AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer

• Published in: Nature communications Vol. 13; no. 1; pp. 4116 - 15
• Main Authors: Bardia, Aditya, Chandarlapaty, Sarat, Linden, Hannah M., Ulaner, Gary A., Gosselin, Alice, Cartot-Cotton, Sylvaine, Cohen, Patrick, Doroumian, Séverine, Paux, Gautier, Celanovic, Marina, Pelekanou, Vasiliki, Ming, Jeffrey E., Ternès, Nils, Bouaboula, Monsif, Lee, Joon Sang, Bauchet, Anne-Laure, Campone, Mario
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 38/77; 38/90; 38/91; 49/23; 59/78; 692/699/67/1059/2326; 692/699/67/1347; 692/699/67/69; 82/80; Anticancer properties; Antitumor activity; Bioavailability; Biopsy; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Constraining; Deoxyribonucleic acid; DNA; Endocrine therapy; ErbB-2 protein; Estrogen Antagonists - therapeutic use; Estrogen receptors; Estrogens; Female; Fulvestrant; Humanities and Social Sciences; Humans; multidisciplinary; Mutation; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Positron emission; Positron emission tomography; Post-menopause; Postmenopause; Receptor, ErbB-2 - genetics; Receptors; Science; Science (multidisciplinary); Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31668-8

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2− advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n  = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18 F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n  = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S . In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status. There is a need for potent and non-toxic estrogen receptor (ER) antagonists to overcome the limitations of existing endocrine therapies. Here the authors report the results from Arm 1 of the Phase 1/2 study (AMEERA-1) among postmenopausal women with ER+/HER2− advanced breast cancer, which evaluates the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of amcenestrant administered as monotherapy.