The Impact of T-DXd in HER2-Positive Breast Cancer

Tanya Gupta, MD, medical oncologist in the Stanford University Department of Medicine, Division of Medical Oncology, evaluates fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and its role in breast cancer treatment.

T-DXd was granted accelerated approval from the FDA in 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who had received 2 or more prior HER2-targeted therapies in the metastatic setting. The approval was based on findings from the DESTINY-Breast01 trial (NCT03248492), a two-part, open-label, single-group, multicenter, phase 2 study in adult patients with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla).

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0:09 | T-DXd is a monoclonal antibody that has the same amino acid sequence as trastuzumab, and it is bound by a linker to a cytotoxic payload, which is a topoisomerase 1 inhibitor. This drug appears to use the bystander effect whereby the payload can permeate to neighboring tumor cells. DESTINY-Breast01 first demonstrated the efficacy of this drug...In this study, patients had received a median of 6 prior lines of therapy, and yet, still had a remarkable overall response rate of just under 61%. DESTINY-Breast02 [NCT03523585] was then the confirmatory phase 3 study, and then DESTINY-Breast03 [NCT03529110] compared T-DXd to T-DM1. It was this study that then established T-DXd as generally our second-line therapy of choice for advanced HER2-positive disease.

1:21 | Specifically, in this study, T-DXd had a quadrupling of the median progression-free survival as compared with T-DM1. The median progression-free survival with T-DXd was just under 29 months as compared with being just under 7 months with T-DM1, which is a really extraordinary increase in median progression-free survival.

1:47 | Finally, T-DXd has been studied in HER2-low disease in DESTINY-Breast04 [NCT03734029]. When compared in that study to physicians' choice of chemotherapy, T-DXd is associated with a significant improvement in median progression-free survival and overall survival.