T-DXd Versus T-DM1 in HER2+ MBC: Results of DESTINY-Breast03

Virginia Kaklamani, MD, DSc, discusses data from the following presentation:

Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. (Cortes, ESMO 2021, Abstract LBA1)

• T-DXd is a HER2-targeting antibody-drug conjugate approved for patients with advanced HER2 (human epidermal growth factor receptor 2)–positive metastatic breast cancer (mBC) based on the results from DESTINY-Breast01 (NCT03248492). This is the first report of DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized phase 3 study comparing the efficacy and safety of T-DXd vs T-DM1 in patients with HER2+ mBC previously treated with trastuzumab and taxane. This is the first reported randomized study of T-DXd in breast cancer.
  • Patients were randomized 1:1.
  • The primary end point was progression-free survival (PFS) by blinded independent central review (BICR).
  • Secondary end points include overall survival (OS), objective response rate (ORR), duration of response, PFS by investigator, and safety.
  • As of May 21, 2021, 524 patients were randomized. Median age was 54 years (range, 20-83).
  • Median treatment duration was 14.3 months (range, 0.7-29.8) with T-DXd vs 6.9 months (range, 0.7-25.1) with T-DM1.
• The hazard ratio (HR) for PFS was 0.2840 (P = 7.8 x 10-22); median PFS not reached for T-DXd vs 6.8 months for T-DM1.
• The estimated 12-month OS event rates were 94.1% (95% CI, 90.3-96.4) for T-DXd and 85.9% (95% CI, 80.9-89.7) for T-DM1; HR: 0.5546 (95% CI, 0.3587-0.8576; P = .007172 did not cross prespecified boundary for significance).
• Similar rates of treatment-emergent adverse events were observed. No drug-related deaths occurred in either arm. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.5% of patients with T-DXd (most [9.7%] grade 1/2; 0 grade 4/5) vs 1.9% with T-DM1 (all grade 1/2).
• T-DXd demonstrated a highly statistically significant and clinically meaningful improvement in PFS vs T-DM1 in patients previously treated with trastuzumab and taxane for HER2+ mBC. These data confirm that T-DXd (trastuzumab deruxtecan) is tolerable with manageable toxicity and a significant improvement in ILD profile vs studies performed in more heavily pretreated patients. This study will lead to a paradigm shift in the treatment of HER2+ mBC.