Treatment with the HER2-targeted antibody–drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) resulted in durable objective responses when given to heavily pretreated patients with HER2-positive breast cancers, according to data from a phase 2 study presented at the 2019 San Antonio Breast Cancer Symposium.

The study’s patient population included women previously treated with HER2-directed therapies, including T-DM1, for whom the investigational T-DXd was effective.

Photo by © MedMeetingImages/Todd Buchanan 2019

“Although HER2-directed therapies such as trastuzumab, pertuzumab and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably, and we do not have a clear standard of care for these patients once resistance occurs,” said Ian Krop, MD, PhD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute, in a press release. “These is clearly an unmet medical need for new and improved therapies for such patients.”

Results from a previous phase 1 study published in The Lancet showed that T-DXd treatment provoked a 59% response rate among patients with advanced breast cancer previously treated with T-DM1. The US Food and Drug Administration as granted priority review to the agent, which is comprised of an HER2 antibody, peptide-based cleavable linker and a novel topoisomerase 1 inhibitor payload.

The current study included a dose-finding arm that determined a recommended T-Dxd dose of 5.4 mg/kg. In the second part of the study, women with confirmed HER2-positive metastatic breast cancer were treated with the recommended dose.

Overall response rate (ORR) by independent central review served as the primary endpoint. 

At the time of reporting, 184 patients (100% women; 55% white; 38% Asian; median age, 55 years) had received treatment with the recommended T-DXd study dose. 

In total, 53% had hormone receptor-positive disease and 45% had hormone receptor-negative disease.

The median prior lines of therapy was 6 (range, 2-27), including 100% trastuzumab and T-DM1, 66% pertuzumab, and 54% other HER2-targeted therapies.

The best reported response to T-DM1 prior to study enrollment was 22% complete or partial response, 21% stable disease, and 36% progressive disease.

A total of 60% of patients remained on T-DXd treatment at the time of reporting. Reasons for discontinuation included progressive disease (21%) and treatment-emergent adverse events (8%). The median duration of treatment was 6.9 months (range, 0.7-16), with 70% receiving treatment for more than 6 months.

The ORR by independent central review was 60% (95% CI, 53-68), with 111 patients achieving a response. These rates were consistent across subgroups, including patients previously treated with pertuzumab (64%) and those with 3 or more prior therapy lines (59%).

The researchers reported a disease control rate of 97% (95% CI, 94-99), stating that only five patients did not have stable disease or better at the first post-baseline scan.

“This suggests that the vast majority of cancers in this population have at least some sensitivity to this agent,” said Krop.

The median progression-free survival was 16.4 months.

Treatment-emergent adverse events occurred in 99% of patients, with 51% experiencing grade 3 or higher adverse events.

The most common any-grade adverse events included nausea (77%), alopecia (48%), fatigue (48%), vomiting (45%), constipation (34%), decreased neutrophil count (31%), decreased appetite (29%), diarrhea (27%) and anemia (26%). 

The most common grade 3 or higher adverse events were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%) and fatigue (5.4%).

In addition, 25 patients developed interstitial lung disease (ILD), which an independent adjudication committee adjudicated as treatment related. 

“While these events were primarily grade 1 or grade 2, there were unfortunately four grade 5 ILD-related deaths on the study,” said Krop. “Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary functions test and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”