Patritumab deruxtecan in HR+/HER2- advanced breast cancer

Data from the ICARUS-BREAST01 phase 2 trial, recently published on Nature Medicine, showed promising activity and manageable tolerability of the antibody-drug conjugate patritumab deruxtecan (HER3-DXd) in patients with HR+/HER2− metastatic breast cancer who progressed on CDK4/6 inhibitors and one line of chemotherapy.

Reliable biomarkers for identifying patients most likely to obtain clinical benefit from antibody-drug conjugate therapies remain an unmet medical need and the mechanisms of action of antibody-drug conjugates are still not well understood. Thus, ICARUS-BREAST01 study was designed to evaluate clinical efficacy, safety but also biomarkers of response and resistance to HER3-Dxd; 99 patients with HR+/HER2− metastatic breast cancer were enrolled to receive HER3-DXd 5.6 mg/kg intravenously every 3 weeks. Results showed a manageable tolerability and an overall response rate of 53.5%; 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 mutations, as well as between progression-free survival and HER3 expression. As authors point out, «findings generate a hypothesis on the mechanism of action of this antibody-drug conjugate, suggesting that target expression and spatial distribution, and antibody-drug conjugate intratumoral distribution, intracellular uptake and subsequent DNA damage, may influence treatment response». The aim of further studies, as researchers say, should be a definition of biomarkers «that will allow optimal patient selection for a given antibody-drug conjugate. Despite the challenges associated with serial sample collection and analysis, such studies are nevertheless important in providing a comprehensive understanding of the mechanisms of action of new antibody-drug conjugates».