Author(s): Komal L. Jhaveri, M.D.
1, Patrick Neven, M.D.
2, Monica Lis Casalnuovo, M.D.
3, Sung-Bae Kim, M.D.
4, Eriko Tokunaga, M.D.
5, Philippe Aftimos, M.D.
6, Cristina Saura, M.D.
7, Joyce O’Shaughnessy, M.D.
8, Nadia Harbeck, M.D.
9, Lisa A. Carey, M.D.
10, Giuseppe Curigliano, M.D.
11,12 https://orcid.org/0000-0003-1781-2518, Antonio Llombart-Cussac, M.D.
13, Elgene Lim, M.D.
14, María de la Luz García Tinoco, M.D.
15, Joohyuk Sohn, M.D.
16 https://orcid.org/0000-0002-2303-2764, André Mattar, M.D., Ph.D.
17, Qingyuan Zhang, M.D.
18, Chiun-Sheng Huang, M.D.
19, Chih-Chiang Hung, M.D.
20, Jorge Luis Martinez Rodriguez, M.D.
21, Manuel Ruíz Borrego, M.D.
22, Rikiya Nakamura, M.D.
23, Kamnesh R. Pradhan, M.D.
24, Christoph Cramer von Laue, Ph.D.
24, Emily Barrett, M.Sc.
24, Shanshan Cao, Ph.D.
24, Xuejing Aimee Wang, Ph.D.
24, Lillian M. Smyth, M.D.
24, and François-Clément Bidard, M.D.
25 https://orcid.org/0000-0001-5932-8949, for the EMBER-3 Study Group*
Background
Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1).
Methods
In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant–abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestr Schumann–abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.
Results
Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant–abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P=0.12). Among 426 patients in the comparison of imlunestrant–abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant–abemaciclib.
Conclusions
Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant–abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.)
Author Affiliations
1 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York; 2 University Hospitals Leuven, Leuven, Belgium; 3 Hospital María Curie, Buenos Aires; 4 Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 5 National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 6 Institut Jules Bordet, Hôpital Universitaire de Bruxelles, Brussels; 7 Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona; 8 Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas; 9 Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, Ludwig Maximilians University Munich University Hospital, Munich, Germany; 10 University of North Carolina at Chapel Hill, Chapel Hill; 11 University of Milan, Milan; 12 European Institute of Oncology, IRCCS, Milan; 13 Hospital Arnau de Vilanova, Valencia, Spain; 14 Garvan Institute of Medical Research and University of New South Wales, Sydney; 15 Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City; 16 Yonsei University College of Medicine, Seoul, South Korea; 17 Mastology Department, Women’s Health Hospital, São Paulo; 18 Harbin Medical University Cancer Hospital, Harbin, China; 19 National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; 20 Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan; 21 Filios Alta Medicina, Monterrey, Mexico; 22 Medical Oncology Department, Hospital Universitario Virgen del Rocío, Seville, Spain; 23 Department of Breast Surgery, Chiba Cancer Center Hospital, Chiba, Japan; 24 Eli Lilly, Indianapolis; 25 Institut Curie and University of Versailles Saint-Quentin-en-Yvelines–Paris-Saclay University, Paris
