T-DXd Outperforms T-DM1 in HER2+ Breast Cancer Treatment

Patients with high-risk, HER2-positive breast cancer have shown promising results with the treatment of fam-trastuzumab deruxtecan-nxki, commonly known as T-DXd. According to findings presented at the 2025 ESMO Congress, T-DXd significantly improved invasive disease-free survival (IDFS) compared to ado-trastuzumab emtansine (T-DM1) in a large population of individuals with residual invasive disease following neoadjuvant therapy.

The interim analysis of the phase 3 DESTINY-Breast05 trial (NCT04622319) revealed that treatment with T-DXd, involving 818 patients, resulted in a 53% reduction in the risk of invasive disease or death compared to T-DM1, which had 817 patients (HR, 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.

During the presentation, Charles E. Geyer Jr., MD, a professor of medicine and chief of the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh Medical Center, noted that the benefits of T-DXd extended across various demographics and treatment backgrounds. “Patients benefited from T-DXd irrespective of age cohorts, region of accrual, hormone receptor status, and disease status at presentation,” he stated.

The findings from this trial come after the earlier phase 3 KATHERINE trial (NCT01772472), which demonstrated that T-DM1 improved IDFS and overall survival (OS) compared to trastuzumab in patients with HER2-positive early breast cancer. However, patients with advanced locoregional disease or positive nodal status post-neoadjuvant therapy had three-year IDFS rates of only 76% and 83%, respectively. This highlights the ongoing need for improved treatment options in this patient population.

Study Overview and Design

The DESTINY-Breast05 trial was a global, multicenter, randomized, open-label study. It enrolled patients who displayed residual invasive disease in the breast and/or axillary lymph nodes after receiving neoadjuvant chemotherapy with HER2-directed therapy. The criteria for high-risk disease included inoperable or operable early breast cancer with axillary node-positive disease. Patients were required to have centrally confirmed HER2-positive disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Participants were randomly assigned in a 1:1 ratio to receive either intravenous T-DXd at 5.4 mg/kg every three weeks or T-DM1 at 3.6 mg/kg every three weeks for 14 cycles. The trial included a 40-day safety follow-up period, with adjuvant endocrine therapy allowed according to local practice.

During the study, IDFS served as the primary endpoint, while disease-free survival (DFS) was a key secondary endpoint. Other secondary endpoints included OS, distant recurrence-free interval (DRFI), brain metastasis-free interval (BMFI), and safety assessments.

A total of 1,635 patients were randomly assigned to either treatment arm, with 806 receiving T-DXd and 801 receiving T-DM1. Notably, patient demographics were largely similar between the two groups, with median ages of 50.3 years for T-DXd and 50.6 years for T-DM1.

Adverse Effects and Treatment Outcomes

The study also monitored adverse effects closely. In the T-DXd arm, 99.5% of patients experienced any-grade treatment-emergent adverse events (TEAEs), with 50.6% reporting grade 3 or higher TEAEs. Serious TEAEs were noted in 17.4% of patients, with some resulting in treatment discontinuation. In comparison, 98.4% of patients in the T-DM1 arm reported any-grade TEAEs, with 51.9% experiencing grade 3 or higher.

Despite the adverse effects, the efficacy of T-DXd appeared to be superior. Lower rates of distant and local recurrences, including central nervous system recurrences, were observed with T-DXd compared to T-DM1. The three-year DFS rates showed a similar trend, at 92.3% for T-DXd versus 83.5% for T-DM1, with a hazard ratio of 0.47 (95% CI, 0.34-0.66; P < .0001). In summary, the results from the DESTINY-Breast05 trial suggest that T-DXd provides a significant improvement in outcomes for patients with high-risk, HER2-positive breast cancer with residual invasive disease after neoadjuvant therapy. Geyer concluded that "Adjuvant T-DXd demonstrated superior efficacy with manageable safety in patients with high-risk, HER2-positive early breast cancer, representing a potential new standard of care in this post-neoadjuvant setting." The findings underscore the need for ongoing research and treatment innovations in the realm of HER2-positive breast cancer, where improved patient outcomes are critically needed.