HER2 Expression Impacts Trastuzumab Deruxtecan Efficacy in Breast Cancer

Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) that delivers a cytotoxic topoisomerase 1 (TOP1) inhibitor to HER2-expressing cells, has been shown to provide clinical benefit to patients with metastatic breast cancer who have been previously treated with anti-HER2–based therapies. Given that the efficacy of ADCs does not always correspond to levels of target antigen expression, Mosele and colleagues conducted a phase II trial (DAISY) to evaluate the efficacy of T-DXd in metastatic breast cancer with variable HER2 expression, in which patients with HER2-overexpressing (n = 72), HER2-low (n = 74), and HER2-nonexpressing (n = 40) metastatic breast cancer were treated with 5.4 mg kg⁻¹ T-DXd every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint of the study was confirmed objective response rate, and secondary endpoints were progression-free survival (PFS) and safety. Of the 177 patients included in the full analysis set, a confirmed objective response was observed in 70.6%, 37.5%, and 29.7% of patients with HER2-overexpressing, HER2-low, and HER2-nonexpressing tumors, respectively, and patients with HER2-overexpressing tumors displayed a higher likelihood of confirmed objective response versus those with HER2-low tumors. When compared with the cohort of patients with HER2-low tumors, the HER2-overexpressing cohort was associated with longer PFS, while the HER2-nonexpressing cohort was associated with a shorter PFS. Evaluation of safety indicated that adverse events were consistent with TOP1 inhibitor toxicity profiles. Exploratory analysis of HER2 expression patterns within the HER2-overexpressing cohort indicated that regions of low HER2 staining and moderate cell density were associated with a non–objective response. Moreover, T-DXd staining was strong in HER2-overexpressing tumors and minimal in HER2-nonexpressing tumors, although confirmed objective responses were observed in the HER2-nonexpressing cohort. Analysis of biopsies at resistance revealed instances of mutations in the DNA repair gene SLX4, as well as intratumoral uptake of T-DXd. Together, these findings demonstrate that HER2 expression influences T-DXd efficacy and support further clinical investigation of additional determinants of response and resistance.

Mosele F, Deluche E, Lusque A, Le Bescond L, Filleron T, Pradat Y, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med 2023;29:2110–20.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.