Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial
Barbara Pistilli, M.F. Mosele, Noémie Corcos, Livia Pierotti, Yoann Pradat, Loïc Le Bescond, Magali Lacroix‐Triki, Ghada Nachabeh, Alexia Alfaro, Cyril Catelain, Bastien Job, Fathia Mami‐Chouaib, Séverine Badel, Françoise Farace, Marianne Oulhen, Patricia Kannouche, Diep Thi Ngoc Tran, Nathalie Droin, Cécile Vicier, Jean‐Sébastien Frenel, Véronique D’Hondt, Florence Dalenc, Thomas Bachelot, Agnès Ducoulombier, Marc Antoine Benderra, Delphine Loirat, Didier Mayeur, Élise Deluche, Jacqueline Deneuve, Rasha Cheikh-Hussin, P. Le Guyader, Nicolas Signolle, Karine Godefroy, Hugues Talbot, Maria Vakalopoulou, Stergios Christodoulidis, Elsa Bernard, Yves Akoli Koudou, Andrea Sporchia, Fumitaka Suto, Lie Li, David Sternberg, Stefan Michiels, Fabrice André, Dalila Sellami, Guillaume Montagnac
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 ). In this single-arm phase 2 trial in patients with HR+HER2− advanced breast cancer, treatment with the HER3-targeting antibody–drug conjugate paritumab deruxtecan led to encouraging objective response rates, and comprehensive exploratory analyses indicate potential biomarkers of response.