Dr Kalinsky on the Future of Treatment With T-DXd in HER2+ Breast Cancer

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 future utility of treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for patients with breast cancer, as well as the evolving role of HER2 classification.

The efficacy of T-DXd has been well established in patients with advanced HER2-positive and HER2-low disease, and the phase 3 DESTINY-Breast06 (NCT04494425) also explored its potential in patients with hormone receptor–positive, HER2-ultralow disease, Kalinsky begins. Data from DESTINY-Breast06 raised an important question: How low can HER2 expression be for T-DXd to remain effective? Key areas of inquiry now include whether HER2 status is crucial for determining treatment eligibility, how accurately HER2 levels are being measured, and whether there is a better predictor of response to T-DXd therapy, Kalinsky emphasizes. As research advances, upcoming randomized trials may help determine whether T-DXd could become a first-line treatment option for patients with HER2-positive breast cancer, Kalinsky states.

Another area of exploration is T-DXd’s role in managing residual disease, he continues. Currently, patients who receive neoadjuvant chemotherapy and HER2-targeted therapies are given ado-trastuzumab emtansine (T-DM1; Kadcyla),according to Kalinsky. However, the phase 3 DESTINY-Breast05 trial (NCT04622319) is comparing T-DM1 with T-DXd in patients with high-risk, HER2-positive breast cancer with residual invasive disease following neoadjuvant therapy, Kalinsky shares, noting that results from this comparison may further expand the drug’s applications, positioning it as a leading therapeutic option across treatment stages.

An ongoing challenge with T-DXd is identifying predictors of toxicity, particularly pneumonitis, which affects fewer than 10% of patients, he expands. This adverse effect can necessitate discontinuation of therapy, even in patients who are otherwise responding well, Kalinsky states. The ability to predict and manage this toxicity would be highly beneficial, as oncologists frequently encounter cases where patients experience a positive treatment response but develop grade 2 or higher pneumonitis, forcing them to discontinue therapy, he emphasizes. Developing reliable methods to foresee and address such toxicities remains a critical focus, as it would enable more consistent and prolonged use of T-DXd in responsive patients, Kalinsky concludes.