ABSTRACT

Antibody–drug conjugates have shown impressive clinical outcomes, particularly in metastatic breast cancer, but biomarkers to predict response and resistance remain unidentified. Here we report the results of ICARUS-BREAST01, a phase 2 study evaluating efficacy, safety and biomarkers of response and resistance to patritumab deruxtecan (HER3-DXd), in patients with HR+HER2− metastatic breast cancer, who previously progressed on CDK4/6 inhibitors and one line of chemotherapy.
From May 2021 to June 2023, 99 patients were enrolled to receive HER3-DXd 5.6 mg kg−1 intravenously every 3 weeks. The study met its primary endpoint, showing an overall response rate of 53.5% (90% confidence interval [44.8– 62.1%]). The most frequent adverse events were fatigue (83%), nausea (75%), diarrhea (53%) and alopecia (40%). Exploratory biomarker analysis of baseline tumor samples suggested preliminary associations between overall response rate and both HER3 spatial distribution and absence of estrogen receptor 1 (ESR1) mutations, as well as between progression-free
survival and HER3 expression, pending further validation. Analysis of on-treatment tumor samples showed that treatment efficacy seems to be associated with antibody–drug conjugate intratumoral distribution and interferon response. Overall, HER3-DXd showed promising activity and
manageable tolerability in patients with HR+HER2− metastatic breast cancer who progressed on CDK4/6 inhibitors. These findings highlight the need for larger trials to define HER3-DXd efficacy relative to other drugs, including antibody–drug conjugates (ClinicalTrials.gov Identifier: NCT04965766).