DESTINY-Breast04 Compared T-DXd with TPC in Patients with HER2-Low Breast Cancer

Approximately 55% of metastatic breast cancers that are formally classified as HER2-negative express low levels of HER2 (immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization according to American Society of Clinical Oncology/College of American Pathologists 2018 guidelines) and are not typically considered candidates for therapy with HER2-targeting monoclonal antibodies or antibody–drug conjugates. In the DESTINY phase 1 trial, T-DXd, an HER2-binding antibody–drug conjugate, showed promising efficacy in patients with low levels of HER2 expression (HER2-low disease) metastatic breast cancer.

Designed by taking into account previous encouraging data, DESTINY-Breast04 (NCT03734029) is the first randomized, multicenter, open-label, phase 3 trial comparing T-DXd with TPC. In this trial, 557 patients with metastatic breast cancer with centrally confirmed HER2-low disease were randomly assigned to receive T-DXd administered at 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary end point was progression-free survival (PFS) in patients with hormone receptor (HR)-positive metastatic breast cancer, as evaluated by blinded independent central review (BICR). PFS by BICR in the full analysis set (HR-positive or HR-negative) and overall survival (OS) in patients with HR-positive metastatic breast cancer and in the full analysis set were key secondary end points. Objective response rate, duration of response, safety, and an exploratory study of patients with HR-negative metastatic breast cancer were among the other end points.

T-DXd and TPC were allocated to 373 and 184 patients (88.7% and 88.6% HR-positive metastatic breast cancer), respectively. Median follow-up was 18.4 months (95% confidence interval [CI], 17.9-19.1). Median treatment length was 8.2 months (range, 0.2-33.3) with T-DXd versus 3.5 months (range, 0.3-17.6) with TPC. The study’s primary end point was met: median PFS was clearly longer in T-DXd–treated HR-positive patients at 10.1 months (95% CI, 9.5-11.5) versus those receiving TPC at 5.4 months (95% CI, 4.4-7.1), corresponding to a hazard ratio of 0.51 (95% CI, 0.40-0.64; P <.0001). Median OS was also significantly more prolonged in the T-DXd versus TPC arm: 23.9 months (95% CI, 20.8-24.8) versus 17.5 months (95% CI, 15.2-22.4), which was associated with a hazard ratio of 0.64 (95% CI, 0.48-0.86; P <. 0028). Similar results were reported for median PFS and OS in the full analysis set patient population, demonstrating superiority of T-DXd. A total of 52.6% of patients receiving T-DXd had grade ≥3 treatment-emergent adverse events compared with 67.4% of patients receiving TPC. In addition, 45 patients had drug-related interstitial lung disease/pneumonitis with T-DXd treatment versus 1 patient with TPC.

DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer that has shown a statistically significant and clinically meaningful improvement in PFS and OS when compared with standard-of-care treatment, irrespective of HR status, with a generally tolerable safety profile.


Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40:17. Abstract LBA3.

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