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<p>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<sup>+</sup>HER2<sup>−</sup> 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<sup>−1</sup> 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<sup>+</sup>HER2<sup>−</sup> 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: <a href="https://clinicaltrials.gov/study/NCT04965766?term=NCT04965766&amp;rank=1">NCT04965766</a>).</p>

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Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月4日

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  • Barbara Pistilli,
  • Fernanda Mosele,
  • Noemie Corcos,
  • Livia Pierotti,
  • Yoann Pradat,
  • Loic Le Bescond,
  • Magali Lacroix-Triki,
  • Ghada Nachabeh,
  • Alexia Alfaro,
  • Cyril Catelain,
  • Bastien Job,
  • Fathia Mami-Chouaib,
  • Severine Badel,
  • Françoise Farace,
  • Marianne Oulhen,
  • Patricia Kannouche,
  • Diep T. N. Tran,
  • Nathalie Droin,
  • Cecile Vicier,
  • Jean Sebastien Frenel,
  • Veronique D’Hondt,
  • Florence Dalenc,
  • Thomas Bachelot,
  • Agnes Ducoulombier,
  • Marc Antoine Benderra,
  • Delphine Loirat,
  • Didier Mayeur,
  • Elise Deluche,
  • Jacqueline Deneuve,
  • Rasha Cheikh-Hussin,
  • Pierre Guyader,
  • Nicolas Signolle,
  • Karine Godefroy,
  • Hugues Talbot,
  • Maria Vakalopoulou,
  • Stergios Christodoulidis,
  • Elsa Bernard,
  • Yves Koudou,
  • Andrea Sporchia,
  • Fumitaka Suto,
  • Lie Li,
  • David W. Sternberg,
  • Stefan Michiels,
  • Fabrice André,
  • Dalila Sellami,
  • Guillaume Montagnac

摘要

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).