T-DXd outperforms T-DM1 in the second-line treatment of HER2+ metastatic breast cancer

February 2023 Cancer trials Andrea Enguita

Previously, trastuzumab deruxtecan (T-DXd ) demonstrated to significantly prolong the PFS compared to trastuzumab emtansine (T-DM1) in the second-line treatment of patients with HER2+ metastatic breast cancer. The updated results of the DESTINY-Breast03 were recently published in The Lancet. With longer follow-up, it becomes clear that this PFS benefit obtained with T-DXd over T-DM1 also translates into a significant overall survival (OS) benefit, reaffirming T-DXd as the standard of care in this setting.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 15-20% of breast cancers. After the failure of first-line treatment, the standard second-line treatment for patients with HER2+ metastatic breast cancer consisted of the antibody-drug conjugate T-DM1, linking a humanised anti-HER2 monoclonal antibody to a potent cytotoxic payload. Recently, however, the DESTINY-Breast03 data challenged this standard of care by showing a 78.5% PFS rate at one year with T-DXd as compared to 34.1% with T-DM1. After two years of follow-up, the prespecified second OS interim analysis reports updated OS, efficacy, and safety results.

Study findings

The phase 3 DESTINY-Breast03 trial included adult patients with HER2+ unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, with an ECOG performance status of 0-1, and at least one measurable lesion per RECIST v1.1. In total, 524 patients were randomly assigned (1:1) to receive 5.4 mg/kg T-DXd (n=261) or 3.6 mg/kg T-DM1 (n=263). The primary endpoint was PFS, with OS as a key secondary endpoint.

After a median follow-up of 28.4 months with T-DXd and 26.5 months with T-DMI, median PFS was 28.8 vs. 6.8 months with T-DXd and T-DM1, respectively (HR[95%CI]: 0.33[0.26–0.43]; p<0.0001). Median OS was not reached, with 72 (28%) vs. 97 (37%) OS events in the T-DXd and T-DMI arms, respectively (HR[95%CI]: 0.64[0.47-0.87]; p=0.0037). This translates into a 12-month OS rate of 94.1% vs. 86.0% with T-DXd and T-DM1, respectively (77.4 vs. 69.9% at 24 months). The number of grade ≥3 treatment-emergent adverse events was similar in patients who received T-DXd vs. T-DM1 (56% vs. 52%). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 15% vs. 3% of patients treated T-DXd vs. T-DM1, with no grade 4 or 5 events in either group.

The updated results of DESTINY-Breast03 solidify the PFS and OS superiority of T-DXd over T-DM1 in the second line treatment of HER2+ metastatic breast cancer patients. Together with the manageable safety profile of T-DXd, these results confirm T-DXd as the standard of care in the second-line setting.


Hurvitz SA, Hegg R, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-17.