Dr Kalinsky on the Implications of DESTINY-Breast06 for T-DXd Use in HER2-Ultralow Breast Cancer

“What was interesting about the study was that there was a small population of patients who had [HER2-]ultralow disease…Within this ultralow population, we’ve seen that a small subset of those patients may benefit [from T-DXd] in the same way [as those with HER2-positive disease].”

Kevin Kalinsky, MD, MS, professor, Department of Hematology and Medical Oncology, director, Division of Medical Oncology, Department of Hematology and Medical Oncology, Emory University School of Medicine; Louisa and Rand Glenn Family Chair in Breast Cancer Research, director, Glenn Family Breast Center, director, Breast Medical Oncology, Winship Cancer Institute of Emory University, discusses the significance of results from the phase 3 DESTINY-Breast06 trial (NCT04494425) evaluating fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with HER2-low and -ultralow breast cancer.

The DESTINY-Breast06 trial investigated T-DXd compared with physician’s choice of chemotherapy in patients with metastatic HER2-low or -ultralow hormone receptor (HR)–positive breast cancer who had progressed on prior endocrine therapy, Kalinsky begins. HER2-low disease was defined as disease with an immunohistochemistry (IHC) score of 1+ or IHC 2+ with negative in situ hybridization (ISH), whereas HER2-ultralow was classified as IHC 0 disease with membrane staining.

The trial built upon findings from the phase 3 DESTINY-Breast04 trial (NCT03734029), which demonstrated significant benefit with T-DXd vs physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer, Kalinsky notes. DESTINY-Breast06 focused exclusively on patients with HR-positive disease and evaluated the efficacy of administering T-DXd earlier in the treatment sequence, he says. Patients were randomly assigned to receive T-DXd or chemotherapy, and the results revealed a progression-free survival benefit with T-DXd, Kalinsky reports.

An intriguing aspect of DESTINY-Breast06 was the inclusion of a subset of patients with HER2-ultralow disease, he continues. Historically, HER2-targeted therapies have been administered to patients with HER2 IHC scores of 1+ or 2+ (non-amplified) or higher, he states. However, data from DESTINY-Breast06 indicate that even patients with HER2-ultralow disease might derive benefit from T-DXd, though the sample size in this subgroup was small, Kalinsky explains. These findings expand the potential application of T-DXd beyond the traditional HER2-low classification and indicate its efficacy across patients with a broader range of HER2 expression levels, he emphasizes.