T-DXd Shows Significant Benefits Over T-DM1 in Breast Cancer Trial

A recent analysis from the phase 3 DESTINY-Breast05 trial has revealed that treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; marketed as Enhertu) significantly enhances invasive disease-free survival (IDFS) in patients with high-risk, HER2-positive primary breast cancer. This improvement is notable when compared to ado-trastuzumab emtansine (T-DM1; Kadcyla), particularly in individuals who have residual invasive disease following neoadjuvant therapy. The findings were presented at the 2025 ESMO Congress.

In the trial, which involved 1,635 patients, those treated with T-DXd (n = 818) exhibited a 53% reduction in the risk of invasive disease or death when contrasted with the T-DM1 group (n = 817). The hazard ratio was reported at 0.47 (95% CI, 0.34-0.66; P < .0001). The three-year IDFS rates stood at 92.4% for T-DXd versus 83.7% for T-DM1, indicating a significant clinical advantage.

Key Findings and Implications

Dr. Charles E. Geyer Jr., who presented the findings, noted that patients benefited from T-DXd regardless of various factors, including age, region of enrollment, hormone receptor status, and whether they received radiation therapy. Geyer is a professor of medicine and chief of the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

The KATHERINE trial, which preceded this research, had shown that T-DM1 improved IDFS and overall survival (OS) in patients with HER2-positive early breast cancer. Despite these findings, patients with advanced locoregional disease or positive nodal status following neoadjuvant therapy had three-year IDFS rates of 76% and 83%, respectively, highlighting a critical gap in treatment effectiveness.

“This data reinforces the unmet need for improved post-neoadjuvant treatment in this population,” Geyer emphasized.

The DESTINY-Breast05 trial was a global, multicenter, randomized, open-label study. It enrolled patients who had residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy combined with a HER2-directed therapy. The criteria required patients to present with high-risk disease, which included inoperable early breast cancer or operable breast cancer with axillary node-positive disease.

Participants were randomly assigned to receive intravenous T-DXd or T-DM1, with the T-DXd group receiving 5.4 mg/kg every three weeks for 14 cycles, while the T-DM1 group received 3.6 mg/kg under the same schedule. The study’s primary endpoint was IDFS, with disease-free survival (DFS) as a key secondary endpoint.

Safety and Patient Outcomes

The trial revealed that 72.3% of patients in the T-DXd arm completed the treatment, with a median study duration of 29.9 months. Conversely, 76.3% of patients in the T-DM1 arm completed their treatment, with a median duration of 29.7 months.

In terms of adverse effects, 99.5% of patients in the T-DXd arm reported treatment-emergent adverse events (TEAEs), with 50.6% experiencing grade three or higher. Serious TEAEs occurred in 17.4% of patients, and those leading to drug discontinuation were noted in 17.9%. In the T-DM1 arm, TEAEs were reported in 98.4% of patients, with 51.9% experiencing severe reactions.

The most common TEAEs for both arms included nausea, decreased neutrophil counts, and fatigue, among others. Notably, the rates of adjudicated drug-related interstitial lung disease (ILD) were comparable between both treatment arms, regardless of the timing of adjuvant radiotherapy.

Dr. Geyer concluded that the results indicate that adjuvant T-DXd demonstrates superior efficacy with manageable safety in patients with high-risk, HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy. This could establish T-DXd as a potential new standard of care in this context.

The findings from the DESTINY-Breast05 trial highlight the importance of continued research and development in effective therapies for HER2-positive breast cancer, particularly for patients facing residual disease after initial treatment.