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

The latest findings from the phase 3 DESTINY-Breast05 trial reveal that treatment with **fam-trastuzumab deruxtecan-nxki** (T-DXd; Enhertu) significantly improves invasive disease-free survival (IDFS) compared to **ado-trastuzumab emtansine** (T-DM1; Kadcyla) in patients with high-risk, HER2-positive breast cancer. This interim analysis was presented at the **March 2025 ESMO Congress** and highlights critical advancements for patients with residual invasive disease following neoadjuvant therapy.

Patients treated with T-DXd showed a remarkable **53% reduction** in the risk of invasive disease or death compared to those receiving T-DM1. Specifically, the hazard ratio was **0.47** (95% confidence interval: 0.34-0.66; P < .0001). The **three-year IDFS rates** were **92.4%** for T-DXd versus **83.7%** for T-DM1, underscoring the potential of T-DXd as a new standard of care in this setting.

Study Details and Patient Demographics

The DESTINY-Breast05 trial involved **1,635 patients** with high-risk, HER2-positive primary breast cancer, all of whom had residual invasive disease after neoadjuvant chemotherapy. Patients were stratified based on disease operability, type of neoadjuvant therapy, hormone receptor status, and post-therapy nodal status. They were randomly assigned to receive either T-DXd or T-DM1 over **14 cycles**, with intravenous administration.

The trial included a diverse patient population, with a median age of **50.3 years** in the T-DXd group and **50.6 years** in the T-DM1 group. Most patients in both arms had **HER2 3+** disease, and a majority were of Asian descent. Notably, **72.3%** of patients in the T-DXd arm and **76.3%** in the T-DM1 arm completed their respective treatment regimens.

Dr. **Charles E. Geyer Jr.**, who presented the findings, noted that the benefits of T-DXd were consistent across various demographic factors, including age, hormone receptor status, and disease status. This indicates the treatment’s broad applicability and effectiveness.

Safety and Adverse Events

While the efficacy of T-DXd is notable, safety profiles are also crucial in treatment decisions. In the T-DXd group, **99.5%** of patients experienced treatment-emergent adverse events (TEAEs), with **50.6%** of these being grade 3 or higher. Common adverse events included nausea, fatigue, and decreased white blood cell counts. Serious TEAEs occurred in **17.4%** of patients, with a specific concern for interstitial lung disease (ILD) linked to treatment.

In comparison, the T-DM1 group reported TEAEs in **98.4%** of patients, with **51.9%** experiencing severe adverse effects. The safety monitoring program for ILD was significant, particularly for patients undergoing radiotherapy during the trial.

Dr. Geyer emphasized the importance of these results, stating, “Adjuvant T-DXd demonstrated superior efficacy with manageable safety in patients with high-risk, HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy, which represents a potential new standard of care in this post-neoadjuvant setting.”

The trial’s findings not only contribute to the evolving landscape of HER2-positive breast cancer treatment but also highlight the ongoing need for improvements in therapeutic options for patients facing high-risk scenarios after initial treatment. The comprehensive data from the DESTINY-Breast05 trial may pave the way for future guidelines and treatment protocols aimed at enhancing patient outcomes.