EU Approves T-DXd for HER2+ Early Breast Cancer With Residual Disease

The European Commission has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as monotherapy for the adjuvant treatment of adult patients with resected HER2-positive breast cancer who have residual invasive disease after neoadjuvant taxane-based and HER2-targeted treatment.¹

The approval follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use and is based on results from the phase 3 DESTINY-Breast05 trial (NCT04622319), which were presented at the 2025 European Society for Medical Oncology (ESMO) Congress and subsequently published in The New England Journal of Medicine.^1-3 It represents the first EU approval of T-DXd in the curative-intent early breast cancer setting.

In the trial, T-DXd reduced the risk of invasive disease recurrence or death by 53% compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive breast cancer and residual invasive disease after neoadjuvant therapy.¹

“For patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy, reducing the risk of disease recurrence is critical for sustained long-term outcomes. The EU approval of trastuzumab deruxtecan, which demonstrated a more than 50 per cent reduction in risk of recurrence compared to standard of care in DESTINY-Breast05, has the potential to change how we treat eligible patients in this setting,” Sibylle Loibl, MD, PhD, of the German Breast Group and Goethe University Medicine Frankfurt, and lead investigator of DESTINY-Breast05, said in the press release.¹

The European decision comes after the FDA granted priority review to T-DXd for this population in March 2026, followed by approval of T-DXd in 2 indications for HER2-positive early breast cancer in May 2026, spanning the neoadjuvant setting based on the phase 3 DESTINY-Breast11 trial (NCT05113251) and the adjuvant setting based on DESTINY-Breast05.^4,5 T-DXd is now approved in more than 35 countries for adjuvant treatment of patients with residual invasive disease based on DESTINY-Breast05.¹

DESTINY-Breast05 Efficacy Findings

At the prespecified interim analysis, T-DXd significantly improved the primary end point of invasive disease-free survival (IDFS) vs T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P <.0001). The 3-year IDFS rates were 92.4% (95% CI, 89.7%-94.4%) with T-DXd vs 83.7% (95% CI, 80.2%-86.7%) with T-DM1.^1,3

The key secondary end point of disease-free survival (DFS) also favored T-DXd (HR, 0.47; 95% CI, 0.34-0.66; P <.0001), with 3-year DFS rates of 92.3% (95% CI, 89.5%-94.3%) and 83.5% (95% CI, 79.9%-86.4%), respectively.³

T-DXd was associated with a 51% reduction in the risk of distant recurrence; the 3-year distant recurrence–free interval rates were 93.9% vs 86.1% (HR, 0.49; 95% CI, 0.34-0.71). The 3-year brain metastasis–free interval rates were 97.6% vs 95.1% (HR, 0.64; 95% CI, 0.35-1.17). Overall survival data were immature at 2.9% maturity, with 3-year rates of 97.4% vs 95.7% (HR, 0.61; 95% CI, 0.34-1.10).^3,4

Fewer recurrences of every type were reported with T-DXd, including distant recurrences (42 vs 77), central nervous system recurrences (17 vs 25), and contralateral invasive disease (0 vs 6).³

“Patients benefited [from T-DXd] irrespective of age cohorts, region of accrual, hormone receptor status, disease status at presentation, post-therapy pathologic nodal status, and dual or single HER2-targeted therapy,” Charles E. Geyer Jr, MD, of the University of Pittsburgh Medical Center Hillman Cancer Center, said during the ESMO presentation.³

Trial Design and Patient Population

DESTINY-Breast05 was a global, multicenter, randomized, open-label phase 3 trial that randomly assigned 1635 patients 1:1 to receive intravenous T-DXd at 5.4 mg/kg (n = 818) or T-DM1 at 3.6 mg/kg (n = 817) every 3 weeks for 14 cycles.³

Eligible patients had centrally confirmed HER2-positive disease with residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant chemotherapy with HER2-directed therapy, an ECOG performance status of 0 or 1, and high-risk disease, defined as inoperable cancer at presentation or pathologically node-positive disease after neoadjuvant therapy. Concomitant adjuvant endocrine therapy was permitted, and radiotherapy could be completed before or given concurrently with study treatment, with ILD monitoring required for patients receiving radiotherapy.

Across both arms, the median age was approximately 50 years, about 71% of patients had hormone receptor–positive disease, roughly 52% presented with inoperable disease, about 80% had positive nodal status after neoadjuvant therapy, and approximately 78% had received dual HER2 blockade with trastuzumab plus pertuzumab. Secondary end points included DFS, overall survival, distant recurrence–free interval, brain metastasis–free interval, and safety.

Safety Profile of T-DXd vs T-DM1

According to the press release, the safety profile of T-DXd was consistent with its known profile, and no new safety concerns were identified. Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 50.6% of patients receiving T-DXd and 51.9% of those receiving T-DM1. Serious TEAEs occurred in 17.4% and 13.6%, and TEAEs leading to discontinuation occurred in 17.9% and 12.9%, respectively.

The most common TEAEs with T-DXd vs T-DM1 included nausea (71.3% vs 29.3%), constipation (32.0% vs 16.2%), decreased neutrophil count (31.6% vs 14.4%), and vomiting (31.0% vs 9.0%). Increased aspartate aminotransferase (25.6% vs 50.2%) and decreased platelet count (21.2% vs 49.8%) were more frequent with T-DM1.

Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 9.6% of patients in the T-DXd arm vs 1.6% in the T-DM1 arm. Most events were low grade, including grade 1 (2.0% vs 1.0%), grade 2 (6.5% vs 0.6%), and grade 3 (0.9% vs 0%) events; grade 5 events occurred in 0.2% of patients receiving T-DXd. Rates of ILD were similar regardless of whether radiotherapy was given sequentially or concurrently. Any-grade left ventricular dysfunction was reported in 2.9% vs 1.7% of patients, respectively.

“The approval of [T-DXd] in the adjuvant setting for patients with residual disease after neoadjuvant treatment has the potential to establish a new benchmark in this curative-intent setting, with more than 92 per cent of patients alive and free of invasive disease at three years,” Dave Fredrickson, executive vice president of the Oncology Haematology Business Unit at AstraZeneca, said in the press release.¹

References

1. Enhertu approved in the EU as adjuvant treatment for patients with residual disease after neoadjuvant treatment for HER2-positive early breast cancer. News release. AstraZeneca. October 27, 2026. Accessed October 30, 2026. https://tinyurl.com/y9v34r7r
2. Loibl S, Park YH, Shao Z, et al; DESTINY-Breast05 Trial Investigators. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. 2026;394(9):845-857. doi:10.1056/NEJMoa2514661
3. Geyer CE, Park YH, Shao Z, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): interim analysis of DESTINY-Breast05. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA1.
4. Enhertu granted priority review in the US as post-neoadjuvant treatment for patients with HER2-positive early breast cancer. News release. March 9, 2026. Accessed October 30, 2026. https://tinyurl.com/yeyjtx7h
5. ENHERTU (fam-trastuzumab deruxtecan-nxki) approved in the US for two new indications for patients with HER2-positive early breast cancer. News release. AstraZeneca. May 15, 2026. Accessed October 30, 2026. https://tinyurl.com/3reyepfu