Managing T-DXd Adverse Events in the Real World

Managing T-DXd Adverse Events in the Real World

With the recent expansion of its indications in breast cancer, the use of trastuzumab deruxtecan (T-DXd; Enhertu) has increased.

“A lot of us use it more frequently now than in the past,” explained Sid Yadav, MD, breast cancer and gynecologist specialist at Mayo Clinic in Rochester, Minnesota. However, he added that dealing with his 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 human epidermal growth factor receptor (HER2) metastatic breast cancer, but was later approved in May 2022 for earlier use in this patient population and in August 2022 for patients with HER2-weak disease, This latest approval was based on data showing an improvement in overall survival that has been described as “practice changing”.

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

The increasing use of this drug has led to a growing awareness among oncologists of the considerable toxicities of T-DXd, Yadav said. Medscape Medical News.

Of the approximately eight patients he has seen or treated over 2 months, Yadav has already seen one case of high-grade interstitial lung disease/pneumonia, a complication “everyone is worried about” because the T-DXd label carries a black box warning of this possibility.

There were other problems in Mayo as well. In a recent week, five patients were admitted for possible T-DXd-related adverse events, including neutropenic fever and sepsis; pneumonitis; severe nausea/vomiting with electrolyte imbalance; pneumonia and non-ST-segment elevation myocardial infarction with low ejection fraction.

It is unclear what proportion of T-DXd recipients accounted for the five admissions. Yadav’s department has more than 10 breast oncologists, so cases could represent perhaps 1-10% of patients, he said.

Her experience prompted Yadav to turn to Twitter to ask other oncologists what complications they have seen with T-DXd.

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

A third oncologist replied that she had “discovered [T-DXd] generally easy to tolerate by patients and [has] no need to admit anyone” so far.

Overall, 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 of concern, as the labeling notes. The interstitial lung disease case also made Yadav a low threshold to order CT scans in patients with signs of shortness of breath and to start steroids if suspected.

However, the most common problem is probably nausea and vomiting. In clinical trials, over 70% of participants reported nausea and over 40% vomiting.

In response, Yadav and his colleagues became more aggressive with prophylaxis. Pretreatment includes steroids, palonosetron and fosaprepitant. Patients are also usually sent home with prochlorperazine, ondansetron, and lorazepam. If that doesn’t help, the team is considering olanzapine.

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

Yadav is still starting to give patients the standard dose of T-DXd for breast cancer – 5.4mg/kg every 3 weeks – but said it’s now faster to reduce the dose if patients don’t were not doing well. He reckons he’s done it several times so far.

The Mayo Clinic’s approaches are consistent with those of a recent article on the management of T-DXd toxicities by Hope Rugo, MD, of the University of California, San Francisco, and colleagues.

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

The review describes the management practices of other healthcare providers and institutions with experience using T-DXd to aid in the safe and effective management of adverse drug reactions, especially as the duration of treatment can be quite long.

Appropriate management of T-DXd-related adverse events will allow for optimal drug exposure and benefit and help avoid premature discontinuation or inappropriate dose reductions, Rugo and colleagues commented.

Yadav reports no relevant conflicts of interest.

ESMO Open. August 11, 2022. Full text

Mr. Alexander Otto is a medical assistant with a Masters in Medical Science and a Journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism Fellow. Email:

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