[This has been a] great discussion. I’ve enjoyed going through those cases with you. We’ll start to wrap up and summarize our discussion. We had a nice discussion about how the landscape for 

 [human epidermal growth factor receptor 2]–positive disease has been changing. I’ll summarize by reiterating what we’ve heard. We still have the current standard of care in the first-line setting, with the bar set at CLEOPATRA with taxane, trastuzumab [Herceptin], and pertuzumab [Perjeta]. The second-line setting is where we’re starting to see the evolution of the treatment approach with trastuzumab deruxtecan [Enhertu] entering that second-line space based on DESTINY-Breast03. HER2CLIMB makes a case for using the tucatinib [Tukysa]–based regimen in the second-line setting as well. For our patients with active CNS [central nervous system] disease, I would use a tucatinib-based regimen in the second-line setting.

As we move into the third-line setting and beyond, we still have T-DM1 [trastuzumab emtansine], particularly for patients who may not have seen it in the adjuvant setting. Then we have trastuzumab deruxtecan, tucatinib, margetuximab [Margenza]–chemotherapy in later lines, neratinib [Nerlynx] and capecitabine [Xeloda] as we’ve discussed, and of course some of our traditional agents like lapatinib [Tykerb] and other chemotherapy combinations. Milana, is there anything coming down the pipeline? What are you excited about as we look forward to the future in terms of how the landscape may continue to change?

 In the metastatic setting, I’ve put patients on the CLEOPATRA regimen plus immunotherapy, so that’s another evolving space certainly in the triple-negative setting. We have data with immunotherapy [based on the] KEYNOTE studies. The IMpassion studies were somewhat disappointing, but in terms of the 

+ space, what’s the role of immunotherapy there? There’s a first-line study that I’ve put patients on, trying to answer that question.

I alluded to the COMPASS trials, and there are a few caveats to that. In lower-risk and older patients, it’s nice to have the neoadjuvant therapy, where the role of carboplatin is not as important as doing that type of adjuvant treatment in the neoadjuvant setting, especially for grade 2 and older patients. This de-escalation idea is something we’ve seen in the breast cancer world with the ADAPT trials and other non-HER2 trials, like COMPASS in the neoadjuvant setting.

We’re getting at this brain metastases prevention issue and the COMPASS adjuvant trial with the addition of tucatinib to T-DM1 [trastuzumab emtansine] in high-risk patients with no pathologic CR [complete response]. I’ve been putting patients on that trial as well. We’re optimizing therapies to the point where we hope these patients don’t become metastatic. But if they do, then we have other options and other strategies to deal with this and with HER2 disease as a chronic disease. That landscape has changed dramatically, so there’s a lot to be excited about.

Videos

A summary of sequencing therapy in the HER2+ metastatic breast cancer treatment paradigm followed by excitement for novel therapies under investigation. 

Considering Novel Therapy for HER2+ Metastatic Breast Cancer

 [This patient] sustained her response. It was a durable response, for about a year. In early 2022, unfortunately, we found progression with new bone metastases and a new liver lesion. She has viscerally driven disease. We scanned her brain again. This time, we did see new subcentimeter lesions, particularly in the left parietal region. These were very small, but were interpreted by the radiologist as probable metastases. She was asymptomatic, and of course we had her see our radiation-oncologist and neurosurgeon as well.

At that point, we had a very interesting discussion about whether she warranted local therapy or if we should go on tucatinib [Tukysa]–based therapy in the third-line setting. Based on some of the data that you mentioned, which Nancy Lynn presented about the intracranial activity of tucatinib, in this asymptomatic patient with very tiny lesions, I felt comfortable going straight to a tucatinib-based regimen in the third-line setting and holding off on radiation. We certainly had the SRS [stereotactic radiosurgery] discussion with this patient, and she preferred to hold off and see how well she did with tucatinib. That’s what we have her on: tucatinib, capecitabine,and Herceptin [trastuzumab] in the third-line setting. We recently started that, so our fingers are crossed for her.

Those are all very good points. We can translate from our lung cancer world in terms of if a patient has asymptomatic brain metastases. We know that TKI [tyrosine kinase inhibitor] is going to get up there, and often we’ll repeat another MRI of the brain 6 to 8 weeks later after starting a TKI-based regimen just to see what’s happening. Are those lesions progressing? Are they stable? A different patient—not the 1 I discussed—had brain metastases that have decreased in size substantially as an asymptomatic patient. We feel much more comfortable doing that now, and we don’t know survival data in terms of continuing to do gamma knife and SRS. We do know that over time, the cognitive defects from brain radiation in these patients, who are living much longer, can be pretty significant in terms of their short-term memory loss and long-term memory issues. That’s totally appropriate, and I have my fingers crossed for her too.

We have great phase 3 survival data from HER2CLIMB, as you alluded to. She’s not in visceral crisis. The only other comment is back to the NALA trial and looking at the ER [estrogen receptor]–HER2 [human epidermal growth factor receptor 2] cross-resistance. I wouldn’t necessarily take her off HER2CLIMB and switch her, but given that cross talk, that could be something to consider down the line. The bone metastases progression, despite being on bone-modifying agents, is probably a little more estrogen receptor and hormone receptor driven. That’s going somewhat unchecked in that case.

Absolutely. Great point. That’s certainly something we have in our back pocket for future lines of therapy.

Before closing out their discussion on the second patient profile, experts review third-line treatment selection for triple-positive metastatic breast cancer.

Patient Profile 2: 3L Therapy for Triple-Positive mBC

I’ll continue with her case. She did very well in the maintenance setting with fulvestrant [Faslodex] and Herceptin [trastuzumab]/pertuzumab [Perjeta]. She had stable disease for about 14 months. Now we’re into 2021 and unfortunately, after about 14 months, she developed a progression of disease in her liver and in her bone that was seen on imaging. We did at the time of progression repeat a brain MRI, and fortunately, she still had no evidence of intracranial disease. Now that we’re in 2021 and the second line, we had the opportunity to treat her with trastuzumab deruxtecan [T-DXd]. We started her with trastuzumab deruxtecan in the second-line setting and she did quite well with this agent. In fact, her first imaging at 3 months showed a complete response and so I’ll just pause there as well because I think this gives us the opportunity to talk about the evolving second-line space. And for this particular patient who was previously exposed to T-DM1 [trastuzumab emtansine] in the adjuvant setting. This is the kind of person that I felt very comfortable bringing in T-DXd based on the DESTINY-Breast03 data in the second-line setting. Of course, in that study, we saw a superior PFS [progression-free survival] and OS [overall survival] for trastuzumab deruxtecan compared with T-DM1 in the second-line setting. Now of course 50% of patients approximately were in the second-line setting in DESTINY-Breast03. The remainder was in later lines. Nonetheless, we’ve seen that trial lead to an update in NCCN [National Comprehensive Cancer Network] guidelines allowing for trastuzumab deruxtecan in the second-line space. Milana, how has your treatment in the second-line setting evolved, if at all?

: I think you bring up the perfect point of what’s the role of T-DM1 now in the metastatic setting in addition to the conundrum that we have with these sort of high-risk patients who are then getting T-DM1 in the adjuvant setting. I think a few comments. One thing that we didn’t discuss in terms of 

 adjuvant care was this is a triple positive patient. Would you have considered doing neratinib [Nerlynx] in that extended adjuvant setting per the ExteNET data? And you alluded to the crosstalk. We do think in terms of the estrogen positivity and 

positivity, there are hypotheses that there might be a bit of a seesaw in terms of maybe when you are suppressing the estrogen, the 

 goes up. Or maybe when you’re suppressing the 

, the estrogen goes up. And neratinib can hit all of those targets and deal with that crosstalk maybe a little bit more than tucatinib [Tukysa] can. I have been using neratinib, especially in the triple-positive types of patients, in the extended adjuvant setting. In terms of that evolving space, so she had received T-DM1 appropriately in the adjuvant setting. Now that’s not really our second line go to, and you alluded to the DESTINY- [Breast] 03 data in terms of using deruxtecan in that setting. Given that most of her disease is all-visceral, she hasn’t developed brain metastases, I think that’s appropriate to continue her on that therapy in addition to bone modulating agents as well. Presumably, she’s on Zometa [zoledronic acid] or Xgeva [denosumab]. And then what are you doing about her estrogen blockade? Are you holding off on that or where are we? It goes back to that question; she’s on chemotherapy because it’s an ADC [antibody-drug conjugate] with chemotherapy, but how are you suppressing her estrogen?

These are all such great points. Just to briefly address your first point about neratinib in the extended adjuvant setting, I fully agree. I think this is an additional agent that’s particularly attractive for hormone receptor-positive and 

-positive diseases. We know from the subgroup analysis in ExteNET that it was the ER [estrogen receptor]-positive patients who really derived the majority of the benefit from neratinib in the extended adjuvant setting. Part of the challenge of course is that this is an older generation trial and so we didn’t have patients in that trial that had been previously exposed to things like pertuzumab and T-DM1. How that may or may not impact the ultimate outcomes, we don’t know. But as you nicely discussed, we have certainly a very robust biologic rationale for combining neratinib and hormonal therapy in the extended adjuvant setting. That being said, I could not convince this patient to do escalated therapy in the adjuvant setting and that’s why we did not use neratinib in that setting. Getting back to the metastatic setting, yes, I absolutely use bone-modifying agents. This particular patient was on Xgeva really from the start, from the finding of her bone metastasis, and finally, you raised the point about hormone therapy with an ADC. I think that’s such a great question and certainly the subject of investigation. Right now, I’m not using hormone therapy with the antibody-drug conjugates until I see some additional data. So this particular patient, we treated with trastuzumab deruxtecan alone in the second-line setting, and fortunately, as I mentioned, she had a very nice complete response.

Expert perspectives on second-line treatment options available for patients who progress with triple-positive metastatic breast cancer.

Patient Profile 2: Second-Line Therapy for Triple-Positive mBC

Let’s move on to a second case. I’m going to present a patient of mine who is a 62-year-old, Caucasian female who originally presented in 2017 with a stage II triple-positive breast cancer, so hormone receptor-positive, HER2-positive. We treated her in the neoadjuvant setting with an anthracycline-based regimen of dose-dense AC [Adriamycin (doxorubicin)+Cytoxan (cyclophosphamide)]-T [Taxol (paclitaxel)] including Herceptin [trastuzumab] and pertuzumab [Perjeta] with the Taxol. She did fairly well with that regimen. Went on to have a mastectomy, which revealed a response but a residual disease of approximately 1.5 centimeters of residual invasive carcinoma. We went on to treat her in the adjuvant setting with T-DM1 [trastuzumab emtansine] plus an aromatase inhibitor [AI] and she did well in the adjuvant setting. She completed her 1 year of T-DM1. Unfortunately, 2 years into her AI, she developed a persistent cough, which subsequently initiated an investigation including imaging. And there we found multiple pulmonary nodules, multiple osseous, metastases, and 3 hepatic lesions that were all radiographically consistent with metastatic disease. This was followed up with a biopsy of 1 of her liver masses and we did confirm metastatic carcinoma. The receptor status remained triple positive. We did do an MRI of the brain at that time for screening purposes and the MRI brain was unremarkable. In 2019, she developed metastatic disease so we treated her in the first-line setting with the classic CLEOPATRA regimen, THP [docetaxel, trastuzumab, and pertuzumab]. At Memorial [Memorial Sloan Kettering Cancer Center, New York, NY], we typically use paclitaxel weekly instead of docetaxel and she did very well on this regimen. She had a partial response after 12 cycles of Taxol. At that time, we stopped the Taxol, and this is essentially 3 months into her treatment. We continued Herceptin and pertuzumab in the maintenance setting. I also added fulvestrant [Faslodex] at this time as a reminder she progressed on an aromatase inhibitor. We added some hormone therapy with assert at this point. I think we can pause there to briefly talk a little bit about how we use maintenance therapy in our patients with triple-positive cancers. I think that this is also an exciting space for investigation. My practice is generally to incorporate hormone therapy with antibody therapy at this time. We’re also seeing clinical trials that are testing novel approaches like the addition of CDK4/6 inhibitors in this setting as well as other agents in this setting. But for now, apart from a clinical trial, I do typically incorporate hormone therapy. Milana, do you take a different approach or is this something that you’re also doing in your patients with triple-positive disease?

: Yes. So I think what’s a little challenging in terms of the triple-positive disease and I know that we’re not in the second- or third-line setting yet per se. When you go back and look at the HER2CLIMB study and you look at the subset analyses in terms of those triple-positive or ER [estrogen receptor] and/or PR [progesterone receptor]and 

-positive patients. You can see that the confidence intervals are wider and part of that, when you think about it, is these patients that were double or triple positive were not allowed to be on anti-estrogen therapy during their chemotherapy. In HER2CLIMB, essentially those patients continued all of those agents, until progression. I just want to point out this is a bit of a dilemma in terms of what to do with hormone receptor-positive and 

-positive patients because clearly, your patient has a metastatic disease but she also has bone mets [metastasis]. You biopsy the liver lesion that was still triple positive but you wonder well, what’s driving what because we do still see a lot of heterogeneity in terms of 

 expression and what’s going where. And certainly, he did the right thing in terms of…I always encourage biopsies certainly at any metastatic first-line setting. Don’t just assume that it’s still 

positive or triple positive, so I think that’s one point. I think it is also important sometimes to re-biopsy and there are a lot of advances in terms of next-generation sequencing. We have a lot of blood opportunities with Guardant [360] or FoundationOne as well. For some of those bone-only patients, if they have tumor shed to be able to pick up circulating tumor DNA for mutation testing. There are PI3 [phosphoinositide 3]kinase inhibitors available as well so there are other strategies. I think that now if she presented, we would probably put her on with residual disease on one of the compass trials in terms of incorporating T-DM1 plus, minus tucatinib in the adjuvant setting. Of course, the KATHERINE data established T-DM1 in the adjuvant setting after neoadjuvant therapy for patients who didn’t have a pathologic complete response. Unfortunately, then this patient progressed in the maintenance setting, and you appropriately continued to have her on dual therapy including fossil decks as well. I think the challenge is well what are we going to do with patients who are still on chemotherapy and how do we throw the anti-estrogen agents into the mix? Certainly, when they are on breaks from chemotherapy, but I think that’s an evolving space.

Absolutely. I think that the crosstalk between the 

 pathway and the estrogen receptor pathway is an exciting area for combining some of the therapies that you just mentioned. Particularly some of the novel molecular therapies like PI3 kinase inhibitors and AKT [protein kinase B] inhibitors and so forth. I do think we’re going to see some data in this space that may influence our practice.

 Just to comment, there’s also the SUMMIT trial and that’s looking more at 

mutations but that is in combination so that’s neratinib [Nerlynx], not tucatinib [Tukysa], with fossil deck. I think that’s another translational area that we can look at data from both including adverse event profiles.

Experts discuss the use of frontline therapy in patients with triple-positive metastatic breast cancer. 

Patient Profile 2: Patient with Triple-Positive mBC

But it sounds like you went on in the third line to T-DM1, is that what happened?

: Yeah, that's what happened. We played around a little bit with Xeloda [capecitabine] dosing as well, because we know that the concomitant GI [gastrointestinal] side effects of neratinib [Nerlynx] in addition to Xeloda can be GI-based. But that didn't go too well. Then we transitioned to T-DM1 and based on her baseline, hepatitis B and D, we did do a lower 3 dose of T-DM1 in terms of managing side effects and LFTs [live function tests]. There is rare nodular hyperplasia that can happen with T-DM1 so that is a concern in a patient who already has stage 4 cirrhosis. She did well on T-DM1 for a while and interestingly, her liver enzymes stayed stable but it was the brain that kept coming back in terms of metastases. It really wasn't her systemic disease in terms of liver medications and all the adenopathy.

 I think you raise a great point certainly about T-DM1 having activity in the later lines as well, I think we think of it classically as a second-line agent. Your case nicely illustrates how the location of disease, particularly CNS [central nervous system] involvement, may influence our sequencing of therapies. What came next after T-DM1?

: She did fine on T-DM1 but unfortunately, she developed another brain metastasis. That was managed with a gamma knife. Then we were at the point where we had the neurosurgeon and the radiation oncologist working together but no resections, more just in terms of side effects of multiple attempts of gamma knife. Then the HER2CLIMB data came out and tucatinib [Tukysa] was approved in April of 2020, so I was able to transition her. She was pretty reluctant at first in terms of, “Oh, you're going to put me on these pills again?” But we worked it all out and what's nice is with the Herceptin [trastuzumab] in the HER2CLIMB regimen being every 3 weeks, I was able to really keep close tabs on her in terms of how she was doing from a toxicity standpoint as were our nurse navigators and our nurse practitioners in our practice to make sure that she was on target with her calendar. She actually tolerated it very well. It's interesting that the difference between having HER2-targeted kinome like tucatinib vs neratinib [Nerlynx], which is hitting one of these dirty kinase inhibitors that's hitting 

[homologous EGF receptor kinase] as well. Because as far as side effects go, she really didn't have diarrhea. We were able to manage her side effects. It was really making sure she was taking her pills appropriately. We even started with a bit of a dose reduction of the Xeloda, too, and then tucatinib dosing based on the package insert because of her stage IV cirrhosis. She tolerated it very well. We were doing well in terms of her systemic disease and not having a lot of systemic disease. She maintained that for a while.

That's fantastic. I think it's interesting because we are not just seeing your thought process with the sequencing, but also the practical sequencing as data emerged over the years. Did you have any concerns about using a TKI [tyrosine kinase inhibitors] like tucatinib again after prior neratinib or even after T-DM1?

: That's an interesting question. She didn't have the Xeloda with the neratinib for very long. I think we got through just a few months, maybe about 4 or 5 months of that. I think we worry and certainly, we see this in the lung cancer world, because I'm a community oncologist, so I see all types of patients, but subspecialize in the breast. There can be selective pressure that happens in terms of mutations. Certainly, in lung cancer, we see this a lot with the 

 inhibitors. I didn't think that she had a long enough course of the neratinib to claim her a TKI failure per se. And we didn't have the DESTINY-03 data yet in terms of up to 60% intracranial response rates. I'll segue to that in a bit with her future history, but I wasn't worried about revisiting a TKI and Xeloda with Herceptin. It is a nice idea in terms of the HER2CLIMB regimen because it's this inside-and-outside type of approach. You have the Herceptin that's targeting the extracellular receptor on HER2 positive cells. Then you've got your generic Xeloda chemotherapy that's cytotoxic, and then you've got your TKI that's acting on the inside of the cells. It's this idea of this inside-and-out blockade, which I think is important to explain to patients in terms of fully targeting therapy. We know that HER2 mechanisms of escape can happen as well. This idea of let's suppress both inside and out and deal with any clones that could be developing that might be HER resistant by a different mechanism, mTOR [mammalian target of rapamycin] PI3 [phosphatidylinositide 3]kinase, some of the things that we're familiar with in terms of mechanisms of resistance. I wasn't concerned about that.

Great point. I think this is a great opportunity to remind folks that in HER2CLIMB, essentially everyone had received treatment with T-DM1 before coming (into the) study.I think the range of prior therapies was between 1 and up to something like 19. Certainly, we know that the drug has activity, tucatinib has activity after multiple prior lines of therapy, as well as early on in treatment. What happened after? How long was she on the tucatinib-based regimen and what happened next?

 She remained on that regimen basically from…some time in spring 2020 to pretty recently, [around November/December of 2021]

That's when we saw the ESMO [European Society For Medical Oncology annual meeting] data, which was presented in September on HER2 deruxtecan. I know we should use generic names. We had seen that data in September and then at San Antonio, [Breast Cancer Symposium] Sarah Hurwitz presented the intracranial response rates as well. We had been having a “What's next?” discussion for a while, so then we transitioned her.I do wonder a little bit, too, we did have to do dose reductions based on her stage IV cirrhosis in terms of the tucatinib and even the Xeloda a bit.I do wonder how much intracranial efficacy was she getting there with some of the dose reductions of the TKI. That was always in the back of my head. That's the last part of the story about continuing to have brain metastases even on TKI regimens. It's interesting because Nancy Lynn has presented data in terms of time to next brain Met [metastases] based on HER2CLIMB too and we know that there's a protection base. It’s not necessarily only treating the brain Mets that's there but it’s prevention for the next one. We can certainly do better in some ways. It's exciting seeing the response rates of a large monoclonal antibody, an antibody-drug conjugate that is upwards of 60%. You always worry about those patients, are the therapies getting up into the brain? With a lot of radiation therapy, we do know that we disrupt that blood-brain barrier and we have sensitive imaging techniques to actually even look at the brain in terms of being able to see the HER agents potentially getting up in there. That’s a bit of a summary of a complicated patient.

What a wonderful outcome. Thank you for taking us through that case and again, I think it was very interesting to see you rapidly implement the data as it was reported to your clinical practice. So very, very interesting.

Shared insights on the use of therapies as a patient progresses with HER2+ metastatic breast cancer, which includes sequencing through T-DM1 [trastuzumab emtansine], tucatinib/capecitabine/trastuzumab, and trastuzumab deruxtecan.

Patient Profile 1: Sequencing Therapies in HER2+ mBC

Let's move on and hear about what happened next. It sounds like she subsequently went on to develop brain metastases.

 Unfortunately, she then developed brain metastases. She did come in with a minor headache after asking. You don't know unless you ask.We scanned her brain, and unfortunately, she did have 2 different areas of brain metastases. She was symptomatic with the headache, but no other concerning symptoms in terms of edema or other impending doom types of things. I referred her to the radiation oncologist where she underwent gamma knife SRS [stereotactic radiosurgery]. I think over the course of her history, she's probably had SRS maybe 7 or 8 times because she's continued to develop brain metastases. We did have discussions about what therapy to go on and she was very comfortable having her hair back and thinking about next-line therapies. In her case, I went a little bit outside the box in terms of using neratinib [Nerlynx] and [capecitabine] Xeloda. The NALA data had been out, but not FDA approved yet at that point.

I recall Adam Brodsky had at ASCO [American Society of Clinical Oncology] a third line HER2 [human epidermal growth factor receptor 2] space session in talking about, ‘What do you do in the third line space at this point?’ Actually, I transitioned her to neratinib, which was approved at that point in the extended adjuvant setting. The approval was 2020 for the NALA data in the third-line setting. We tried Xeloda with the idea that there's going to be hopefully some blood-brain barrier penetration where chemotherapy gets up into the brain. We know that those cells are HER2-positive and what TKIs [tyrosine kinase inhibitors] we have out there. Now, lapatinib [Tykerb] has been available for a long time in that space. My experience with lapatinib is diarrhea and rash and some of the – doesn’t play well with hepatitis medications and hepatitis itself in terms of LFTs [liver function tests]. That's why I chose neratinib. I had a lot more recent experience in the extended adjuvant setting, and I knew the NALA data was out there. That went OK. I think the calendar was confusing for her to be taking all these different medications. And then the challenge in the metastatic setting, as opposed to the extended adjuvant setting, is really dose escalation of neratinib in terms of tolerability of diarrhea. The control trial has really revolutionized how we do neratinib dose escalation in terms of starting slow with a ramp-up. But in the metastatic setting, you have to ramp up quickly. This patient had a lot of diarrhea and was working on her calendar, but she almost came back and threw the pills in my face in terms of being so frustrated with all of it.

At that point, we had segued into SBRT [stereotactic body radiation therapy] gamma knife. And then we went to T-DM1 [trastuzumab emtansine], which is more in your typical second-line setting. I gave the TKI a shot, but tucatinib hadn't been approved yet. And the HER2CLIMB data, which is phase 3 data, hadn't been publicly available or really reported on yet.

The diarrhea can certainly be tough. And I think you raised some important points regarding to prophylaxis and findings from the control study. I certainly also use the ramp-up approach, the dose-escalation approach, with neratinib, which of course, was the most successful approach, at least in the control trial.

Expert perspectives on the selection of second-line therapy when patients progress with HER2+ metastatic breast cancer.

Patient Profile 1: Second-Line Therapy for HER2+ mBC

That being said, I’d like to get to our cases. I think you have a really interesting case that we’d like to discuss today. Could you go ahead and tell us about your patient?

 My patient originally presented to the hospital. I saw her as a consult in the hospital. She was having pretty profound shortness of breath, to the point where her scans showed SVC [superior vena cava] obstruction. She had a lot of adenopathy, lymph nodes that were swollen in the mediastinum, lymph nodes that were swollen in her neck. I was actually thinking this might be lymphoma or even a type of lung cancer. But then when I did her breast examination and felt underneath her arm in the axilla, she had, unfortunately, a fungating type of breast mass. That was a hint in terms of what we were dealing with. She had systemic imaging, so she had CT scans, bone scans, and then she also had a baseline brain study at that point, with the thinking that this could be a lung cancer possibly as well. She had a biopsy, and this was HER2-positive metastatic breast cancer.

In the hospital, I started her on the CLEOPATRA regimen. She got Taxotere [docetaxel] chemotherapy. She got Herceptin [trastuzumab] and pertuzumab. Unfortunately, she had a Taxotere reaction. We were able to manage that and then switched her taxane therapy and continued that, and it was really remarkable within about 2 cycles. She was in the hospital for almost 3 weeks, so it spanned 2 whole cycles. Concomitantly, she was also diagnosed with hepatitis B and D, which was a bit of a challenge to try and manage her LFTs [liver function tests] and the Taxotere adverse effects. It was rocky, really rocky. But we got her out of the hospital, and within 2 cycles, a lot of the adenopathy started to just melt away. Her SVC syndrome remarkably improved. She didn’t need to have any radiation therapy, because that was an initial consult there, in terms of do we need to act quickly? She responded extremely well, and she had tumor markers CA [cancer antigen] 27, 29, and 15-3 that were through the roof. And her liver enzymes improved remarkably. We were able to transition her to an outpatient pretty quickly, and then continued that regimen for quite a few cycles, about 6 to 9 cycles, where she continued to have resolution of all the lymph nodes and the breast mass shrunk. She was able to manage that as well in terms of wound care, feeling much better, going from a bedbound performance status to being able to participate in her kids’ lives.

She continued that regimen, and then we transitioned her to Herceptin and pertuzumab in the maintenance setting without chemotherapy. That was great because she got all of her hair back and she could participate in birthdays and graduation pictures and stuff like that. She did really well in terms of her systemic control from all those lymph nodes, liver metastases, etc. Unfortunately, the disease came back, and we had been doing MRIs of her brain. Just to segue a bit on that, not at that time, but when we saw that HER2CLIMB data, I have changed my practice in the last 2 years or so by doing MRIs of the brain about every 6 months and/or at any progression. I think arguably if we treat a brain metastasis earlier, we don’t necessarily know how that influences overall survival. And I think that if patients aren’t symptomatic, we could have a different discussion about that with our radiation oncology colleagues. If we’re putting them on a tyrosine kinase inhibitor, like tucatinib, do we wait for that to work if those patients are asymptomatic? Maybe we can pause there for a second and talk a bit about her history and an almost 2-year history of being on a first-line CLEOPATRA-type regimen and in the maintenance setting until unfortunately she developed a brain metastasis. We can talk about how we manage that.

That’s so fascinating. Thank you for sharing, and what a great feature of her history that you were able to get her to family events and so forth. I think the comments you made about screening for brain metastasis are very interesting, as we’ve all thought about how our practice may change. I’ve done the same, I have to say, I’ve started to do more frequent MRIs of the brain. I think that’s largely because, in the past, we simply didn’t have very effective systemic agents for CNS [central nervous system] disease. Now that we do, I feel that we have the rationale to do that screening. I also get brain MRIs now, at least at the time of progression, whenever there’s progression. That can now inform the treatments that we select. The other point that you made was concerning the continued impressive efficacy that we see from CLEOPATRA. This continues to be a long-term efficacious regimen, and particularly once in the maintenance setting, I think that it’s very tolerable for our patients. How long did your patient stay in the maintenance setting, and did you have to add any therapies in that setting to help her?

: She remained on Herceptin and pertuzumab for almost 2 years. It was well over 18 months of being in that phase. Now, this was pre-Phesgo in terms of being able to do a shot. She was coming in for her infusion every 3 weeks and doing, like I said, incredibly well. A comment to your point about MRIs of the brain, I think it’s also really important to do a complete neurologic exam. Sometimes you can pick up little nystagmus or other stuff, even if the patients don’t have headaches. Really screening for headaches or any visual changes, that kind of stuff. She did remarkably well. Then there’s also the other question of if somebody’s tumor markers have normalized, originally, we were staging her every 3 months or so. I wasn’t necessarily checking a brain MRI every 3 months, but there’s that question of, why don’t we space out our scans a little more? Should we do it every 4 months? How comfortable are we with that in terms of following patients whose tumor markers have normalized? 

Most of her systemic disease had improved remarkably, to the point where she was almost NED [no evidence of disease] systemically on this maintenance. This patient did have quite a bit of burden of disease, and she didn’t have brain metastases at baseline. But I have had patients come to me who’ve been on maintenance for even 5 years, and maybe they had a solitary bone lesion or 1 area that could have been zapped, and they come to me for the consult of “how long should I be on this for?” I think that’s another question in terms of therapy for life. I think we all have that feeling that you have to continue the therapy. In that particular patient, I ended up doing a baseline brain MRI. Unfortunately, she had asymptomatic brain metastases, which is too bad. She did extremely well, but then unfortunately, she developed brain metastases after brain metastases.

Those were a lot of great points that you raised. I’ll plug that I think the maintenance setting is an area where we are seeing a lot of investigation, and that may evolve in the near future. This is an area that is ripe for the development of novel biomarkers. Certainly, for exceptional responders like your patient, looking at things like circulating tumor DNA and so forth to guide our management are things that are coming down the pipeline. Before we move into the second-line setting, just a reminder to folks that even in the first-line setting, we may see data soon where we challenge what our current paradigm is with DESTINY-Breast09, which is testing trastuzumab-deruxtecan vs trastuzumab-deruxtecan with pertuzumab vs the CLEOPATRA regimen. There is a lot of investigation in this space.

Centering discussion on a patient profile of HER2+ metastatic breast cancer, experts elucidate frontline therapy selection in this setting.

Patient Profile 1: Frontline Therapy for HER2+ mBC

Before we get to the cases, I want to briefly touch on some of the recent data that came out of the San Antonio [Breast Cancer Symposium] this past December. I will mention that I was particularly struck by long-term data from the HER2CLIMB trial. We also saw some subgroup analysis from the DESTINY-Breast03 study. I’ll point out that in the longer-term follow-up of HER2CLIMB that was presented at San Antonio, we continue to see the overall survival benefit and we continue to see prolonged overall survival benefits. So we certainly know that tucatinib is indeed an active agent.

In the DESTINY-Breast-03 subgroup analysis that we saw at San Antonio, we got a signal that trastuzumab-deruxtecan may also have CNS [central nervous system] activity in the patients within that trial who had stable brain metastasis. Now we have data from a large prospective randomized controlled trial, HER2CLIMB, showing the activity of tucatinib-based therapy in patients with stable and active brain metastases, as well as subgroup data from DESTINY-Breast-03 showing that trastuzumab-deruxtecan might have activity in patients with stable brain metastasis.

Of course, we also have data from the TUXEDO trial and the DEBRA study, both suggesting that trastuzumab-deruxtecan has activity in stable brain metastasis, and possibly in active brain metastasis as well, although, additional data are needed. As you mentioned, Milana, this is a major area of need for our patients with HER2-positive breast cancer. You mentioned that in HER2CLIMB, almost 50% of patients who had a baseline MRI had brain metastasis. This is higher than some of the prior observational cohort data, which suggested 30% to 40% of patients. I think that if we start screening our asymptomatic patients, we’ll find that the rates of CNS involvement are actually even higher.

Before moving on to the patient profiles, expert panelists review recent clinical trial data that have impacted treatment selection and sequencing in HER2+ metastatic breast cancer.

Recent Trial Data in HER2+ Metastatic Breast Cancer

 I’d like to turn it over to Dr Dolezal and ask her to speak a bit about how the guidelines for treating metastatic breast cancer in the HER2-positive space have recently changed.

 Thank you so much, Neil. I appreciate that nice overview of the landscape. You outlined nicely all the different ways we can target the HER2 family, both from outside of the cell, in terms of the monoclonal antibodies and the antibody-drug conjugates. I like to think of those sort of as a magic bullet where you’re bringing chemotherapy directly into those HER2-positve or HER2-low, which is a whole different discussion, types of cancer cells, as opposed to the tyrosine kinases that work from more the inside of the cell on that signaling pathway. They do have what we call blood-brain barrier penetration. That’ll be relevant for the cases that we discuss today. 

In terms of the guidelines, the pandemic has shown an explosion of some new agents in the HER2 space that have offered a lot more options in the third, fourth, fifth line of treatment of metastatic HER2-positive breast cancer. You talked about neratinib, which we have used in the extended adjuvant setting, but that was also approved in the metastatic setting in combination with Xeloda [capecitabine]. You mentioned tucatinib, which is another tyrosine kinase inhibitor that was also approved during this pandemic, in April of 2020. Even though everybody was at home, the FDA was still busy looking at these drug approvals.

In terms of the landscape that’s changed, we’ve had a lot of updates in these lines of therapy. Typically we’ve done the first line with CLEOPATRA, which has been a combination of chemotherapy Taxotere [docetaxel]with pertuzumab, which is a HER dimerization inhibitor, in addition to Herceptin [trastuzumab]. That overall survival continues to be impressive in terms of patients living past 4 to 5 years. In the second-line setting, typically we had done T-DM1 [trastuzumab emtansine], and that’s another different type of antibody-drug conjugate. That’s a HER2 antibody with a Herceptin-like backbone, but it is linked by a cleavable linker to a type of chemotherapy called maytansine that gets into those cancer cells. It has a smaller antibody-to-drug ratio. Typically we’ve done that in the second-line setting.

Then in the third-line setting, there have been different approvals, including a different antibody-drug conjugate. In the second and third-line settings there is also a tyrosine kinase inhibitor option. Really when you look at the guidelines, it’s the patient selection and personalized care depending on where their disease is. I like to think of it like we’re not just cooks anymore. We’re sort of a chef in terms of how we personalize our treatments based on where a patient’s disease is and how much disease they have. That’s relevant when we talk about this second-line setting, now with more recent data, and third-line settings in terms of patients who have what we call visceral metastases.

What that means is patients who have HER2-positive breast cancer that’s gone to either their liver or their lungs, and maybe it hasn’t hit the brain yet. In those kinds of patients, they might present with pain, they might present with difficulty breathing, they might present with abnormal liver enzymes, or other types of adverse effects of their cancers affecting those areas. In that case, we might choose one therapy over another because we want to shrink those tumors quickly, we want the patient to feel better. Maybe their performance status, which is a measure of how well they’re doing, how much time are they spending in bed? Are they able to do their activities of daily living? That is a factor that we think about when we treat patients. Then the other side of that is, has this cancer gone to their brain yet? We know that HER2-positive breast cancer has a proclivity for going into the brain, and that hasn’t been something that we’ve been able to tackle very well with the larger monoclonal antibodies. Certainly, radiation therapy, gamma knife stereotactic, and even whole brain radiation has been an option.

The guidelines are evolving in terms of this first-line, second-line, third-line setting. In the second- and third-line setting, tucatinib, which is a tyrosine kinase inhibitor that’s HER2 specific, as opposed to lapatinib and even neratinib, which you had mentioned before, that are more pan-HER family and they have a different adverse effect profiles, specifically hitting the EGFR/HER1, where you have more diarrhea. Tucatinib is now approved in the second and greater line metastatic advanced HER2-positive space. That is in combination with oral chemotherapy Xeloda, in addition to Herceptin IV [intravenous]. That is based on the HER2CLIMB study. We’ll talk a little more about that and the population in that study. That study did include different buckets of patients, but it included patients who had asymptomatic brain metastases. About 26% of the patients in that clinical trial had a baseline brain MRI as part of their staging and screening for the clinical trial. That’s how the brain metastases were discovered. We’ll dig a little deeper into that clinical trial and what patient population we would use that agent in. It’s a great new option that’s available.

In terms of other agents out there, there are different antibody-drug conjugates than T-DM1 that I had mentioned, which typically we use in the second-line setting after progression on a CLEOPATRA-type regimen. The one agent I’m talking about is in HER2, and that’s an antibody-drug conjugate, but it is linked to a different cytotoxic chemotherapy in the class of irinotecan and is an agent that patients with breast cancer haven’t seen much in their treatment trajectory. We have used it very frequently in gastrointestinal malignancies. Irinotecan has been a core agent there. This is one of the metabolites of irinotecan, but because it’s actually bound to the HER2 backbone antibody, the chemotherapy portion is only getting released into the cancer cells, and so by default, there’s not as much systemic throughout the body toxicity and less diarrhea and some of the adverse effects that we expect with that agent. That’s an exciting newer agent that’s also been available in the third-line space, typically in terms of the original FDA approval, and that was based on a phase 2 study with very impressive overall response rates. What that means is that the tumors are shrinking, and we can see that on scans.

More recently, that agent has shown very impressive results in a clinical trial that looked at HER2 in addition to T-DM1 in a head-to-head in the second-line HER2-positve setting. That was originally presented at ESMO [European Society for Medical Oncology annual meeting]. The data have continued to be very impressive in terms of the progression-free survival and a 

 value that I don’t think I’ve ever seen of 10 to the minus 22, which is pretty amazing when you start having data like that, especially given that the comparator arm was also a very active regimen per the EMELIA trial in the second-line setting, and overall survival hasn’t yet to be reached. The hazard ratios were so impressive that there was almost a 70% improvement in progression-free survival, and also very impressive response rates.

That gives you a bit of meat on the bones. This has even been incorporated into our NCCN [National Comprehensive Cancer Network] guidelines in terms of the first line, second line, and third line. That’s where the patient selection comes in as to where is the disease, is there disease in the liver and the lungs, is there disease in the brain in terms of needing to protect the brain and treat brain metastases, and how do we do that? We’ll talk a bit about some of the adverse effects I alluded to, like diarrhea. The other one that is important to call out in HER2 is interstitial lung disease. That’s something that can manifest as a cough or shortness of breath. Fortunately, during COVID-19, we’ve been very astute at picking up any sort of respiratory symptoms. But even for asymptomatic patients, there are guidelines in terms of how to monitor those patients, and when we use steroids and discontinuation of that particular agent. I know I spoke a lot about the landscape and the changing guidelines, and I think it’s really exciting to have all of these new options available for patients who are living much longer with this disease, including with brain metastases.

Shared insight on the optimal sequencing of therapeutic agents for patients undergoing treatment for HER2+ metastatic breast cancer. 

Selecting and Sequencing Therapy for HER2+ Breast Cancer 

Hello everyone. My name is Dr Neil Iyengar. I’m a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. I’m joined by Dr Milana Dolezal, who is also a medical oncologist. Today we’ll be discussing recent updates in the management and treatment of HER2-positive advanced and metastatic breast cancer. I’d like to start by providing a general overview in terms of the many new advances we’ve seen within the past few years. This has been a really exciting area for clinical advances.

We’ll start by reviewing some of the newer agents that have become available to us in the clinic. I think we’re all very familiar with the classical antibodies trastuzumab and pertuzumab, which bind the extracellular domain of HER2 and thereby block HER2 dimerization, association with HER3,and subsequent signaling. We’re also seeing the development of bispecific antibodies, which target multiple domains. Ultimately this kind of binding of the extracellular domains inhibits ligand-independent HER2/HER3 association, thereby halting the cell cycle and cancer cell proliferation. Another area of exciting development is antibody-drug conjugates. This is what we’ll spend some time discussing today. Here we see the combination of protein targeting with a cytotoxic payload, which results in both halting of the cell cycle, as well as a direct cytotoxic effect. We also now have novel HER2-targeted immunomodulatory approaches, such as margetuximab, which is of course an anti-HER2 antibody that also stimulates an immune response.

If we move into the cell, we have small-molecule tyrosine kinase inhibitors [TKIs], which have recently been improved and are showing exciting activity for advanced metastatic HER2-positive breast cancer, including patients with CNS [central nervous system] involvement. The TKIs target the intercellular domain of the HER family. I think we’re all familiar with lapatinib, which is a reversible inhibitor of HER2 and HER1, or EGFR. We now have neratinib, which is an irreversible pan-HER inhibitor, as well as tucatinib, which is a reversible inhibitor that is highly specific to HER2. Each of these have distinct toxicity profiles based on their receptor specificity or lack thereof and have helped us to improve the toxicity profile of these agents when treating our patients.

If we think about the overview or the timeline of FDA approvals for HER2-positive breast cancer, we’ve really come a long way since the approval of trastuzumab in the early 1990s for metastatic disease. We had a bit of a dry spell until lapatinib in 2007, followed by pertuzumab and T-DM1 [trastuzumab emtansine]. It was really in 2013 that we started seeing approvals in the earlier stage setting, including pertuzumab, neratinib, and T-DM1. Very recently we’ve seen the approvals of 4 new agents in the metastatic setting. This includes trastuzumab-deruxtecan, tucatinib, neratinib, and margetuximab.

Comprehensive insight on therapeutic classes and agents approved in the setting of HER2+ metastatic breast cancer, with a specific focus on how these therapies fit into current treatment strategies. 

Milana Dolezal, MD, MSci

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