FDA Grants BTD to T-DXd in HER2+ BC With Residual Invasive Disease Post NAT

Results from the DESTINY-Breast05 trial revealed that T-DXd was superior to T-DM1 in these patients with HER2-positive early breast cancer.

The FDA has granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of patients with HER2-positive early breast cancer with residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant treatment and high risk of recurrence, according to a press release from the developer, AstraZeneca.1

In the phase 3 DESTINY-Breast05 trial (NCT04622319), T-DXd demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) and DFS vs trastuzumab emtansine (T-DM1; Kadcyla) in the aforementioned patient population. The FDA’s decision followed results from the trial that were simultaneously presented during a Presidential Symposium at the European Society of Medical Oncology (ESMO) 2025 Congress and published in The New England Journal of Medicine.2,3

The 3-year IDFS was 92.4% (95% CI, 89.7%-94.4%) with T-DXd and 83.7% (95% CI, 80.2%-86.7%) with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P <.0001); 6.2% and 12.5% of patients in each respective group experienced an IDFS event. The IDFS benefit with T-DXd was consistent across all prespecified subgroups, including patients 65 years or older (HR, 0.31; 95% CI, 0.11-0.86), those with hormone receptor–negative status (HR, 0.37; 95% CI, 0.22-0.65), and those who received sequential radiotherapy (HR, 0.35; 95% CI, 0.19-0.64). Notably, the first IDFS event was distant recurrence in 42 patients who received T-DXd and 77 who received T-DM1, with CNS recurrences in 17 and 25, respectively.

The 3-year DFS was 92.3% (95% CI, 89.5%-94.3%) with T-DXd and 83.5% (95% CI, 79.9%-86.4%) with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P <.0001), with DFS events observed in 6.4% vs 12.6%, respectively. The 3-year distant recurrence-free interval (DRFI) was 93.9% (95% CI, 91.4%-95.7%) vs 86.1% (95% CI, 82.5%-89.1%), respectively (HR, 0.49; 95% CI, 0.34-0.71); the 3-year brain metastasis-free interval (BMFI) rate was 97.6% (95% CI, 97.6%-98.5%) vs 95.8% (95% CI, 93.6%-97.2%), respectively (HR, 0.64; 95% CI, 0.35-1.15). Additionally, at 2.9% maturity, the 3-year overall survival was 97.4% (95% CI, 95.8%-98.4%) vs 95.7% (95% CI, 93.5%-97.2%), respectively (HR, 0.61; 95% CI, 0.34-1.10).

“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,” stated Susan Galbraith, executive vice president of Oncology Hematology R&D at AstraZeneca, in the press release.1 “This breakthrough therapy designation highlights the impressive clinical benefit of [trastuzumab deruxtecan] over the current standard of care and underscores its potential to become an important treatment option in the post-neoadjuvant setting.”

Patients in the DESTINY-Breast05 trial received either intravenous T-DXd at 5.4 mg/kg every 3 weeks for 14 cycles or intravenous T-DM1 at 3.6 mg/kg every 3 weeks for 14 cycles. Eligible patients in the trial had residual invasive disease in the breast and/or axillary nodes after neoadjuvant chemotherapy with HER2-directed therapy, high-risk disease, centrally confirmed HER2-positive early breast cancer, and an ECOG performance status of 0 or 1.

The primary end point was IDFS. Secondary end points included DFS, which was a key end point, as well as OS, DRFI, BMFI, and safety.

Overall, treatment-emergent adverse events (TEAEs) occurred in 99.5% and 98.4% of each group, with grade 3 or higher events occurring in 50.6% of the T-DXd group and 51.9% of the T-DM1 group. In the T-DXd arm, TEAEs were associated with treatment discontinuation, dose reductions, and death in 17.9%, 26.4%, and 0.4%, respectively. Causes of death included interstitial lung disease (ILD)/pneumonitis and respiratory tract infection. AEs of special interest were ILD/pneumonitis and left ventricular dysfunction, which, respectively, occurred in 9.6% and 2.9% of the T-DXd arm.

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://shorturl.at/XUZTa
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. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA1.
3. Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. Published online December 10, 2025. doi:10.1056/NEJMoa2514661