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

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 for Medical Oncology Congress 2025 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 central nervous system 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 postneoadjuvant 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 research and development 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 postneoadjuvant 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. Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA1.
3. Loibl S, Park YH, Shao Z, et al; DESTINY-Breast05 Trial Investigators. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. Published online December 10, 2025. doi:10.1056/NEJMoa2514661