T-DXd Granted Breakthrough Therapy Designation in Post-Neoadjuvant HER2-Positive Early Breast Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu; Daiichi Sankyo, Inc., AstraZeneca), an antibody-drug conjugate (ADC), has been granted breakthrough therapy designation by the FDA as a post-neoadjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer who have residual invasive disease following neoadjuvant therapy. The designation reflects the growing body of evidence supporting T-DXd’s clinical benefit across multiple stages of HER2-positive breast cancer and signals the potential for an expedited regulatory pathway in an area of significant unmet need.¹

Breakthrough therapy designation is reserved for therapies intended to treat serious or life-threatening conditions and supported by preliminary clinical evidence indicating substantial improvement over existing therapies on clinically meaningful end points. For patients with HER2-positive early breast cancer who do not achieve a pathologic complete response after neoadjuvant therapy, residual disease remains a strong predictor of recurrence and poorer long-term outcomes, underscoring the need for more effective post-surgical treatment strategies.¹

Clinical Rationale for Post-Neoadjuvant Use

Despite advances in HER2-targeted therapies, a subset of patients with early-stage disease continues to experience residual invasive cancer after neoadjuvant treatment with taxane-based chemotherapy and HER2-directed agents. These patients face a higher risk of disease recurrence, and while escalation strategies such as adjuvant ado-trastuzumab emtansine (T-DM1) have improved outcomes, relapse remains a concern. T-DXd’s novel ADC design, combining a HER2-targeted monoclonal antibody with a topoisomerase I inhibitor payload via a cleavable linker, has demonstrated potent antitumor activity, including in tumors with heterogeneous HER2 expression.²

The breakthrough therapy designation in the post-neoadjuvant setting is supported by emerging clinical data suggesting that T-DXd may further reduce recurrence risk compared with existing adjuvant options. Although full trial results have not yet been disclosed, the designation highlights FDA recognition of the therapy’s potential to meaningfully improve outcomes for this high-risk patient population.¹

Expanding Role of T-DXd Across HER2

T-DXd’s momentum in early breast cancer builds on its established role in advanced and metastatic disease. In January 2025, the FDA approved T-DXd in combination with pertuzumab (Perjeta; Genentech) for first-line treatment of patients with unresectable or metastatic HER2-positive breast cancer, based on data demonstrating improved progression-free survival compared with standard regimens.³ This approval marked a significant shift in frontline treatment paradigms and further solidified T-DXd as a cornerstone therapy in HER2-positive disease.

The growing list of regulatory milestones reflects a broader trend toward earlier use of highly active ADCs in breast cancer, with the goal of preventing recurrence rather than managing advanced disease. From a clinical perspective, this evolution emphasizes the importance of tailoring treatment intensity based on response to neoadjuvant therapy and residual disease status.

Implications for Pharmacy Practice

For pharmacists, T-DXd’s breakthrough therapy designation in the post-neoadjuvant setting has several practical implications. Oncology pharmacists play a critical role in evaluating emerging data, supporting treatment selection, and counseling patients on expected benefits and potential toxicities. T-DXd is associated with unique safety considerations, including interstitial lung disease and pneumonitis, which require early recognition, prompt intervention, and close multidisciplinary coordination.

Conclusion

The FDA’s breakthrough therapy designation for T-DXd as post-neoadjuvant therapy in HER2-positive early breast cancer underscores the rapid pace of innovation in this space. As clinical trial data continue to mature, T-DXd may redefine standards of care for patients with residual disease following neoadjuvant treatment. For pharmacists, these developments reinforce the importance of ongoing education and engagement in evidence-based oncology practice as novel therapies move earlier in the treatment continuum.^1-3

REFERENCES

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) granted Breakthrough Therapy Designation in the US as post-neoadjuvant therapy for patients with HER2-positive early breast cancer. Astrazeneca-us.com. Published December 22, 2025. Accessed December 22, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-granted-Breakthrough-Therapy-Designation-in-the-US-as-post-neoadjuvant-therapy-for-patients-with-HER2-positive-early-breast-cancer.html

2. Understanding The Results. Enhertu.com. Accessed December 22, 2025. https://enhertu.com/en/breast/enhertu-results?utm_source=google&utm_medium=cpc&utm_campaign=%7CCN%7CDTCB%7CBR%7CmBC%7CENH%7CAZ%7CInformation%7CInfo&utm_content=Breast+Trials%7CTXT%7CNational%7CA:A%7C1%7CEX&utm_term=enhertu+study&gclsrc=aw.ds&gad_source=1&gad_campaignid=23369840097&gbraid=0AAAAAClWdheFwT2-2Maa6Vh00Hgequm69&gclid=CjwKCAiA9aPKBhBhEiwAyz82J6XGl687SMNC80hrQS7a-GA2dMfr2szCrxa9N7nrLubbkwd_Gtv-MRoCcMEQAvD_BwE

3. McGovern G. FDA Approves T-DXd With Pertuzumab for First-Line Treatment of Advanced HER2+ Breast Cancer. Published December 15, 2025. Accessed December 22, 2025. https://www.pharmacytimes.com/view/fda-approves-t-dxd-with-pertuzumab-for-first-line-treatment-of-advanced-her2-breast-cancer