Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study

作者：Komal Jhaveri, Elgene Lim, Rinath Jeselsohn, X. Cynthia, Erika Hamilton, Cynthia R. Osborne, Manali Ajay Bhave, Peter A. Kaufman, J. Thaddeus Beck, Luís Manso, Ritesh Parajuli, Hwei-Chung Wang, Jessica J. Tao, Seock‐Ah Im, Kathleen Harnden, Kan Yonemori, Ajay Dhakal, Patrick Neven, Philippe Aftimos, Jean‐Yves Pierga, Yen‐Shen Lu, Timothy Larson, Yolanda Jerez, Kostandinos Sideras, Joohyuk Sohn, Sung‐Bae Kim, Cristina Saura, Aditya Bardia, Sarah Sammons, Francesca Bacchion, Yujia Li, Eunice Yuen, Shawn T. Estrem, Vanessa Rodrik-Outmezguine, Bastien Nguyen, Roohi Ismail‐Khan, Lillian M. Smyth, Muralidhar Beeram · 发表于：Journal of Clinical Oncology · 年份：2024 · DOI：10.1200/jco.23.02733 · 被引用次数：42 · 研究领域：Advanced Breast Cancer Therapies、HER2/EGFR in Cancer Research、Breast Cancer Treatment Studies

PURPOSE Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1- mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2–negative (HER2–) ABC experience is reported here. METHODS An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label. RESULTS Overall, 262 patients with ER+/HER2– ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (...