Research Summary

Trastuzumab Deruxtecan Improves Outcomes in High-Risk HER2-Positive Early Breast Cancer

Edited by:
Ashton L. Stahl

Key Highlights

  • Postneoadjuvant T-DXd significantly improved invasive disease-free survival compared with T-DM1 in high-risk HER2-positive early breast cancer.
  • The 3-year invasive disease-free survival rate was 92.4% with T-DXd and 83.7% with T-DM1.
  • Gastrointestinal and hematologic adverse events were more common with T-DXd; interstitial lung disease occurred in 9.6% of patients.

A prespecified interim analysis from the international DESTINY-Breast05 phase 3 trial reports that trastuzumab deruxtecan (T-DXd) improved invasive disease-free survival compared with trastuzumab emtansine (T-DM1) in patients with high-risk, residual HER2-positive early breast cancer. The findings, published in The New England Journal of Medicine, provide new evidence for potential changes in postneoadjuvant treatment strategies.

The open-label, randomized trial enrolled 1,635 patients with centrally confirmed HER2-positive early breast cancer who had residual invasive disease after neoadjuvant therapy. Participants were assigned 1:1 to receive T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) every 21 days for 14 cycles. The primary endpoint was invasive disease-free survival; key secondary endpoints included disease-free survival and safety. Median follow-up was approximately 30 months in each arm.

Study Findings

At the interim cutoff, invasive disease events or deaths occurred in 6.2% of patients treated with T-DXd and 12.5% of those treated with T-DM1, yielding a hazard ratio of 0.47 (95% CI, 0.34-0.66; P < .001). The 3-year invasive disease-free survival rate was 92.4% with T-DXd and 83.7% with T-DM1. Most events were distant recurrences, observed in 5.1% and 9.4% of patients, respectively.

Disease-free survival results were consistent: 3-year rates were 92.3% with T-DXd and 83.5% with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66). Overall survival data were immature, with deaths occurring in 2.2% and 3.5% of patients, respectively.

Safety profiles differed between agents. T-DXd was associated with higher rates of nausea (71.3%), constipation (32.0%), neutropenia (31.6%), and vomiting (31.0%). T-DM1’s most common events included increased AST (50.2%), thrombocytopenia (49.8%), and increased ALT (45.3%). Adjudicated drug-related interstitial lung disease was more frequent with T-DXd (9.6% vs 1.6%), including 2 fatal cases.

Clinical Implications

According to the study authors, the results suggest that T-DXd may offer a more effective postneoadjuvant treatment option for patients with high-risk HER2-positive early breast cancer, producing clinically meaningful improvements in invasive disease-free survival compared with T-DM1. However, they emphasize the importance of monitoring for interstitial lung disease, an identified risk associated with T-DXd.

The trial’s limitations include its open-label design and relatively brief follow-up period. At this interim assessment, brain metastasis–free interval and overall survival results remained immature. Ongoing translational research aims to explore how biomarker profiles may relate to differential responses to T-DXd versus T-DM1. Additionally, the small number of Black participants limits the generalizability of the findings to this population.

Expert Commentary

“These interim results from the DESTINY-Breast05 trial show the superior clinical benefit of postneoadjuvant T-DXd as compared with T-DM1 in patients with HER2-positive early breast cancer with residual invasive disease and a high risk of recurrence. The safety profile of T-DXd continues to require careful monitoring and selected preventative interventions to ameliorate the severity of adverse events,” the researchers concluded.

Reference

Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. 2025; doi:10.1056/NEJMoa2514661