Dr Yuan on the Evolving Landscape of ADCs in HER2+ Breast Cancer

"The take-home message here is that ADCs are here. We're calling [for] different mechanisms and perhaps different payloads [with] some of those [ADCs] in clinical trials."

Yuan Yuan, MD, PhD, the director of Breast Medical Oncology Medicine and the medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center, as well as a health sciences clinical professor at the University of California, Los Angeles (UCLA), discussed the rapid expansion of antibody-drug conjugates (ADCs) in breast cancer treatment and the evolving landscape of therapeutic targets and payload design, as presented by her UCLA colleague Kelly E. McCann, MD, during an OncLive State of the Science Summit in Breast Cancer.

Yuan began by noting that ADCs have represented one of the most significant therapeutic advances in breast oncology over the past 2 years. Beyond established targets such as HER2 and TROP2, multiple new investigational approaches are emerging, including HER3-directed agents and ADCs leveraging novel cytotoxic payloads. In McCann's presentation, she referenced current use of sacituzumab govitecan-hziy (Trodelvy), which targets TROP2, and fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), a HER2-directed ADC, Yuan recounted. T-DXd demonstrated benefit in patients with HER2-low metastatic breast cancer in the phase 3 DESTINY-Breast04 (NCT04556773), including a subset with triple-negative disease, and ongoing evaluation in HER2-ultralow disease is being explored in the phase 3 DESTINY-Breast06 (NCT04494425).

Yuan further highlighted datopotamab deruxtecan (Dato-DXd; Datroway), another TROP2-directed ADC with a topoisomerase I inhibitor payload, and emphasized that many ADCs in development share similar payload classes. For example, both sacituzumab govitecan and Dato-DXd rely on topoisomerase I inhibition, potentially contributing to overlapping resistance patterns. She underscored the need for diversification in ADC design, including incorporation of alternative payload types such as microtubule inhibitors, dual-payload constructs, or agents enabling bispecific receptor targeting.

Yuan concluded that ADCs are firmly established in metastatic breast cancer and will continue to expand into earlier-line settings.