On May 15, 2026, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (T-DXd) (Enhertu) for two separate indications for the treatment of adult patients with HER2-positive early-stage breast cancer.
The first indication is for the neoadjuvant treatment of adult patients with HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH+]) stage II or III breast cancer, as determined by an FDA-authorized test, followed by treatment with a taxane, trastuzumab, and pertuzumab (THP). The second indication is for the treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease after neoadjuvant HER2-targeted treatment.
The FDA also simultaneously approved two companion diagnostic devices, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, both of which are for identifying HER2-positive (IHC 3+ or ISH+) patients for treatment with T-DXd, consistent with the approved drug labeling.
Efficacy and Safety
Efficacy of T-DXd followed by THP was evaluated in the randomized, three-arm, open-label, multicenter DESTINY-Breast11 trial (ClinicalTrials.gov identifier NCT05113251), which enrolled 927 adult patients with HER2-positive, high-risk, early-stage breast cancer. Patients were randomly assigned (1:1:1) to receive eight cycles of neoadjuvant treatment with either T-DXd for four cycles followed by THP (n = 321) for four cycles, or doxorubicin and cyclophosphamide for four cycles followed by THP (n = 320), or an additional investigational therapy (n = 286) for eight cycles, until completion of planned therapy, or disease progression.
The major efficacy outcome measure was the centrally assessed pathological complete response rate, defined as the absence of invasive cancer in the breast and axillary lymph nodes following surgery. The pathological complete response rate was 67.3% (95% confidence interval [CI] = 61.9%–72.4%) in the T-DXd plus THP arm and 56.3% (95% CI = 50.6%–61.8%) in the doxorubicin and cyclophosphamide plus THP arm (P = .003), which was statistically significant. However, the secondary endpoints of event-free survival and overall survival were not statistically controlled or powered. The results from the adjuvant trial, DESTINY-Breast05, provided supportive evidence for the neoadjuvant indication.
Efficacy of T-DXd for adjuvant treatment was evaluated in DESTINY-Breast05 (ClinicalTrials.gov identifier NCT04622319), a randomized, two-arm, open-label, multicenter trial that enrolled 1,635 adults with HER2-positive breast cancer with residual invasive disease after neoadjuvant therapy. Patients were randomly assigned (1:1) to receive either T-DXd (n = 818), or trastuzumab emtansine (T-DM1) (n = 817), for a maximum of 14 cycles, or until disease recurrence or unacceptable toxicity.
The major efficacy outcome measure was invasive disease-free survival, defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional efficacy outcome measures included disease-free survival and overall survival. The 3-year invasive disease-free survival rate was 92.4% (95% CI = 89.7%–94.4%) in the T-DXd arm and 83.7% (95% CI = 80.2%–86.7%) in the T-DM1 arm (hazard ratio [HR] = 0.47, 95% CI = 0.34–0.66; P < .0001). The 3-year disease-free survival rate was 92.3% (95% CI = 89.5%–94.3%) and 83.5% (95% CI = 79.9%–86.4%) in the respective arms (HR = 0.47, 95% CI = 0.34–0.66; P < .0001). At the time of the invasive disease-free survival analysis, a total of 47 patients (2.9%) had died across both study arms.
The prescribing information includes a boxed warning for interstitial lung disease and pneumonitis, and warnings and precautions for neutropenia and left ventricular dysfunction.
Recommended Dosage
The recommended dose of T-DXd for neoadjuvant treatment is 5.4 mg/kg every 3 weeks for four cycles, followed by the THP regimen for four cycles. The recommended dose of T-DXd for adjuvant treatment is 5.4 mg/kg every 3 weeks for a maximum of 14 cycles unless there is disease recurrence or unacceptable toxicity.
Both reviews were conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology drugs among international partners. For these reviews, FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, Switzerland’s Swissmedic, Singapore’s Health Sciences Authority, the United Kingdom’s Medicines and Healthcare products Regulatory Agency, and the Israel Ministry of Health. The applications may still be under review at the other regulatory agencies.
These reviews used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
The application for the neoadjuvant indication was granted standard review and the application for the adjuvant indication was granted a Priority Review. T-DXd received Breakthrough Designation status for the adjuvant indication.
