Abstract P6-10-06: A preoperative window-of-opportunity study of imlunestrant in estrogen receptor-positive, HER2-negative early breast cancer: Results from the EMBER-2 study
Authors: Neven Patrick , Stahl Nicole , Vidal Maria , Martín Miguel , Harbeck Nadia , Kaufman Peter A. , Bidard Francois-Clement , Fasching Peter A. , Aftimos Philippe , Hamilton Erika , Carter Stacey , Schmid Peter , Wheatley Duncan , Bhave Manali , Hunt Kelly K. , Kulkarni Swati A. , Ismail-Khan Roohi , Karacsonyi Claudia , Estrem Shawn T. , Ozbek Umut , Nguyen Bastien , Ciruelos Eva 
Published: March 2023

Abstract
Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. In a phase 1 study, imlunestrant monotherapy showed favourable safety, pharmacokinetics (PK) and preliminary efficacy in heavily pre-treated ER-positive (ER+) advanced breast cancer patients (Jhaveri ASCO 2022). Here, we present pharmacodynamic (PD) data from the preoperative window of opportunity (WOO) study (EMBER-2, NCT04647487), evaluating the biological activity of imlunestrant monotherapy in ER+, HER2-negative (HER2-) early breast cancer (EBC).
Methods: Post-menopausal women with stage I–III operable ER+ (&gt;50%) or Allred score &gt;5, HER2- untreated EBC ≥1 cm in diameter were randomized 1:1 to imlunestrant 400 mg once daily (QD) or imlunestrant 800 mg QD for 15 days (treatment window of -2 to +7 days) up to the surgery date. Pre- and on-treatment tumor samples were compared for changes in PD biomarkers. Primary study objective was change in ER expression (measured by IHC and quantified by H-score). Secondary objectives were change in progesterone receptor (PR) expression (measured by IHC and quantified by H-score) and Ki-67 (measured by IHC and expressed by percentage positive scoring) along with evaluation of safety and tolerability.
Results: From Apr 28, 2021, to Mar 11, 2022, 58 patients were enrolled of which 54 were biomarker-evaluable for ER expression (400 mg: n = 28; 800 mg: n = 26). Patient demographics and tumor characteristics for all enrolled patients were similar across cohorts, with a median age of 64 years (50-83), 72% invasive ductal carcinoma (IDC), 28% invasive lobular carcinoma (ILC), 59% stage I, 36% stage II and 5% stage III disease. 91% of the patients had a compliance rate higher than 80%. Among biomarker evaluable patients, relative reduction in PD biomarkers after a median of 15 days (range 13 to 23 days) of treatment are presented in Table 1. There was no significant difference in PD biomarker modulation noted between the two imlunestrant doses (400 mg vs 800 mg) or based on tumor histology (IDC, ILC). Imlunestrant was well tolerated. There were no discontinuations due to adverse events (AEs). Treatment-related AEs (TRAEs) were mainly grade 1, most commonly: fatigue (10%), diarrhea (9%), hot flushes (7%), and nausea (5%). There were no TRAEs of diarrhea and nausea observed at the 400 mg dose. No grade 3 or higher TRAEs were reported.
Conclusion: Imlunestrant demonstrated evidence of target engagement along with consistent biological activity across all evaluated dose levels and was well tolerated in an EBC population, further supporting continued adjuvant development in the ongoing EMBER-4 study. Additional biomarker analyses for the EMBER-2 study are also planned.
Table 1. Relative reduction in PD biomarkers from Baseline to Day 15
Citation Format: Patrick Neven, Nicole Stahl, Maria Vidal, Miguel Martín, Nadia Harbeck, Peter A. Kaufman, Francois-Clement Bidard, Peter A. Fasching, Philippe Aftimos, Erika Hamilton, Stacey Carter, Peter Schmid, Duncan Wheatley, Manali Bhave, Kelly K. Hunt, Swati A. Kulkarni, Roohi Ismail-Khan, Claudia Karacsonyi, Shawn T. Estrem, Umut Ozbek, Bastien Nguyen, Eva Ciruelos. A preoperative window-of-opportunity study of imlunestrant in estrogen receptor-positive, HER2-negative early breast cancer: Results from the EMBER-2 study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-06.