Dr Geyer on the FDA Approval of Post-Neoadjuvant T-DXd for HER2+ Breast Cancer

“The benefit [with T-DXd] was huge, so we expected the FDA was likely to approve it based on the strength of the data, because it was designed, if the study was positive and the drug was safe, [for the indication to] get approval, which it did.”

Charles E. Geyer, MD, a professor of medicine and chief of Malignant Hematology and Medical Oncology in the Department of Medicine at the University of Pittsburgh and the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the significance of the FDA approval of post-neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with HER2-positive breast cancer.

On May 15, 2026, the FDA approved T-DXd for the treatment of adult patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant HER2-directed treatment. This regulatory decision was backed by findings from the phase 3 DESTINY-Breast05 trial (NCT04622319), in which patients who received T-DXd (n = 818) achieved a 3-year invasive disease-free survival rate of 92.4% (95% CI, 89.7%-94.4%) compared with 83.7% (95% CI, 80.2%-86.7%) in those who received ado-trastuzumab emtansine (Kadcyla; T-DM1; n = 817; HR, 0.47; 95% CI, 0.34-0.66; P < .0001).

At the first interim analysis, T-DXd produced a 53% reduction in the risk of recurrence relative to T-DM1, marking a substantial decline in recurrence risk, Geyer reported. The data also generated early evidence suggesting that T-DXd may help prevent some brain metastases, he noted. Geyer also emphasized that diligent monitoring with chest CT scans to detect lung disease was central to administering T-DXd safely during the trial. Despite this vigilance, a risk remained, as 3 patients died from interstitial lung disease during the trial, he stated. Nonetheless, Geyer characterized the overall benefit of post-neoadjuvant as substantial, leading the trial investigators to anticipate its FDA approval in this setting, given the strength of the data and the trial’s design.

The central uncertainty of the research, Geyer explained, concerned the breadth of the indication: Whether the indication would be confined to the highest-risk patients or extended to those excluded from the trial who nevertheless face a recurrence risk of approximately 15% to 20% over 7 to 8 years. The indication ultimately includes patients with residual invasive cancer and is therefore a broader indication than the trial population, Geyer concluded.