Dr Tolaney on the Efficacy of T-DXd in HER2+ Breast Cancer in the Post-Neoadjuvant Setting

“T-DXd reduced risk of recurrence by half. That is a big deal, because almost all the events were distant events. [T-DXd had] a huge effect on outcomes in these [patients with] high-risk HER2-positive [disease]. I think this will change practice.”

Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology and associate director at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, discussed the clinical implications of the phase 3 DESTINY-Breast05 trial (NCT04622319) evaluating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive breast cancer with residual disease after neoadjuvant therapy.

The DESTINY-Breast05 trial enrolled 1635 patients who were randomly assigned 1:1, resulting in 818 patients in the T-DXd arm and 817 patients in the T-DM1 arm. Key eligibility criteria mandated that patients needed to have confirmed HER2-positive breast cancer and residual invasive disease in the breast and/or axillary lymph nodes after receiving neoadjuvant chemotherapy combined with HER2-directed therapy. Furthermore, patients had to present with high-risk disease, defined as either inoperable early breast at baseline leading to residual disease, or operable early breast cancer at baseline with axillary node–positive disease after neoadjuvant therapy.

The findings demonstrated that T-DXd generated a statistically significant and clinically meaningful improvement in invasive disease–free survival (IDFS) compared with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). The 3-year IDFS rate was 92.4% (95% CI, 89.7%-94.4%) for T-DXd compared with 83.7% (95% CI, 80.2%-86.7%) for T-DM1. Nearly all events documented in this high-risk population were distant events. The benefit with T-DXd was also observed in other key end points, including DFS (HR, 0.47; 95% CI, 0.34-0.66; P < .0001) and distant recurrence-free interval (HR, 0.49; 95% CI, 0.34-0.71). Lower distant and locoregional recurrences, including numerically fewer central nervous system metastases and deaths, were observed with T-DXd.

The substantial efficacy demonstrated in reducing the risk of recurrence and improving outcomes for these very high-risk HER2-positive patients strongly supports the conclusion that adjuvant T-DXd represents a potential new standard of care in the post-neoadjuvant setting, according to Tolaney.