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Spotlight

This roundtable series considers antibody-drug conjugate and other therapies for patients with HER2-positive breast cancer, as discussed by key opinion leaders at virtual live events and interviews.

HER2+ Breast Cancer Treated With Antibody-Drug Conjugates

Specifically, how do site(s) of progression and tumor burden factor into your decision making?

What is your preferred second-line therapy for patients with hormone receptor­–positive, HER2-positive metastatic breast cancer who develop progression involving multiple metastatic sites—including brain—after completing 1 year of first-line docetaxel, trastuzumab, and pertuzumab (THP)?

It's important to a lot of you where the disease burden is in terms of your decision on what to do in the second-line setting. Can anybody elaborate on that? Why is it important? How would it help you? [Most of us would use] trastuzumab deruxtecan [Enhertu; T-DXd] for a patient who had bone metastases. What kind of situation would you do something different if they had the disease somewhere else—visceral disease, like liver or brain metastases?

 For brain metastases, tucatinib [Tukysa] had good data, that it penetrates the [brain] from what I remember.

 I think with the standard patient who shows up, whether they have liver, liver and bone, or brain-only metastatic disease, it's hard to imagine you do something other than what everybody picked with T-DXd. I'm trying to imagine a scenario where [I would] substitute chemotherapy and I can't think of one.

 What about tucatinib-based therapy? If somebody had brain metastases, would that ever sway you?

 I would say it depends, but I think you'd need to control the brain metastases with resection with a neurosurgeon or with radiation, and I'm not sure it would sway my systemic treatment.

 I guess the only place that I wouldn't use T-DXd is if the patient had a history of pneumonitis or some sort of a pulmonary issue.

 If the patient has brain metastases, I will be more inclined to use the HER2CLIMB regimen [NCT02614794] with the tucatinib.

 I don't think that there's absolute consensus within the field. It's something that we have been considering, and as Dr Enzinger brought up, there are also toxicity issues that are different between T-DXd and the other HER2-directed therapies.

If somebody has multiple metastatic sites, including the brain, and they've already had a year of THP [docetaxel (Taxotere), trastuzumab (Herceptin), and pertuzumab (Perjeta)], would people still mostly use T-DXd or would you use tucatinib or something else?

 As my colleague said, tucatinib has good data, but what I heard from one of the presentations in the past is that when you see the brain metastasis, it means the blood-brain barrier is already broken, so your drugs are going to cross the blood-brain barrier. T-DXd, I think, does work for the metastasis too, but it's kind of controversial. [If] you want to choose tucatinib vs T-DXd, what's the burden of the disease, and how much concern do you have about [the different drugs]? If I have to choose one, I would probably say try with the T-DXd, but have a low threshold to switch over to tucatinib quickly.

 You’re right, that is the working hypothesis for how large biomolecules like antibody-drug conjugates or even antibodies can get into the brain and cross the blood-brain barrier, given that theoretically they shouldn't be able to. The thought is that the blood-brain barrier gets broken down because of the tumor and its dysregulation of the vasculature, and that's how it works. There are clear studies that antibody-drug conjugates get into a tumor when someone has a brain metastasis. I think that the most likely explanation is that the blood-brain barrier is no longer intact when there's a tumor there.

What are your general impressions of the follow-up data from the DESTINY-Breast03 trial (NCT03529110)?

What stands out to you about the efficacy or safety profile?

 Does anyone have thoughts or questions on the DESTINY-Breast03 data?

 I think they are pretty compelling data. After the DESTINY-Breast03 trial came out, it's hard to not go to T-DXd for the second line. One of my hesitations is that I have seen grade 2 to maybe grade 3 pneumonitis from one of the first patients I ever gave T-DXd to. It's a great drug, and it's a bit scary to me still, even with all these data. I don't think there are any ways that we know of to mitigate against possible pneumonitis. My patient who had pretty significant pneumonitis was a nonsmoker, never had lung disease, and yet she still had significant interstitial lung disease [ILD]. I don't know if you have thoughts on that, probably having used it more than I have.

 We don't have great predictive characteristics on who's more likely to develop the pneumonitis with this drug. The studies so far have shown people of Japanese background are more likely and they're more likely to get pneumonitis in general.

 Patients treated at a higher dose than what we typically use is not really relevant, but it was in previous clinical trials. There were some data to suggest that very heavily pretreated patients were more likely to develop pneumonitis, but I think almost all of our patients used it much earlier.

I think it is hard to identify pretreatment who's likely to develop pneumonitis. The important thing is that you monitor for it. Most of us are doing chest CT scans on a regular basis. The trials used it every 6 weeks. I think that tends to be hard to do in practice, but many people use every 9 weeks. It's also important to let your patients know so if they have pulmonary symptoms, that they let you know or when they go to the emergency department, they let people know that they're on this drug because at least at this point, early detection and starting steroids is the best way to try to mitigate the more serious consequences.

If it's caught early, if it's asymptomatic and it resolves, you can restart the T-DXd, and we have pretty clear data that doing that allows people to stay on the drug.

 But if it becomes symptomatic, the guidelines and the FDA label [say it is] to be permanently discontinued. So catching early not only can help prevent it from progressing to higher grade, but it also can allow you to get the patient back on the drug. Given the efficacy we've seen, it's definitely in a patient's best interest to be able to stay on the drug longer.

 How do you counsel your patients to watch for the symptoms of ILD? The cough and the wheezing are not specific symptoms; at what point do they make a phone call, and you make a decision to get a CAT scan to rule out ILD?

 It's a very fair point. I think you have to look at who the patient is. If it's someone who you know chronically has pulmonary symptoms because of either cancer or some other underlying respiratory disease, that is harder, but in those patients, you have to look for a change in their baseline—either in dyspnea or cough or new fevers. In patients who don't have underlying pulmonary disease, it's easier.

As with any kind of serious toxicity, like we do with checkpoint inhibitors, we have to use our clinical judgment about what constitutes a degree of change that you feel like needs further investigation. As we all get used to using this drug, just like we got used to using checkpoint inhibitors, we learn how to get our clinical sense more finely tuned. The important point right now, especially if you haven't used it a lot, is to remember that this is something that can be quite serious and be aware of that. Especially early on, I have a pretty low threshold for bringing people in and at least evaluating them in the clinic. It doesn't mean everybody needs to be scanned, but [one should] at least be evaluating them and laying eyes on them.

1. Lin NU, Borges V, Anders C, et al. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. 

 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

2. Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. 

. 2023;34(suppl 2):S334-S390. doi:10.1016.j.annonc.2023.09.554

3. Rugo HS, Crossno CL, Gesthalter YB, et al. Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer

. 2023;19(8):539-546. doi:10.1200/OP.22.00480

4. Bardia A, Harnden K, Mauro L, Pennisi A, Armitage M, Soliman H. Clinical Practices and Institutional Protocols on Prophylaxis, Monitoring, and Management of Selected Adverse Events Associated with Trastuzumab Deruxtecan. 

. 2022;27(8):637-645. doi:10.1093/oncolo/oyac107

During a Case-Based Roundtable® event, Ian Krop, MD, PhD, and event participants discussed how different types of metastases and treatment toxicity would affect therapy given to patients with triple-positive breast cancer in the second article of a 2-part series.

Therapy Changes for Metastases and Toxicity Discussed in Breast Cancer

 For those of you who are selecting first-line regimens, what chemotherapy do you use? Do you use paclitaxel, or do you use docetaxel? Docetaxel is actually the one used in the in the original randomized trial.

I usually use paclitaxel. I prefer using paclitaxel rather than docetaxel.

 I have used both. I have had good results with both.

 They're both clearly effective. There are phase 2 studies using paclitaxel, and then there was the original phase 3 study using docetaxel. I think some oncologists, including myself, find that paclitaxel tends to be better tolerated in the metastatic setting, but it does require weekly visits, and docetaxel is typically given every 3 weeks so there is that issue. For some patients, frequency of visits can be an issue, and docetaxel helps that.

 The docetaxel regimen in some patients has a particular fatigue/asthenia component that is relevant and has to be considered.

 I agree. Does anybody use other HER2 therapies besides trastuzumab [Herceptin] and pertuzumab [Perjeta]? Have you considered jumping to something like trastuzumab deruxtecan [Enhertu; T-DXd]?For those people who've done that, what were your reasons for starting with something other than trastuzumab/pertuzumab as your HER2 therapy?

 [If] the time gap of the relapse is quite long, I think trastuzumab/pertuzumab makes sense to be re-tried. But if it was within 6 months, maybe then...you go to the second-line HER2 like T-DXd.

 That is consistent with the way the trial was [done]. There was a trial looking at T-DXd in the second-line setting. But it did allow patients who had relapsed within 6 months of their adjuvant or neoadjuvant treatment. The guidelines now have been updated to say, even potentially if they've relapsed within 12 months, you can consider using what's typically considered a second-line therapy like T-DXd.

How was that 6-month interval defined? I know clinically in gynecologic oncology that's been defined, although arbitrarily, that's probably not a good landmark. Also, when would you employ a tyrosine kinase inhibitor [TKI] targeting HER2/neu as maintenance, as opposed to continuing what you've discontinued?

 In the trials and in practice, the way it's defined is the 6-month interval or 12-month interval, depending on the way you want to practice, is from the last dose of their adjuvant or neoadjuvant—in most cases, it's adjuvant—trastuzumab or trastuzumab/pertuzumab. So it's basically when they finish their antibody therapy that's when the clock starts—finish their adjuvant or HER2 therapy, not their endocrine therapy. I don't think it's very common, but some patients get adjuvant neratinib [Nerlynx] after their antibody therapy. You could count from when they finished their neratinib but that's pretty uncommon these days.

You also asked about TKIs. We generally don't use them in first-line therapy, but there are some situations where some people would use them in the second line.

Then in terms of maintenance therapy…in this patient case, she dropped the taxane and was on trastuzumab and pertuzumab as antibodies. Do you leave people on antibodies [only]? Or have you been using endocrine therapy for these patients? In the original trial, endocrine therapy wasn't allowed, but many of us knowing that there are some preclinical and clinical data suggesting that if you block the endocrine pathway with either aromatase inhibitor or other endocrine therapy, along with the antibodies, that you could potentially have better benefit. It hasn't been demonstrated in a definitive trial, but many of us do that, and I wondered if people thought about that in practice. This is after you've stopped the chemotherapy, and the patients is just on trastuzumab and pertuzumab, or even just on trastuzumab alone in your hormone receptor–positive patients. Do you tend to add an aromatase inhibitor or fulvestrant in that situation?

 [For a patient who has] triple-positive disease and went 3 years and didn’t have visceral disease, is there anybody who wouldn't give chemotherapy? Just give the anti-HER2 therapy and maybe the anti-endocrine therapy with a [CDK4/6 inhibitor], and not give the taxane to avoid the toxicity of that, since you're not curing her?

 In my experience, if the patient is presenting with a lot of bulk of disease, it is helpful in the beginning.

 Yes, to try to reduce them, improve their symptoms, and then potentially switch to just antibodies or maintenance.

There was a substantially-sized trial that wasn't looking specifically at that question—it wasn't comparing chemotherapy vs a non-chemotherapy regimen—but it looked at endocrine therapy plus trastuzumab vs endocrine therapy plus trastuzumab and pertuzumab. It was called PERTAIN [NCT01491737], and it wasn't comparing against chemotherapy, but it allowed people to look at how patients did with only endocrine therapy and trastuzumab/pertuzumab. You could do inductive chemotherapy in that trial, which made it a little hard to interpret. But if you look specifically at the patients who didn't get chemotherapy, they had a median progression-free survival of approximately 27 months with endocrine therapy and trastuzumab/pertuzumab.

 That's a select population, but I think to your point, it's an option that for select patients you could consider it in practice.

In practice, I don't think many of us see such patients very often, but you can imagine a patient with many comorbidities or very little disease burden who we can say could get benefit without having to use chemotherapy for a period of time. And for some patients, that probably is a worthwhile option.

Arpino G, de la Haba Rodríguez J, Ferrero JM, et al. Pertuzumab, Trastuzumab, and an Aromatase Inhibitor for HER2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer: PERTAIN Final Analysis. 

. 2023;29(8):1468-1476. doi:10.1158/1078-0432.CCR-22-1092

During a Case-Based Roundtable® event, Ian Krop, MD, PhD, discussed the use of chemotherapy in patients with HER2- and hormone receptor–positive metastatic breast cancer in combination with trastuzumab.