Both adjuvant therapy with trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) have shown to improve progression-free survival in patients with HER2-positive, metastatic breast cancer. In a head-to-head comparison, T-DXd proved to outperform T-DM1.

T-DXd is a HER2-targeting antibody-drug conjugate for the treatment of previously treated patients with advanced, HER2-positive, metastatic breast cancer, based on the DESTINY-Breast01 study (NCT03248492) [1]. Before, the EMILIA trial (NCT00829166) showed T-DM1 to be beneficial in this population [2]. In the randomized, multicentre, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), the efficacy and safety of T-DXd and T-DM1 are evaluated in patients with HER2-positive, metastatic breast cancer previously treated with trastuzumab and taxane. In the primary analysis, T-DXd demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS) versus T-DM1 [3]. Now, Dr. Sara Hurvitz (University of California, CA, USA) presented results from subgroup analyses of DESTINY-Breast03, including patients with brain metastases [4]. In DESTINY-Breast03, 524 patients with unresectable or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 every 3 weeks. The primary endpoint was PFS. T-DXd demonstrated superior PFS versus T-DM1 (HR 0.28; P<0.0001); median PFS was not reached for T-DXd versus 6.8 months for T-DM1; 12-month PFS rate was 79.7% versus 34.2%, respectively. Median PFS favoured T-DXd over T-DM1 independent of HR status, prior trastuzumab treatment, and number of prior lines of therapy. Overall, confirmed ORR for T-DXd was 79.7% (16.1% CR, 63.6% PR) versus 34.2% (8.2% CR, 25.5% PR) for T-DM1. For patients with stable brain metastases at baseline (n=82), median PFS was 15.0 months for T-DXd versus 3.0 months for T-DM1 (HR 0.25). In this subgroup, ORR was 67.4% (4.7% CR, 62.8% PR) for T-DXd versus 20.5% (0 CR, 20.5% PR) for T-DM1. In addition, intracranial response rate in these patients was 63.9% (27.8% CR, 36.1% PR) for T-DXd versus 33.4% (2.8% CR, 30.6% PR) for T-DM1. Overall, the safety profile of T-DXd was manageable and comparable with its known safety profile. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 27 (10.5%) patients treated with T-DXd and 5 (1.9%) patients treated with T-DM1 overall, with no grade 4 or 5 events. “DESTINY-Breast03 met its primary endpoint with T-DXd demonstrating a superior PFS versus T-DM1. Consistent PFS and ORR benefits with T-DXd versus T-DM1 were observed across subgroups in patients with HER2-positive, metastatic breast cancer previously treated with trastuzumab and taxane, including in patients with brain metastases,” concluded Dr. Hurvitz. “These data support T-DXd becoming the standard of care for second-line treatment in HER2-positive, metastatic breast cancer.”

  1. Modi S, et al. N Engl J Med 2020;382:610-621.
  2. Verma S, et al. N Engl J Med 2012;367:1783-1791.
  3. Cortés J, et al. Ann Oncol. 2021;32 (suppl_5):1283-1346, LBA1
  4. Hurvitz S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. SABCS 2021 Virtual Meeting, abstract GS3-01.

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