T-DXd Demonstrates Superior IDFS in HER2-Positive Early Breast Cancer

The anti-HER2 antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; Enhertu) demonstrated a highly statistically significant and clinically meaningful improvement in invasive disease-free survival (IDFS) when compared with trastuzumab emtansine (T-DM1; Kadcyla) in patients with high-risk, HER2-positive early breast cancer following neoadjuvant therapy.¹

These positive high-level results, derived from a planned interim analysis of the global, phase 3 DESTINY-Breast05 trial (NCT04622319), indicate a potential shift in the adjuvant treatment paradigm for a patient population with substantial residual disease burden and elevated risk of recurrence. Full data will be presented during a presidential symposium at the European Society of Medical Oncology (ESMO) 2025 Congress in October.

“This landmark trial is the first to directly compare [T-DXd] and T-DM1 in early breast cancer, and the results clearly show that [T-DXd] delivers superior outcomes, indicating that it may be a better option for patients with high-risk HER2-positive disease in the post neoadjuvant setting. These results from DESTINY-Breast05, coupled with DESTINY-Breast11 [NCT05113251], underscore our commitment to moving [T-DXd] into early-stage HER2-positive breast cancer where patients can achieve sustained long-term outcomes, increasing the opportunity for cure,” said Susan Galbraith, executive vice president of Oncology Hematology Research and Development at AstraZeneca, in a press release.¹

What Is the DESTINY-Breast05 Study?

The DESTINY-Breast05 trial is a multicenter, randomized, open-label, active-controlled study evaluating T-Dxd vs T-DM1 in the post neoadjuvant setting.^1,2 The patient cohort included those with HER2-positive primary breast cancer who had residual invasive disease in the breast or axillary lymph nodes after completing neoadjuvant treatment, classifying them as high risk for disease recurrence. IDFS, the primary end point, was defined as the time from randomization to the first occurrence of invasive breast cancer recurrence, distant recurrence, or death from any cause. The magnitude of benefit observed met the prespecified criteria for statistical significance and clinical relevance at the time of the interim analysis.¹

What Is the Clinical Relevance for Patients With Residual Disease?

Approximately half of patients diagnosed with HER2-positive early breast cancer fail to achieve a pathologic complete response (pCR) following neoadjuvant systemic therapy. Lack of pCR is a critical prognostic factor, placing these patients at an elevated, persistent risk of relapse and progression to metastatic disease, despite receiving post neoadjuvant standard of care, historically represented by T-DM1 based on prior clinical data.

The direct comparison of 2 HER2-directed ADCs—T-DXd and T-DM1—in a curative-intent setting represents a landmark trial design. The superior IDFS data yielded by T-DXd suggest that its distinctive mechanism of action, particularly its cleavable tetrapeptide-based linker and high drug-to-antibody ratio (DAR) of a topoisomerase I inhibitor payload, may confer a therapeutic advantage in eradicating micrometastatic disease in this high-risk population. The highly membrane-permeable payload is designed to induce a significant bystander effect, allowing the cytotoxic agent to kill adjacent tumor cells regardless of their HER2 expression levels, a factor that may be key to addressing heterogeneous residual disease.

What Was the Safety Profile of T-DXd in DESTINY-Breast05?

The safety profile of T-DXd observed in DESTINY-Breast05 was reported as consistent with its known profile, with no new safety concerns identified. Clinicians must continue to monitor for known risks associated with the ADC, including myelosuppression, gastrointestinal toxicities, and the risk of drug-related interstitial lung disease/pneumonitis, an adverse event requiring proactive clinical surveillance and management.

What Is the Study Design of DESTINY-Breast05?

The DESTINY-Breast05 study enrolled 1635 patients across several global regions, including Asia, Europe, Oceania, North America, and South America, in collaboration with prominent cooperative groups such as the National Surgical Adjuvant Breast and Bowel Project Foundation and the German Breast Group. Along with the primary end point of IDFS, key secondary end points include overall survival (OS), distant recurrence-free interval, and brain metastases-free interval.²

At the time of this planned interim analysis, the data for OS were not yet mature, and subsequent analyses will be required to fully characterize the long-term survival benefit. However, the statistically robust improvement in IDFS, often considered a critical surrogate end point in early-stage trials, is expected to accelerate regulatory consideration globally.

REFERENCES:

1. Enhertu demonstrated highly statistically significant and clinically meaningful improvement in invasive disease-free survival vs. T-DM1 in DESTINY-Breast05 Phase III trial in patients with high-risk early breast cancer following neoadjuvant therapy. News release. AstraZeneca. September 29, 2025. Accessed September 30, 2025. https://tinyurl.com/yfyz6jp7

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. Accessed September 30, 2025. https://clinicaltrials.gov/study/NCT04622319