From the Journals

Managing trastuzumab deruxtecan adverse events in the real world


With recent expansions in its breast cancer indications, there has been an increase in the use of trastuzumab deruxtecan (T-DXd; Enhertu).

“A lot of us are using this more frequently now than we were in the past,” explained Sid Yadav, MD, a breast and gynecologic cancer specialist at the Mayo Clinic in Rochester, Minn. However, he added that managing its adverse events has been a “bit of a learning curve for all of us.”

The antibody-drug conjugate has been on the market since 2019 for metastatic human epidermal growth factor receptor (HER2)–positive breast cancer, but it was then approved in May 2022 for earlier use in this patient population and in August 2022 for patients with HER2-low disease. This latest approval was based on data showing an improvement in overall survival that was described as “practice changing.

In addition, T-DXd is also approved for use in metastatic HER2-mutated non–small cell lung cancer and metastatic HER2-positive gastric and gastroesophageal junction adenocarcinoma.

Expanding use of this drug has led to growing awareness among oncologists of T-DXd’s considerable toxicities, Dr. Yadav told this news organization.

Among the eight or so patients he’s seen or treated over 2 months, Dr. Yadav has already seen one case of high-grade interstitial lung disease/pneumonitis, a complication that “everybody worries about” because the label for T-DXd carries a black box warning of this possibility.

There have been other issues at Mayo Clinic, as well. In one recent week, five patients were admitted for possible T-DXd adverse events, including neutropenic fever and sepsis; pneumonitis; severe nausea/vomiting with electrolyte imbalance; pneumonia, and non–ST elevation myocardial infarction with low ejection fraction.

It’s unknown what proportion of T-DXd recipients the five admissions represented. Dr. Yadav’s service has over 10 breast oncologists, so the cases could represent maybe 1%-10% of patients, he said.

His experience prompted Dr. Yadav to turn to Twitter to ask fellow oncologists what complications they’ve seen with T-DXd.

One said that his “real-world toxicity experience [has been] worse than the trial data,” which isn’t unusual, another oncologist noted, because real-world patients are often sicker than trial participants and more vulnerable to toxicities.

A third oncologist countered that she has “found [T-DXd] generally easy for patients to tolerate and [has] not needed to admit anyone” so far.

Overall, Dr. Yadav said that in his experience there are issues that need to be considered with T-DXd beyond interstitial lung disease.

As with any chemotherapy, neutropenia and infections are a concern, as the labeling notes. The interstitial lung disease case has also made Dr. Yadav have a low threshold to order CT in patients with any hints of shortness of breath and to start steroids if there’s any suspicion.

Probably the most common issue, however, is nausea and vomiting. In clinical trials, over 70% of participants reported nausea and over 40% experienced vomiting.

In response, Dr. Yadav and his colleagues have become more aggressive with prophylaxis. Pretreatment includes steroids, palonosetron, and fosaprepitant. Patients are also usually sent home with prochlorperazine, ondansetron, and lorazepam. If these don’t help, the team considers olanzapine.

They have also learned that “it’s important to spend that extra 15-20 minutes upfront” with patients before starting T-DXd to explain the risk for nausea and vomiting and how it will be managed, Dr. Yadav commented. “We do chemotherapy teaching for every patient, but I think we spend more time [now] talking about nausea and vomiting with this subset,” he said.

Dr. Yadav still starts patients on the standard breast cancer dose of T-DXd – 5.4 mg/kg every 3 weeks – but said he’s quicker now to lower the dose if patients aren’t doing well. He estimates he’s done that a couple of times so far.

Approaches at the Mayo Clinic are in line with those in a recent article on managing T-DXd toxicities by Hope Rugo, MD, from the University of California, San Francisco, and colleagues.

These authors conclude that adverse events related to T-DXd are frequent but are most commonly low grade and manageable. Nausea and vomiting are among the most common, and they note that interstitial lung disease/pneumonitis is an important adverse event, for which proactive monitoring, diagnosis, and management are key.

The review describes management practices of other health care providers and institutions with experience in using T-DXd to help with safe and effective management of the drug’s adverse events, particularly since the duration of treatment may be quite long.

Proper management of T-DXd–related adverse events will allow optimal exposure to and benefit from the drug and will help avoid premature discontinuation or improper dose reductions, Dr. Rugo and colleagues commented.

Dr. Yadav reports no relevant conflicts of interest.

A version of this article first appeared on

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