TOP TAKES FROM IAN KROP, MD, PHD, AND PARTICIPANTS
- The location of metastatic disease (e.g. bone vs visceral) can influence the choice of second-line therapy, with T-DXd potentially preferred for bone-predominant disease for some participants.
- Tucatinib-based regimens may be considered for patients with brain metastases, given its ability to penetrate the blood-brain barrier, according to Krop.
- When asked, Krop explains that monitoring for and early management of pneumonitis is crucial for patients receiving T-DXd, as it can be a serious adverse event, though predictive factors remain unclear.
DISCUSSION QUESTIONS
- 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)?
Ian Krop, MD, PhD: 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?
Tara Berman, MD, MS: For brain metastases, tucatinib [Tukysa] had good data, that it penetrates the [brain] from what I remember.1
Krop: That is true, it does have good data.
Barbara Civiello, MD: 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.
Krop: What about tucatinib-based therapy? If somebody had brain metastases, would that ever sway you?
Civiello: 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.
Peter C. Enzinger, MD: T-DXd also has activity in the brain.2 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.
Santosh Kumar, MD: If the patient has brain metastases, I will be more inclined to use the HER2CLIMB regimen [NCT02614794] with the tucatinib.
Krop: 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?
Inder Lal, MD: 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.
Krop: 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.
DISCUSSION QUESTIONS
- 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?
Krop: Does anyone have thoughts or questions on the DESTINY-Breast03 data?
Nancy E. Kaddis, MD, MPH: 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.
Krop: 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.3 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.4 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.
Lal: 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?
Krop: 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.
REFERENCES:
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. J Clin Oncol. 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. Ann Oncol. 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. JCO Oncol Pract. 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. Oncologist. 2022;27(8):637-645. doi:10.1093/oncolo/oyac107
