Trastuzumab Deruxtecan Shows “Spectacular” Efficacy in Late-Line Setting for HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer who receive targeted therapy can now anticipate survival benefits similar to or better than those experienced by patients with HER2-negative disease, according to Sara Hurvitz, MD, Director, Breast Cancer Clinical Trials Program, UCLA Health, Los Angeles. Most HER2-positive patients now have a number of treatment options available to them and can often receive numerous sequential lines of therapy over the course of many years.

“HER2-targeted therapy has literally altered the history of this disease,” Dr Hurvitz said.

However, according to Dr Hurvitz, long-term durable remissions are still rare in the metastatic setting because of the development of treatment resistance, and newer therapies are needed to prevent or treat resistant disease. This need has compelled research forward in the past several years, resulting in the development of several promising novel agents in the setting of clinical trials.

One of these novel agents is the antibody-drug conjugate, trastuzumab deruxtecan (DS-8201). At the 37th Annual Miami Breast Cancer Conference, Dr Hurvitz discussed the impressive results seen with this drug but warned providers to be cautious of the risk for interstitial lung disease (ILD).

Results from the phase 2 single-arm DESTINY-Breast01 clinical trial were originally presented at the 2019 San Antonio Breast Cancer Symposium. This noncomparative study evaluated the efficacy and safety of single-agent DS-8201 in HER2-positive, TDM-1 resistant, or refractory metastatic disease. Approximately half of patients had hormone receptor co-expression, and HER2 immunohistochemical analysis was 3+ in the majority (83.7%) of patients, but 15.2% had lower expression. Ninety-two percent had visceral disease, and 13% had a history of brain metastases. Dr Hurvitz discussed the data related to the 5.4-mg/kg dosing cohort of 184 patients.

“And drum roll…,” she said. “We’re seeing an objective response rate close to 61%, with a nice long duration of response of almost 15 months. This is pretty spectacular in this late-line setting.”

In December 2019, the FDA granted accelerated approval to DS-8201 for patients with HER2-positive metastatic breast cancer who have received ≥2 previous lines of anti–HER2-based regimens, and it was added to the National Comprehensive Cancer Network Breast Cancer Guidelines in February 2020.

“But it can never just be a great story; there always has to be something, right?” said Dr Hurvitz. “One thing I think we’re all a little bit concerned about, and certainly have to be aware of and alert our patients to, is ILD.”

She noted that although this toxicity is not unique to DS-8201, 4 (2.2%) patients in the study had grade 5 events.

“So, it’s very important that if we notice even asymptomatic ground glass opacities on the scans, which would qualify as a grade one ILD, that we hold therapy,” Dr Hurvitz cautioned.

However, another study by Powell and colleagues looked at a total of 665 patients treated with this drug to evaluate the incidence of ILD as well as factors that may predict for the development of this serious side effect. The study showed that patients with breast cancer who were treated with DS-8201 at a dose of 5.4 mg/kg experienced grade 5 events at a rate of 0.4%. “So, I think this is evolving,” Dr Hurvitz said.

They also showed a higher likelihood of developing ILD with a higher dose (≥6.4 mg/kg), Japanese origin, and a higher previous number of therapies. The median time to ILD onset was 149 days.

“It can be as soon as the first month or as late as a year or more into treatment, so you always have to be vigilant,” Dr Hurvitz said. “Many of us in clinical practice pull back on the frequency of our surveillance scans when we see a great response in our patients that seems to be durable, but this is one area where I think we should be continuing those scans to make sure we’re not seeing ground glass opacities develop.”

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