Trastuzumab deruxtecan (T-DXd) Provides Significant Clinical Benefit Over Trastuzumab emtansine (T-DM1), Marking a Potential Shift in the Therapeutic Standard for HER2+ Breast Cancer

Breast cancer is the second most common type of cancer and one of the leading causes of cancer-related death worldwide. HER2 is a tyrosine kinase receptor protein with a growth-promoting function, present on the surface of several tumor types, including breast cancer. HER2 protein overexpression, often due to gene amplification, is associated with more aggressive disease and poorer prognosis. Approximately one in five cases of breast cancer is classified as HER2-positive.

The global phase III DESTINY-Breast05 study (NCT04622319) evaluated trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with early-stage, high-risk HER2-positive breast cancer with residual invasive disease after taxane- and anti-HER2–based neoadjuvant therapy (with or without pertuzumab). This was a multicenter, open-label, randomized (1:1) study that enrolled 1,635 patients (T-DXd: n = 818; T-DM1: n = 817) across Asia, Europe, Oceania, North America, and South America, conducted in collaboration with international cooperative groups.

Participants received either T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg, both administered every three weeks for up to 14 cycles. The primary endpoint was invasive disease-free survival (IDFS), and key secondary endpoints included disease-free survival (DFS), overall survival (OS), distant recurrence-free interval, and brain metastasis–free interval (BMFI).

In the interim analysis presented at ESMO 2025, with a data cutoff of July 2, 2025, and a median follow-up of approximately 30 months, the study demonstrated a statistically significant and clinically meaningful benefit with T-DXd compared to T-DM1. Both IDFS and DFS were superior with T-DXd, showing a 53% reduction in the risk of invasive recurrence or death (HR 0.47; 95% CI 0.34–0.66; p < 0.0001). IDFS events occurred in 6.2% of patients treated with T-DXd versus 12.5% with T-DM1. Similar results were observed for DFS, with events in 6.4% versus 12.6%, respectively (HR 0.47; 95% CI 0.34–0.66; p < 0.0001).

Additionally, a favorable trend was observed for BMFI with T-DXd (HR 0.64; 95% CI 0.35–1.17), suggesting potential protection against central nervous system metastases, a particularly relevant outcome in HER2-positive disease.

Regarding safety, the adverse event profile of T-DXd was generally manageable and consistent with previous findings. Treatment-emergent grade ≥3 adverse events occurred in 50.6% of patients receiving T-DXd and 51.9% receiving T-DM1. Drug-related interstitial lung disease (ILD) was reported in 9.6% of patients treated with T-DXd (including two grade 5 events) and 1.6% with T-DM1 (no fatal cases). Most ILD events were grade 1 or 2 and manageable with early intervention. Treatment-related fatal adverse events were rare (0.4% with T-DXd and 0.6% with T-DM1).

These findings confirm that T-DXd provides substantial improvements in IDFS and DFS, with statistically and clinically significant benefits, representing a potential paradigm shift in adjuvant therapy for patients with HER2-positive breast cancer and residual disease after neoadjuvant treatment.

Overall, the benefit-risk profile of T-DXd remains favorable. Although overall survival data are still immature, the marked reduction in recurrence risk suggests a significant clinical impact and the potential to redefine the standard of care.

 Reference

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2.    A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated May 9, 2025.

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