Practice-changing results of T-DXd in HER2-low breast cancer 

Trastuzumab deruxtecan (T-DXd) outperformed therapy by physician’s choice in patients with HER2-low unresectable or metastatic breast cancer who had received 1 or 2 previous lines of chemotherapy, in the DESTINY-Breast04 trial. T-DXd is the first HER2-targeted therapy to outperform the standard-of-care in terms of progression-free survival (PFS) and overall survival (OS) in the hard-to-treat HER2-low breast cancer population. 

“The HER2-status of patients with breast cancer is defined by immunohistochemistry (IHC) scores, with HER2-low being defined as having an IHC score of 1+ or 2+ with in situ hybridisation (ISH)-negative status,” explained Prof. Shanu Modi (Memorial Sloan Kettering Cancer Center, NY, USA). The options for these patients, especially in later lines of therapy, are limited [1]. The DESTINY-Breast04 trial (NCT03734029) randomised patients with HER2-low unresectable or metastatic breast cancer to T-DXd (n=373) or chemotherapy by physician’s choice (n=184) [2]. Patients had received 1 or 2 prior lines of chemotherapy and were refractory to endocrine therapy if they were HR-positive. PFS by independent central review was the primary endpoint of this study. Of note, approximately 90% of the patients were HR-positive, whereas 10% were HR-negative.

The median PFS of patients on T-DXd was superior to that of patients on chemotherapy (9.9 vs 5.1 months; HR 0.50; P<0.0001) and the same was true for the HR-positive subset of patients (10.1 vs 5.4 months; HR 0.51; P<0.0001; see Figure). Moreover, the median OS favoured T-DXd over chemotherapy in the general population (23.4 vs 16.8 months; HR 0.64; P=0.0010) and in the HR-positive subset of patients (23.9 vs 17.5 months; HR 0.64; P=0.0028). An exploratory analysis displayed that HR-negative patients are likely to benefit from T-DXd as well in terms of PFS (8.5 vs 2.9 months; HR 0.46) and OS (18.2 vs 8.3 months; HR 0.48). The results were consistent across subgroups.

Figure: Progression-free survival of HR-positive patients versus the full analysis set [2]



T-DXd, Trastuzumab deruxtecan; TPC, chemotherapy by physician’s choice; mPFS, median progression-free survival; mo, months.

The safety analysis did not reveal new safety issues. Neutropenia was more frequently observed in the chemotherapy arm, whereas nausea was more often reported in the T-DXd arm. Prof. Modi added that the cases of nausea were mostly grade 1 or 2 events, which should be manageable in practice. In total, 16% of the patients in the T-DXd arm experienced treatment-emergent adverse events that led to dose discontinuation, compared with 8% in the chemotherapy arm. ILD/pneumonitis occurred in 12.1% of the patients on T-DXd: 3.5% grade 1, 6.5% grade 2, 1.3% grade 3, and 0.8% grade 5 events. Decreased left ventricular ejection fraction occurred in 4.3% of the patients on T-DXd: 0.3% grade 1, 3.8% grade 2, and 0.3% grade 3.

“T-DXd is the first HER2-targeted therapy to demonstrate improved efficacy in HER2-low metastatic breast cancer, establishing a new standard-of-care for this population, which covers approximately 50% of the total metastatic breast cancer population,” concluded Dr Modi.

1. Tarantino P, et al. J Clin Oncol. 2020;38(17):1951–1962.
2. Modi S, 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. LBA3, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.

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Posted on 5 August, 202229 February, 2024