FDA Approves T-DXd in 2 Indications for HER2+ Early Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as neoadjuvant or adjuvant treatment for adult patients with HER2-positive early breast cancer.¹

For patients in the neoadjuvant setting, T-DXd was approved following a taxane, trastuzumab (T-DM1; Herceptin), and pertuzumab (THP) for those with HER2-positive stage II or III breast cancer. In the adjuvant setting, T-DXd was approved for those with HER2-positive breast cancer who have residual invasive disease following T-DM1 with or without pertuzumab and a taxane-based treatment.

The approval is based on results from the phase 3 DESTINY-Breast11 trial (NCT05113251), which assessed if T-DXd with or without THP vs dose-dense doxorubicin plus cyclophosphamide (ddAC) followed by THP would elicit a response, and the phase 3 DESTINY-Breast05 trial (NCT04622319) assessing T-DXd vs T-DM1.^2,3

The approval also noted a warning for interstitial lung disease and embryo-fetal toxicity. There were no contraindications.

“HER2-positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence for patients as early as possible to achieve the best long-term outcomes. The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery. These 2 new indications in HER2-positive early breast cancer will evolve how we treat patients in these settings and support trastuzumab deruxtecan as a potential new standard of care in early-stage disease,” Shanu Modi, MD, attending physician at Memorial Sloan Kettering Cancer Center, said in the press release.

The DESTINY-Breast11 Trial: Redefining Neoadjuvant Standards

The trial randomly assigned 927 patients to receive either T-DXd monotherapy (8 cycles), T-DXd followed by THP (T-DXd-THP; 4 cycles each), or the standard-of-care (SOC) control of ddAC followed by THP (ddAC-THP). Eligible patients had high-risk disease, defined as clinical stage T3 or greater with N0 status, or any T stage with N1-3 node-positive involvement.

Superior Pathologic Complete Response Rates

The primary end point of the trial was pathologic complete response (pCR) in the intent-to-treat population. Neoadjuvant T-DXd followed by THP demonstrated a statistically significant and clinically meaningful improvement in pCR rates compared with the anthracycline-containing SOC:

• T-DXd-THP: 67.3%
• ddAC-THP: 56.3%

The absolute pCR rate difference was 11.2% (95% CI, 4.0%-18.3%; P = .003). Subgroup analyses further highlighted the efficacy of the T-DXd-THP regimen across hormone receptor (HR) statuses:

• HR-positive: 61.4% for T-DXd-THP vs 52.3% for ddAC-THP
• HR-negative: 83.1% for T-DXd-THP vs 67.1% for ddAC-THP

While the T-DXd monotherapy arm was closed early by the Independent Data Monitoring Committee (IDMC)—partly due to a lower pCR rate (43.0%) compared with the other arms—it still offered a viable non-anthracycline option for specific clinical scenarios.

A Shift in the Safety Paradigm

For many clinicians, the most compelling aspect of the DESTINY-Breast11 data is the improved safety profile of T-DXd-based regimens over anthracycline-taxane sequences. Standard anthracycline regimens are notoriously linked to cardiotoxicity and secondary leukemias.

DESTINY-Breast11 revealed substantially lower rates of severe adverse events (AEs) with T-DXd:

• Grade 3 or higher AEs: 37.5% for T-DXd-THP and 22.6% for T-DXd monotherapy, compared to 55.8% for ddAC-THP
• Serious AEs: Approximately 10% for both T-DXd arms vs 20.2% for ddAC-THP
• Cardiotoxicity: All-grade left-ventricular dysfunction was notably lower in the T-DXd-THP (1.3%) and T-DXd monotherapy (0.7%) arms compared to the ddAC-THP arm (6.1%)

Managing Interstitial Lung Disease

As with all T-DXd applications, interstitial lung disease (ILD) remains a key safety consideration. In DESTINY-Breast11, all-grade adjudicated drug-related ILD/pneumonitis rates were low and balanced across all 3 arms: 4.9% for T-DXd, 4.4% for T-DXd-THP, and 5.1% for ddAC-THP. Clinicians are advised to maintain rigorous monitoring, including high-resolution CT scans every 6 weeks during neoadjuvant treatment, to ensure early detection and management.

Clinical Implications for Patients Who Are High Risk

Achieving pCR is a well-established prognostic indicator for event-free survival (EFS) in HER2-positive breast cancer. Early EFS data from the trial favored the T-DXd-THP arm, with a hazard ratio of 0.56 (95% CI, 0.26–1.17) compared with SOC.

DESTINY-Breast05 Trial Results

In this trial, there was a 53% reduction in the risk of invasive disease or death between the T-DXd and T-DM1 arms (HR, 0.47; 95% CI, 0.34-0.66; P <.0001). The 3-year invasive disease-free survival (IDFS) rates were 92.4% (95% CI, 89.7%-94.4%) vs 83.7% (95% CI, 80.2%-86.7%), respectively.

A disease-free survival (DFS) benefit was noted with T-DXd vs T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P <.0001). The 3-year DFS rates were 92.3% (95% CI, 89.5%-94.3%) vs 83.5% (95% CI, 79.9%-86.4%), respectively.

DESTINY-BREST05 Safety Results

Between the T-DXd and T-DM1 arms, the most commonly reported treatment-emergent adverse effects were nausea (71.3%; 29.3%), constipation (32.0%; 16.2%), and decreased neutrophil counts (31.6%; 14.4%).

ILD between the T-DXd and T-DM1 arms were 9.6% vs 1.6% for any-grade, 2.0% vs 1.0% for grade 1, 6.5% vs 0.6% for grade 2, 0.9% vs 0% for grade 3, 0% vs 0% for grade 4, and 0.2% vs 0% for grade 5.

The FDA previously accepted a supplemental biologics license application for T-DXd plus THP in October 2025.³

References

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) approved in the US for two new indications for patients with HER2-positive early breast cancer. News release. AstraZeneca. May 15, 2026. Accessed May 18, 2026. https://tinyurl.com/3reyepfu
2. Harbeck N, Modi S, Pusztai L, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2026;37(2):166-179. doi:10.1016/j.annonc.2025.10.019
3. 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.
4. ENHERTU followed by THP supplemental biologics license application accepted in the U.S. for patients with high-risk HER2 positive early-stage breast cancer prior to surgery. News release. Daiichi Sankyo. October 1, 2025. Accessed April 23, 2026. https://tinyurl.com/bdbzdc7w