The Importance of Trastuzumab Deruxtecan in HER2+ Breast Cancer Treatment

In season 4, episode 2 of Targeted Talks, Sara A. Hurvitz, MD, associate professor at the David Geffen School of Medicine at UCLA; medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit; co-director of the Santa Monica-UCLA Outpatient Oncology Practices; and director of the Breast Cancer Clinical Trials Program at UCLA, discusses key advances in the HER2-positive breast cancer space and interesting ongoing research.

Fam trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is one of the most important targeted therapies in the space. According to Hurvitz, the drug made its introduction in 2019 as part of a phase 1, single-arm trial (DESTINY-Breast01; NCT03248492) that include heavily-pretreated patients with HER2-positive breast cancer. In the study T-DXd achieved an objective response rate (ORR) of over 60%, and a progression-free survival (PFS) of over 16 months. Hurvitz explains that at the time, oncologists had never seen such impressive results with any therapy for HER2-positive breast cancer. These data led to the accelerate approval of T-DXd.

Then, in the DESTINY-Breast03 (NCT03529110), a confirmatory trial, investigators explored T-DXd versus trastuzumab emtansine (Kadcycla; T-DM1). T-DXd demonstrated a statistically significant improvement in PFS vs T-DM1, says Hurvitz, as well as improvement in ORR, and a trend toward improvement in overall survival (OS).

In 2022, DESTINY-Breast04 (NCT03734029) findings were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting and later published. In this study, T-DXd was administered to patients with HER2-low, hormone receptor–positive metastatic breast cancer (mBC) and achieved a 36% reduction in the risk of death compared with physician’s choice of chemotherapy. DESTINY-Breast04 led to the FDA approval of T-DXd for the treatment of HER2-low mBC.

In terms of ongoing research, studies of bispecific antibodies, antibody drug conjugates, and bispecific T-cell engager therapies are interesting. The unanswered questions in the field, according to Hurvitz, include how to properly treat patients with brain metastases and leptomeningeal disease as well as how to sequence available therapies.