The FDA has granted approval for fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu) for two indications in HER2-positive early-stage breast cancer, expanding treatment options in both neoadjuvant and adjuvant settings. The approvals are based on clinical trial data demonstrating improved efficacy outcomes compared with standard-of-care regimens.

Clinical Takeaway

T-DXd is now approved for neoadjuvant treatment followed by taxane, trastuzumab, and pertuzumab (THP) in Stage II or III HER2-positive breast cancer, as well as for adjuvant treatment in patients with residual invasive disease following neoadjuvant therapy. The neoadjuvant approach achieved a 67.3% pathological complete response rate, while adjuvant treatment demonstrated a 3-year invasive disease-free survival rate of 92.4%.

Approved Indications

  • Neoadjuvant indication: T-DXd followed by THP for adult patients with HER2-positive Stage II or III breast cancer (IHC 3+ or ISH+)
  • Adjuvant indication: T-DXd for adult patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant treatment with trastuzumab and taxane-based therapy
  • Companion diagnostics: FDA approved PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH DNA Probe Cocktail for patient identification

Clinical Trial Evidence

  • DESTINY-Breast11 (Neoadjuvant):
    • Design: Randomized, three-arm, open-label trial (N=927)
    • Primary endpoint: Pathological complete response (pCR) rate
    • Key result: pCR rate of 67.3% (T-DXd-THP) vs 56.3% (ddAC-THP) (p=0.003)
  • DESTINY-Breast05 (Adjuvant):
    • Design: Randomized, two-arm, open-label trial (N=1,635)
    • Primary endpoint: Invasive disease-free survival (IDFS)
    • Key result: 3-year IDFS of 92.4% (T-DXd) vs 83.7% (T-DM1) (HR 0.47, p<0.0001)

Dosing and Administration

  • Neoadjuvant treatment: 5.4 mg/kg every 3 weeks for 4 cycles, followed by THP regimen for 4 cycles
  • Adjuvant treatment: 5.4 mg/kg every 3 weeks for a maximum of 14 cycles unless disease recurrence or unacceptable toxicity occurs

Safety Profile

  • Boxed Warning: Interstitial lung disease (ILD) and pneumonitis, which may be severe, life threatening, or fatal
  • Warnings and Precautions:
    • Neutropenia
    • Left ventricular dysfunction

Key Clinical Implications

✔ Significant improvement in pathological complete response rates in the neoadjuvant setting

✔ Superior invasive disease-free survival compared to T-DM1 in the adjuvant setting

✔ Companion diagnostics ensure appropriate patient selection for HER2-positive disease

✔ Requires careful monitoring for interstitial lung disease and cardiac function

✔ Adjuvant indication received breakthrough designation and priority review

Bottom Line

The dual FDA approval of T-DXd in early-stage HER2-positive breast cancer represents a paradigm shift in treatment approaches, offering clinicians evidence-based options for both neoadjuvant and adjuvant settings. The superior efficacy outcomes, particularly the 11% absolute improvement in pCR rates and the 53% reduction in risk of invasive disease recurrence, position T-DXd as a new standard of care consideration for appropriate patients.

Sources:

  • U.S. Food and Drug Administration. (2026). FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki for HER2-positive early-stage breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage