FDA Alert

FDA Approves T-DXd for Neoadjuvant and Adjuvant HER2-Positive Early-Stage Breast Cancer

Anthony Calabro, MA

Key Highlights

  • The FDA approved Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) for 2 indications in HER2-positive early-stage breast cancer.
  • The neoadjuvant indication is for T-DXd, followed by taxane, trastuzumab, and pertuzumab in adults with HER2-positive stage II or III breast cancer.
  • The adjuvant indication is for patients with residual invasive disease after neoadjuvant trastuzumab, with or without pertuzumab, and taxane-based therapy.
  • The FDA also approved 2 companion diagnostic devices to identify HER2-positive patients eligible for T-DXd.

On May 15, the FDA approved Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd; Daiichi Sankyo, Inc) for 2 separate indications in adults with HER2-positive early-stage breast cancer. T-DXd, followed by taxane, trastuzumab, and pertuzumab, is approved for neoadjuvant treatment of adults with HER2-positive (IHC 3+ or ISH+) stage II or III breast cancer, as determined by an FDA-authorized test. T-DXd is also approved for adjuvant treatment of adults with HER2-positive breast cancer who have residual invasive disease after neoadjuvant treatment with trastuzumab, with or without pertuzumab, and taxane-based treatment.

The neoadjuvant approval was based on DESTINY-Breast11, a randomized, 3-arm, open-label, multicenter trial of 927 adults with HER2-positive, high-risk, early-stage breast cancer. Patients received T-DXd for 4 cycles, followed by taxane, trastuzumab, and pertuzumab; doxorubicin and cyclophosphamide, followed by taxane, trastuzumab, and pertuzumab; or an additional investigational therapy. The pathological complete response rate was 67.3% with T-DXd, followed by taxane, trastuzumab, and pertuzumab, vs 56.3% with doxorubicin and cyclophosphamide, followed by taxane, trastuzumab, and pertuzumab (P = .003). Event-free survival and overall survival were secondary endpoints but were not statistically controlled or powered.

The adjuvant approval was based on DESTINY-Breast05, a randomized, 2-arm, open-label, multicenter trial of 1,635 adults with residual invasive disease after neoadjuvant therapy. The 3-year invasive disease-free survival rate was 92.4% with T-DXd vs 83.7% with trastuzumab emtansine (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). At the time of the analysis, 47 patients, or 2.9%, had died across both study arms.

The prescribing information includes a boxed warning for interstitial lung disease and pneumonitis, as well as warnings and precautions for neutropenia and left ventricular dysfunction.

For neoadjuvant treatment, the recommended dose is 5.4 mg/kg every 3 weeks for 4 cycles, followed by taxane, trastuzumab, and pertuzumab for 4 cycles. For adjuvant treatment, the recommended dose is 5.4 mg/kg every 3 weeks for a maximum of 14 cycles, unless disease recurrence or unacceptable toxicity occurs.

Reference
US Food and Drug Administration. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. Accessed on May 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage