Dr Gadi on Results From of the DESTINY-Breast06 Trial in HR+/HER2-Low Breast Cancer

VK Gadi, MD, PhD, deputy director, University of Illinois Cancer Center, professor, Department of Medicine, Division of Hematology/Oncology, director, Medical Oncology, University of Illinois College of Medicine Chicago, discusses primary results from the phase 3 DESTINY-Breast06 trial (NCT04494425) investigating treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in hormone receptor (HR)–positive, HER2-low and -ultralow breast cancer.

DESTINY-Breast06 explored the use of the antibody-drug conjugate (ADC) T-DXd vs physician’s choice of chemotherapy in the metastatic setting for patients with HER2-low or -ultralow disease who progressed on prior endocrine therapy. HER2-low disease was defined as those with an immunohistochemistry (IHC) score of 1+ or IHC 2+ and negative in situ hybridization (ISH). HER2-ultralow disease was defined as an IHC score of 0 with membrane staining.

Data from the open-label, randomized study were presented at the 2024 ASCO Annual Meeting. These results demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit with T-DXd vs physician’s choice of chemotherapy in patients with HER2-low disease, which were consistent in the HER2-ultralow population, Gadi reports. In the intention-to-treat (ITT) population, comprising both HER2-low and HER2-ultralow populations, the median PFS increased from 8.1 months with chemotherapy to 13.2 months with T-DXd, resulting in a hazard ratio (HR) of 0.63 (95% CI, 0.53-0.75; P < .0001). This 5.1-month difference in median PFS was also observed with T-DXd in the HER2-low group alone (HR, 0.62; 95% CI, 0.51-0.74; P < .0001).

Overall survival (OS) data were immature at the data cutoff, but a trend toward improved OS was observed with T-DXd vs chemotherapy, Gadi continues. At approximately 40% maturity, the 12-month OS rate in the HER2-low population was 87.6% with T-DXd and 81.7% with chemotherapy (HR, 0.83; 95% CI, 0.66-1.05; P = .1181). In the ITT population, these rates were 87.0% and 81.1%, respectively (HR, 0.81; 95% CI, 0.65- 1.00).

The safety profile of T-DXd was consistent with prior data. Although T-DXd is not considered to be tolerated as well as other agents, the efficacy margin is large enough to support its consideration for those in this population, Gadi explains. As such, treatment with T-DXd will likely be an individualized patient decision, he notes.

Overall, results from DESTINY-Breast06 indicate that T-DXd should be considered a standard of care for patients with HER2-low and -ultralow breast cancer who progressed on endocrine-based therapy. These data may support future regulatory approval for T-DXd in earlier treatment lines, as well as subsequent guideline updates in HER2-low breast cancer, Gadi speculates.