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.
Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
ISSN
1527-7755
Date Issued
2024-09-06
Author(s)
Jhaveri, Komal L
Lim, Elgene
Jeselsohn, Rinath
Ma, Cynthia X
Hamilton, Erika P
Osborne, Cynthia
Bhave, Manali
Kaufman, Peter A
Beck, J Thaddeus
Manso Sanchez, Luis
Parajuli, Ritesh
Wang, Hwei-Chung
Tao, Jessica J
Im, Seock-Ah
Harnden, Kathleen
Yonemori, Kan
Dhakal, Ajay
Neven, Patrick
Aftimos, Philippe
Pierga, Jean-Yves
Larson, Timothy
Jerez, Yolanda
Sideras, Kostandinos
Sohn, Joohyuk
Kim, Sung-Bae
Saura, Cristina
Bardia, Aditya
Sammons, Sarah L
Bacchion, Francesca
Li, Yujia
Yuen, Eunice
Estrem, Shawn T
Rodrik-Outmezguine, Vanessa
Nguyen, Bastien
Ismail-Khan, Roohi
Smyth, Lillian
Beeram, Muralidhar
Abstract
Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in 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.
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.
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 (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of mutation status.
Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.
SDGs
Type
journal article