Dr Pegram on the Implications and Safety of T-DXd in HR+/HER2-Low and -Ultralow Breast Cancer

Mark Pegram, MD, Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology, associate dean, Clinical Research Quality the Stanford University School of Medicine; associate director, Clinical Research, the Stanford Comprehensive Cancer Institute; medical director, the Stanford Clinical Translational Research Unit, discusses the implications of data from the primary analysis of the phase 3 DESTINY-Breast06 trial (NCT04494425) which evaluated fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in pretreated patients with hormone receptor–positive, HER2-low and -ultralow metastatic breast cancer. Notably, these data were presented at the 2024 ASCO Annual Meeting.

The randomized DESTINY-Breast06 trial marks an initial step beyond endocrine therapy treatment in HR-positive metastatic disease, he begins. The trial yielded positive results and a highly significant p-value. The median progression-free survival (PFS) in the cohort of patients with HER2-low disease (n = 359) was 13.2 months with T-DXd vs 8.1 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.74; P < .0001), indicating a statistically significant and clinically relevant benefit with the antibody-drug conjugate (ADC) compared with the control, he reports. As a result, T-DXd may become a new option for select patients with hormone receptor–positive disease in the future, Pegram details.

It is also important to be aware of the adverse effects (AEs) associated with T-DXd, according to Pegram. The safety data from DESTINY-Breast06 revealed expected AEs, including gastrointestinal toxicity, alopecia, and interstitial lung disease (ILD), with some cases of grade 5 ILD. No new safety signals were detected, but it is crucial to monitor for these known toxicities, he advises.

T-DXd may be most suitable for high-risk patients who had a short duration of benefit from prior endocrine therapy, especially those with visceral disease or rapid progression, he continues. For patients requiring a quick response, the ADC is a sensible option, Pegram notes. Conversely, patients with a slow, indolent disease progression and a long history of response to CDK4/6 inhibitors plus endocrine therapy might consider other non-ADC options, such as capecitabine (Xeloda), Pegram says.

Ultimately, most patients will receive various treatments over time, so the order of administration may not be critically important, Pegram explains. Nonetheless, the robust data from DESTINY-Breast06 appear promising for patients who need a rapid treatment response to regain disease control after becoming resistant to endocrine therapy, Pegram concludes.