FDA Gives Breakthrough Therapy Designation to Post-Neoadjuvant T-DXd for HER2+ Early Breast Cancer

The FDA has granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the post-neoadjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant treatment and who are at high risk of disease recurrence.¹

This designation was based on data from the phase 3 DESTINY-Breast05 trial (NCT04622319), which compared T-DXd vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in this population. Findings presented at the 2025 ESMO Congress and published in The New England Journal of Medicine showed that patients who received T-DXd (n = 818) achieved a 3-year invasive disease–free survival (IDFS) rate of 92.4% (95% CI, 89.7%-94.4%) vs 83.7% (95% CI, 80.2%-86.7%) among those who received T-DM1 (n = 817; HR, 0.47; 95% CI, 0.34-0.66; P < .0001).²

“This tenth breakthrough therapy designation reinforces how [T-DXd] continues to deliver transformational results that advance the treatment of breast cancer,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.¹ “We look forward to working with the FDA with the goal of bringing [T-DXd] to the post-neoadjuvant setting of HER2-positive early breast cancer, as DESTINY-Breast05 clearly demonstrated that [T-DXd] may help halt invasive disease recurrence over the current standard of care [SOC], resulting in potentially more patients achieving a cure.”

What was the design of the DESTINY-Breast05 trial?

This global, multicenter, open-label study enrolled 1635 patients across Asia, Europe, North America, Oceania, and South America. Eligible patients had centrally confirmed HER2-positive breast cancer with residual invasive disease in the breast and/or axillary lymph nodes after receiving neoadjuvant chemotherapy with a HER2-directed therapy, high-risk disease prior to neoadjuvant therapy and an ECOG performance status of 0 or 1.²

The trial randomly assigned patients to receive intravenous (IV) T-DXd at 5.4 mg/kg every 3 weeks for 14 cycles, or IV T-DM1 at 3.6 mg/kg on the same dosing schedule.

The primary end point of this trial is investigator-assessed IDFS.^1,2 Investigator-assessed disease-free survival (DFS) serves as a key secondary end point. Other secondary end points are overall survival (OS), distant recurrence–free survival, brain metastasis–free interval (BMFI), and safety.

What additional efficacy findings were seen in DESTINY-Breast05?

Patients who received T-DXd also achieved a higher 3-year DFS rate vs those who received T-DM1, at 92.3% (95% CI, 89.5%-94.3%) vs 83.5% (95% CI, 79.9%-86.4%) (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). Furthermore, the 3-year distant recurrence–free interval rates in these respective arms were 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). Moreover, the 3-year BMFI rates were 97.6% (95% CI, 96.2%-98.5%) vs 95.1% (95% CI, 93.6%-97.2%), respectively (HR, 0.64; 95% CI, 0.35-1.17). Additionally, the 3-year OS rate was 97.4% (95% CI, 95.8%-98.4%) with T-DXd vs 95.7% (95% CI, 93.5%-97.2%) with T-DM1 (HR, 0.61; 95% CI, 0.34-1.10).

What safety findings from DESTINY-Breast05 are important to note?

Among patients who received T-DXd, 99.5% experienced any-grade treatment-emergent adverse effects (TEAEs), and 50.6% had grade 3 or higher TEAEs. The most commonly reported TEAEs in this arm were nausea (71.3%), constipation (32.0%), decreased neutrophil counts (31.6%), vomiting (31.0%), decreased white blood cell counts (29.7%), fatigue (29.5%), radiation pneumonitis (28.8%), anemia (28.3%), increased aspartate aminotransferase levels (25.6%), increased alanine aminotransferase levels (23.7%), diarrhea (23.2%), decreased platelet counts (21.2%), decreased appetite (20.0%), headache (15.8%), and arthralgia (10.3%).

“For patients with residual disease after neoadjuvant treatment, the post-neoadjuvant setting represents a critical opportunity to reduce the risk of recurrence and prevent progression to metastatic disease,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Hematology R&D at AstraZeneca, added in the news release. “This breakthrough therapy designation highlights the impressive clinical benefit of [T-DXd] over the current SOC and underscores its potential to become an important treatment option in the post-neoadjuvant setting.”

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. News release. AstraZeneca. 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. 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. Ann Oncol. 2025;36(suppl 2):S1671-S1672. doi:10.1016/j.annonc.2025.09.021