T-DXd Gains EU Approval in Residual HER2+ Early Breast Cancer

The European Commission has approved trastuzumab deruxtecan (Enhertu; T-DXd) as single-agent adjuvant therapy for adult patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant treatment with a taxane and HER2-directed therapy.¹

The decision follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use and marks the first European Union (EU) approval of T-DXd in a curative-intent early breast cancer setting.

The approval is based on findings from the randomized, open-label phase 3 DESTINY-Breast05 trial (NCT04622319), in which T-DXd (n = 818) reduced the risk of invasive disease recurrence or death by 53% compared with ado-trastuzumab emtansine (Kadcyla; T-DM1; n = 817), with a hazard ratio (HR) of 0.47 (95% CI, 0.34-0.66; P < .0001).^1-3 Events for the primary end point of invasive disease–free survival (IDFS) occurred in 51 patients (6.2%) in the T-DXd arm vs 102 patients (12.5%) in the T-DM1 arm, and the 3-year IDFS rates were 92.4% (95% CI, 89.7%-94.4%) vs 83.7% (95% CI, 80.2%-86.7%), respectively.^2,3

How was the DESTINY-Breast05 trial designed?

Eligible adult patients had HER2-positive early breast cancer confirmed by central testing, an ECOG performance status of 0 or 1, and invasive disease remaining in the breast or axillary nodes after neoadjuvant chemotherapy plus HER2-targeted therapy. Patients qualified as high risk if their disease was inoperable at presentation or if operable disease remained node positive after neoadjuvant therapy.

Patients were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg or T-DM1 at 3.6 mg/kg intravenously every 3 weeks for 14 cycles. The primary end point was investigator-assessed IDFS. The key secondary end point was disease-free survival (DFS), and other secondary end points included overall survival (OS), distant recurrence–free interval (DRFI), brain metastasis–free interval (BMFI), and safety.^1-3 In the T-DXd and T-DM1 arms, respectively, hormone receptor–positive disease was present in 71.0% and 71.4% of patients, and 52.7% and 51.9% of patients had inoperable disease at presentation.^2,3 The findings were presented at the 2025 ESMO Congress and simultaneously published in The New England Journal of Medicine.

What efficacy data supported the EU approval of T-DXd for residual HER2-positive breast cancer?

DFS events occurred in 52 patients (6.4%) in the T-DXd arm vs 103 patients (12.6%) in the T-DM1 arm, with 3-year DFS rates of 92.3% (95% CI, 89.5%-94.3%) vs 83.5% (95% CI, 79.9%-86.4%), respectively (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). In these respective arms, DRFI events occurred in 42 patients (5.1%) vs 81 patients (9.9%), with 3-year rates of 93.9% (95% CI, 91.4%-95.7%) vs 86.1% (95% CI, 82.5%-89.1%; HR, 0.49; 95% CI, 0.34-0.71).

Central nervous system recurrence occurred in 17 patients (2.1%) vs 26 patients (3.2%; BMFI HR, 0.64; 95% CI, 0.35-1.17). At 2.9% maturity, OS events occurred in 18 patients (2.2%) vs 29 patients (3.5%), with 3-year OS rates of 97.4% (95% CI, 95.8%-98.4%) vs 95.7% (95% CI, 93.5%-97.2%; HR, 0.61; 95% CI, 0.34-1.10). The IDFS findings were consistent across patient subgroups, including those with hormone receptor–positive (HR, 0.54; 95% CI, 0.35-0.82) and hormone receptor–negative (HR, 0.37; 95% CI, 0.22-0.65) disease.

What is the safety profile of T-DXd in the residual HER2-positive breast cancer setting?

Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 50.6% of patients receiving T-DXd vs 51.9% of those receiving T-DM1, and serious TEAEs occurred in 17.4% vs 13.6% of patients, respectively. Treatment discontinuation due to TEAEs occurred in 17.9% vs 12.7% of patients, and 72.3% vs 76.3% of patients completed all 14 cycles. In the T-DXd arm, nausea (71.3%), constipation (32.0%), decreased neutrophil count (31.6%), and vomiting (31.0%) were the most common TEAEs.

Adjudicated drug-related interstitial lung disease (ILD) occurred in 9.6% of patients receiving T-DXd vs 1.6% of those receiving T-DM1. In the T-DXd arm, ILD was reported at grade 1 in 2.0% of patients, grade 2 in 6.5% of patients, grade 3 in 0.9% of patients, and grade 5 in 0.2% of patients. Left ventricular dysfunction occurred in 2.9% of patients in the T-DXd arm vs 1.7% of patients in the T-DM1 arm. TEAEs were associated with death in 0.4% vs 0.6% of patients, respectively.

What is the regulatory status of T-DXd for residual HER2-positive breast cancer in the United States?

On May 15, 2026, the FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as adjuvant therapy for adult patients with HER2-positive breast cancer (immunohistochemistry 3+ or in situ hybridization–positive) and residual invasive disease after neoadjuvant trastuzumab (Herceptin), with or without pertuzumab (Perjeta), plus a taxane.⁴ The label specifies a dose of 5.4 mg/kg every 3 weeks for up to 14 cycles. The FDA label carries a boxed warning for ILD and pneumonitis, and warnings for neutropenia and left ventricular dysfunction.

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 27, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/enhertu-approved-eu-for-her2-positive-ebc.html
2. Loibl S, Park YH, Shao Z, et al. 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-M, 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. Ann Oncol. 2025;36(suppl 2):S1556-S1557. doi:10.1016/j.annonc.2025.09.021
4. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. Updated May 16, 2026. Accessed October 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage