Dr Tan on the Clinical Relevance of T-DXd in HER2-Low/Ultralow Metastatic Breast Cancer

“These are interesting data with seeing an improved PFS using an ADC in the first-line setting compared with chemotherapy. But we also need to weigh the adverse effects [associated] with this ADC.”

Antoinette Tan, MD, MHS, chair of the Department of Solid Tumor and Investigational Therapeutics, chief of the Section of Breast Medical Oncology, and director of the Phase I Program at Atrium Health Levine Cancer; and a clinical professor in the Department of Internal Medicine, Wake Forest University School of Medicine, discussed the clinical implications of findings from the DESTINY-Breast06 trial (NCT04494425), which evaluated fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) vs chemotherapy in patients with chemotherapy-naive, HER2-low or -ultralow metastatic breast cancer.

DESTINY-Breast06 trial demonstrated a significant improvement in progression-free survival (PFS) with T-DXd compared with physician’s choice of chemotherapy. In the HER2-low cohort, T-DXd outperformed chemotherapy. A comparable trend was observed in the HER2-ultralow subgroup, where T-DXd also conferred a longer PFS relative to standard chemotherapy regimens.

These findings are noteworthy, as they suggest that the use of an antibody-drug conjugate (ADC) like T-DXd in the first-line setting can result in superior disease control compared with traditional cytotoxic chemotherapy, according to Tan. However, although the efficacy data are compelling, it is crucial to consider the associated toxicity profile of T-DXd, she said. The trial data indicated a higher incidence of grade 3 or higher adverse effects in patients treated with T-DXd compared with those treated with chemotherapy. Additionally, there was an increased risk of interstitial lung disease, an established and potentially serious complication associated with T-DXd, Tan explained.

In January 2025, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic, hormone receptor (HR)–positive, HER2-low or -ultralow breast cancer, as determined by an FDA-approved test, that has progressed on at least 1 endocrine therapy in the metastatic setting. This regulatory milestone raises important clinical questions regarding patient selection and optimal treatment sequencing following endocrine therapy, Tan emphasized. In clinical practice, there remain patients who may still derive benefit from less intensive options, such as capecitabine—a well-tolerated, orally administered cytotoxic agent frequently used as a bridge between endocrine therapy and intravenous chemotherapy, she noted.

Nonetheless, for patients with HR-positive, HER2-low metastatic breast cancer and a high visceral disease burden or significant symptomatic presentation, the rapid and durable disease control demonstrated by T-DXd in DESTINY-Breast06 makes the ADC an appealing first-line option, she reported. Ultimately, a tailored, patient-specific approach incorporating shared decision-making is essential in determining the appropriateness of T-DXd, particularly in the first-line metastatic setting, Tan concluded.