CHMP Recommends Adjuvant T-DXd for HER2+ Early Breast Cancer With Residual Invasive Disease

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion recommending the approval of 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 following treatment with neoadjuvant taxane-based and HER2-targeted therapy.¹

The positive opinion was based on findings from the phase 3 DESTINY-Breast05 trial (NCT04622319), which were presented at the 2025 ESMO Congress and published in The New England Journal of Medicine.^1,2 In the trial, T-DXd (n = 818) reduced the risk of invasive disease recurrence or death by 53% vs ado-trastuzumab emtansine (T-DM1; Kadcyla; n = 817), the current adjuvant standard of care (SOC) in this setting (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). At 3 years, 92.4% (95% CI, 89.7%-94.4%) of patients in the T-DXd arm were alive and free of invasive disease vs 83.7% (95% CI, 80.2%-86.7%) of those in the T-DM1 arm. The invasive disease–free survival (IDFS) benefit with T-DXd was consistent across all prespecified patient subgroups.

“[T-DXd] cut the risk of disease recurrence by more than half compared [with] adjuvant SOC for patients with residual disease, and if approved, could redefine post-surgery care in the European Union, keeping patients disease free for longer and increasing the potential for cure,” Susan Galbraith, executive vice president of oncology hematology research and development at AstraZeneca, stated in a news release.¹

T-DXd is already approved in the United States and other countries for the adjuvant treatment of patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant treatment, based on data from DESTINY-Breast05.

“Patients with HER2-positive early breast cancer who have residual disease after neoadjuvant treatment experience a substantially higher risk of recurrence, making effective adjuvant treatment especially important,” John Tsai, global head of R&D at Daiichi Sankyo, added in the news release. “This positive CHMP opinion underscores the potential role of [T-DXd] in the curative-intent setting where it is critical to maximise the potential for sustained long-term outcomes.”

How was the DESTINY-Breast05 trial designed?

DESTINY-Breast05 is a global, multicenter, randomized, open-label trial evaluating T-DXd at 5.4 mg/kg vs T-DM1 in patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy and a high risk of recurrence.^1,2 High risk was defined as inoperable cancer before neoadjuvant therapy or pathologically positive axillary lymph nodes after neoadjuvant therapy.¹ Patients were randomly assigned 1:1 to receive T-DXd or T-DM1, each administered intravenously every 3 weeks for 14 cycles.²

Randomization was stratified by extent of disease at presentation, HER2-targeted neoadjuvant therapy (single or dual), hormone receptor status, and post-neoadjuvant pathologic nodal status.^1,2 Investigator-assessed IDFS served as the primary end point, and investigator-assessed disease-free survival (DFS) was the key secondary end point. Other secondary end points included overall survival (OS), distant recurrence–free interval (DRFI), brain metastasis–free interval (BMFI), and safety. The trial enrolled patients across Asia, Europe, North America, Oceania, and South America.

What efficacy was observed in DESTINY-Breast05?

At the interim analysis, 51 IDFS events had occurred in the T-DXd arm vs 102 in the T-DM1 arm.² For the key secondary end point of DFS, the 3-year rate was 92.3% (95% CI, 89.5%-94.3%) with T-DXd vs 83.5% (95% CI, 79.9%-86.4%) with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P < .0001).

A benefit favoring T-DXd was also observed in terms of DRFI, with a 3-year rate of 93.9% (95% CI, 91.4%-95.7%) vs 86.1% (95% CI, 82.5%-89.1%) with T-DM1 (HR, 0.49; 95% CI, 0.34-0.71). Fewer central nervous system recurrences were observed with T-DXd; the 3-year BMFI rate was 97.6% (95% CI, 96.2%-98.5%) vs 95.8% (95% CI, 93.6%-97.2%) with T-DM1 (HR, 0.64; 95% CI, 0.35-1.17). OS data remained immature, at 2.9% maturity, with a numerical benefit favoring the T-DXd arm (HR, 0.61; 95% CI, 0.34-1.10).

What was the safety profile of T-DXd in DESTINY-Breast05?

The safety profile of T-DXd was consistent with its known profile, with no new safety concerns identified.¹ Among safety-evaluable patients treated with T-DXd (n = 806), grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 50.6% vs 51.9% of those treated with T-DM1 (n = 801).² TEAEs led to treatment discontinuation in 17.9% of patients in the T-DXd arm vs 12.9% of those in the T-DM1 arm, and more than 72% of patients in each arm completed the planned 14 cycles of therapy.

Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 9.6% of patients treated with T-DXd vs 1.6% of those given T-DM1; the majority of events in the T-DXd arm were grade 1 or 2, with 2 grade 5 events (0.2%). The investigators reported that adjuvant radiotherapy timing (sequential or concurrent) showed no meaningful differences in adjudicated drug-related ILD.

References

1. Enhertu recommended for approval in the EU by CHMP as adjuvant treatment for patients with residual disease after neoadjuvant treatment for HER2-positive early breast cancer. News release. AstraZeneca. September 18, 2026. Accessed September 18, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/enhertu-recommended-for-approval-in-eu-in-early-bc.html
2. Geyer CE Jr, Park YH, Shao Z, et al. Trastuzumab deruxtecan vs trastuzumab emtansine in high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy: interim analysis of DESTINY-Breast05. Ann Oncol. 2025;36(suppl 2):S1556-S1557. doi:10.1016/j.annonc.2025.09.021