Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer

作者：Mario Campone, Michelino De Laurentiis, Komal Jhaveri, Xichun Hu, Sylvain Ladoire, Anne Patsouris, Claudio Zamagni, Jiuwei Cui, Marina Elena Cazzaniga, Timuçin Çil, Katarzyna J. Jerzak, C.S. Fuentes, Tetsuhiro Yoshinami, Álvaro Rodríguez-Lescure, Ahmet Sezer, Andrea Fontana, Valentina Guarneri, Andrea Molckovsky, Marie‐Ange Mouret‐Reynier, Umut Demırcı, Yongqiang Zhang, Olga Valota, Dongrui R. Lu, Marcella Martignoni, Janaki Parameswaran, Xin Zhi, Erika Hamilton · 发表于：New England Journal of Medicine · 年份：2025 · DOI：10.1056/nejmoa2505725 · 被引用次数：120 · 研究领域：Protein Degradation and Inhibitors、HER2/EGFR in Cancer Research、Advanced Breast Cancer Therapies

BackgroundVepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin–proteasome system. MethodsIn this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan–Meier methods and hazard ratios with a stratified Cox proportional-hazards model. Research Summary Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Breast Cancer ResultsA total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progres...