your group, Aditya? Are we going to give it indefinitely until intolerability or until progression? We are going to presume the PFS is going to be incredibly long because it was extremely long in the second-line. It is hopefully going to be even significantly longer in the first-line setting.

I think it is really hard to give T-DXD every 3 weeks for that long. I would say mostly fatigue and GI toxicity really creep up on you. But at the same time, we are not going to really have an evidence basis for an induction strategy. I do not know what have you thought about that?

Dr Bardia: No, it is a good question. We have to see the data, but I think besides PFS, so as per press release, it is a positive study, so I would expect the PFS to be better than DB03, as you nicely highlighted. The question is going to be overall survival in DESTINY-Breast09. Do you see an overall survival improvement very similar to DESTINY-Breast03 and what the magnitude of that is and also the quality of life. If someone is on the drug for years, what is their impact on their quality of life, the patient reported outcomes? I think those would be additional components to consider besides just looking at PFS.

DrWaks: Yeah, that is a great point. I think the OS point is the same one that comes up for DESTINY-Breast04 vs DESTINY-Breast06 when we are thinking about HER2-low breast cancer. We know T-DXd is an incredibly effective drug, but how does the ordering impact the really, really long-term trajectory of these patients' disease? At the end of the day, in many cases, only OS can tell us that.

Dr Bardia: The other thing would be complete responses, the CR rates. Is there a subset of patients who have complete response? Yes, we do not use the term cure in metastatic disease, or at least if you use the term complete remission or prolonged remission, that could have an impact from a patient perspective. The looking at the CR rate would also be important in this trial.

Dr Waks: Yeah. I think that is great point. I think also at the same time, we know from the 8-year follow up of the PATINA trial that there is a subset of patients who at 8 years are still progression-free on their maintenance HP, a way less toxic regimen that is about 15% to 20%, but still it is some, it is a real proportion. Those are the patients in the STOP-HER2 trial. Trying to figure out who are those patients who can really get away with less toxic therapy is going to be super important too.

Dr Bardia: Yeah, no, excellent point. The other, I guess, layer as you brought up is looking at the results with the hormone receptor-positive lens. The results in hormone receptor-positive HER2-positive vs hormone receptor-negative HER2-positive in DESTINY-Breast09. So looking forward to the results of the trial.

Dr Waks: That would be great. Absolutely.

Speaker: Well, let us give thanks to our faculty for an excellent program and a great discussion. Thanks to all of you, our learners for joining us today. As a reminder, please complete your evaluation and rate this program in order to receive CME credit and go online for more content and education, including downloadable slides, a patient checklist and infographic that you can share with your patients as well as the decision support tool associated with this topic.

Thanks again and enjoy the rest of your day.

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