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FAQs: T-DXd in HER2-Low ABC
Frequently Asked Questions: Expanding the Spectrum of HER2 Positivity in Advanced Breast Cancer With T-DXd

Released: February 13, 2023

Expiration: February 12, 2024

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Key Takeaways
  • T-DXd is now approved in the United States and the European Union for second-line treatment of unresectable or metastatic HER2-positive breast cancer, including HER2 low (IHC 1+ or IHC 2+/ISH-), following progression on at least 1 anti-HER2 regimen.
  • T-DXd carries the risk of lung complications such as interstitial lung disease, and regular imaging to monitor patients is recommended.
  • Toxicities from T-DXd can present differently in different patients; healthcare professionals must be alert to the spectrum of potential effects.
  • Consider rebiopsy in patients who seem to have shifted from HER2 zero to HER2 positive, as they may become candidates for T-DXd during the disease course.

In this commentary, breast cancer experts Heather McArthur, MD, MPH; Nadia Harbeck, MD; PhD; and Komal Jhaveri, MD, answer questions from a live audience of healthcare professionals on the optimal use of trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody–drug conjugate. In addition, they discuss clinical implications of HER2-low status and expanding the spectrum of HER2 positivity. These key learning points were discussed during a live satellite symposium at the 2022 San Antonio Breast Cancer Symposium.

Which patients are eligible for T-DXd?

Nadia Harbeck, MD, PhD:
In clinical practice in Germany, T-DXd for previously treated HER2-positive breast cancer has been available only for a relatively short time―since June 2022. The DESTINY-Breast03 and DESTINY-Breast04 studies had very strict inclusion and exclusion criteria, which I use to guide real-world use. For example, T-DXd should not be given to anyone with a pulmonary infection or severe chronic obstructive pulmonary disease. But otherwise, I would recommend T-DXd to most patients in second line, even for those with pulmonary metastases.

Heather McArthur, MD, MPH:
We are still learning from patient experiences. We had a patient with HER2-positive, HER-low advanced breast cancer whom we treated with T-DXd who had fatal complications but no predisposing conditions. Moreover, it can be challenging to know when to hold the drug based on grade 1 pneumonitis, which is asymptomatic and requires radiographic imaging. Historically, we have done imaging only every 12 weeks. On more recent DESTINY-Breast studies, imaging was conducted every 6 weeks (NCT03248492). However, this frequency is not acceptable to most patients, so we have chosen to do imaging every 9 weeks with T-DXd.

Komal Jhaveri, MD:
I agree with both of you.

For patients receiving T-DXd for more than 1 year, how often do you conduct CT imaging for pulmonary function?

Nadia Harbeck, MD, PhD:
In my practice, those patients who have received T-DXd for more than 12 months are on a clinical trial and must follow the trial protocol. Looking at the data, most cases of interstitial lung disease (ILD) occur in the first year, and after that there is no accumulation.

Komal Jhaveri, MD:
Time to ILD in the trials was approximately 142 days. The question now is, do we need to perform frequent imaging of patients in the beginning? To be cautious, I am doing it every 9 weeks in the beginning. If they have had no substantial issues by 1 year, I shift to every 12 weeks. This is a shared decision-making process, and the patient and I together decide what is appropriate, taking the overall toxicity profile into consideration.

What toxicities have you seen from T-DXd in clinical practice?

Heather McArthur, MD, MPH:
It has varied. For example, one of my patients from the original phase I trial still is receiving treatment after achieving a complete response and remains asymptomatic. In stark contrast, another patient recently received 2 doses for HER2-low disease, and she had horrible nausea and vomiting despite prophylaxis. She no longer wanted to be treated with T-DXd. We have much to learn about the pharmacodynamics and genomics of T-DXd and whether there are differences in tolerability and activity.

Do you consider rebiopsy in patients who initially had HER2 zero status, particularly to ensure its not rally HER2 1+ (eg, HER2 low)?

Nadia Harbeck, MD, PhD:
We usually have a biopsy from the first metastasis, and if there are discordant results, we would follow the HER2-low result and not the HER2-zero result. That said, I would rebiopsy a patient who may have become HER2 positive, despite the potential for heterogeneity in repeated biopsies. Because the data supporting T-DXd are so positive in this setting, it is important to determine HER2-low status if possible.

Heather McArthur, MD, MPH:
I have done the same. When I rebiopsy patients who were N2 positive, I did find HER2 expression and offered them T-DXd.

If a patient develops ILD with trastuzumab emtansine (T-DM1), is it reasonable to give them T-DXd?

Komal Jhaveri, MD:
I would not offer such a patient T-DXd. ILD is a very rare occurrence with T-DM1 to begin with, but if a patient already has developed ILD on T-DM1, I would feel nervous subsequently treating them with T-DXd.

How do you manage grade 3 asthenia and nausea in patients receiving T-DXd?

Heather McArthur, MD, MPH:
We use a triplet prophylactic regimen and then prescribe antiemetics. For most patients, that has been successful.

Komal Jhaveri, MD:
I also have had success with supportive medications and with a triplet antinausea regimen, and I have not struggled with managing grade 3 nausea. Dose reduction also can be used. Certainly, nausea is the most common toxicity we see in our patients, but it can be managed successfully.

In addition to T-DXd, what other options exist for treating patients with HER2-low disease and brain metastases?

Nadia Harbeck, MD, PhD:
Data from the HER2-positive space are somewhat stronger for tucatinib in patients with brain metastases, and this is reflected in the European Society for Medical Oncology guidelines. For example, results from the TUXEDO-1 trial of T-DXd in patients with HER2-positive breast cancer and brain metastases show an intracranial response in 73% of the intention-to-treat population of 15 patients and 79% of the per-protocol population of 14 patients. Thus, I will opt for tucatinib in this setting.

The phase IIIb/IV DESTINY-Breast12 study is currently evaluating T-DXd in patients with advanced HER2-positive breast cancer, with or without brain metastases, and results likely will be available within 1 year showing whether it is effective for brain metastases (NCT04739761). 

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