• Komal L Jhaveri, Patrick Neven, Monica Lis Casalnuovo, Sung-Bae Kim, Eriko Tokunaga, Philippe Aftimos, Cristina Saura, Joyce O'Shaughnessy, Nadia Harbeck, Lisa A Carey, Giuseppe Curigliano, Antonio Llombart-Cussac, Elgene Lim, María de la Luz García Tinoco, Joohyuk Sohn, André Mattar, Qingyuan Zhang, Chiun-Sheng Huang, Chih-Chiang Hung, Jorge Luis Martinez Rodriguez, Manuel Ruíz Borrego, Rikiya Nakamura, Kamnesh R Pradhan, Christoph Cramer von Laue, Emily Barrett, Shanshan Cao, Xuejing Aimee Wang, Lillian M Smyth, François-Clément Bidard, and EMBER-3 Study Group.
• From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (K.L.J.); University Hospitals Leuven, Leuven, Belgium (P.N.); Hospital María Curie, Buenos Aires (M.L.C.); Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (S.-B.K.); National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan (E.T.); Institut Jules Bordet, Hôpital Universitaire de Bruxelles, Brussels (P.A.); Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (C.S.); Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas (J.O.); the Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, Ludwig Maximilians University Munich University Hospital, Munich, Germany (N.H.); the University of North Carolina at Chapel Hill, Chapel Hill (L.A.C.); the University of Milan, Milan (G.C.); the European Institute of Oncology, IRCCS, Milan (G.C.); Hospital Arnau de Vilanova, Valencia, Spain (A.L.-C.); Garvan Institute of Medical Research and University of New South Wales, Sydney (E.L.); Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City (M.L.G.T.); Yonsei University College of Medicine, Seoul, South Korea (J.S.); the Mastology Department, Women's Health Hospital, São Paulo (A.M.); Harbin Medical University Cancer Hospital, Harbin, China (Q.Z.); National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei (C.-S.H.); the Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan (C.-C.H.); Filios Alta Medicina, Monterrey, Mexico (J.L.M.R.); the Medical Oncology Department, Hospital Universitario Virgen del Rocío, Seville, Spain (M.R.B.); the Department of Breast Surgery, Chiba Cancer Center Hospital, Chiba, Japan (R.N.); Eli Lilly, Indianapolis (K.R.P., C.C.L., E.B., S.C., X.A.W., L.M.S.); and Institut Curie and University of Versailles Saint-Quentin-en-Yvelines-Paris-Saclay University, Paris (F.-C.B.).
• N. Engl. J. Med. 2024 Dec 11.

BackgroundImlunestrant 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).MethodsIn 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 imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.ResultsOverall, 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.ConclusionsAmong 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.).Copyright © 2024 Massachusetts Medical Society.

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