Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer
Aditya Bardia, Virginia Kaklamani, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca G Bagley, Yamei Wang, Maureen G Conlan, Peter Kabos, Aditya Bardia, Virginia Kaklamani, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca G Bagley, Yamei Wang, Maureen G Conlan, Peter Kabos
Abstract
Purpose: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D).
Methods: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability.
Results: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction.
Conclusion: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.
Conflict of interest statement
Aditya BardiaConsulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Health, Inc., Immunomedics, Genentech/Roche, Innocrin Pharma, Sanofi, Puma Biotechnology, Daiichi Sankyo/AstraZenecaResearch Funding: BioTheranostics Virginia KaklamaniHonoraria: Celgene, Eisai, Genentech, Novartis, Pfizer, Genomic Health, Puma Biotechnology, AstraZeneca, Seattle Genetics, Daiichi SankyoConsulting or Advisory Role: Amgen, Eisai, Puma Biotechnology, Celldex, AstraZeneca, AthenexSpeakers' Bureau: Eisai, Genentech, Celgene, Novartis, Genomic Health, Puma Biotechnology, PfizerResearch Funding: Eisai Sharon WilksHonoraria: Seattle GeneticsConsulting or Advisory Role: Seattle GeneticsResearch Funding: Seattle Genetics Donald RichardsConsulting or Advisory Role: Ipsen, Taiho Pharmaceutical, Seattle Genetics/Astellas, Mirati Therapeutics Wael HarbResearch Funding: AI Therapeutics Cynthia OsborneHonoraria: Agendia, Guardant Health, Breast Cancer Index, Seattle Genetics, ImmunomedicsSpeakers' Bureau: Novartis, LillyTravel, Accommodations, Expenses: Novartis, Lilly Robert WesolowskiConsulting or Advisory Role: Puma Biotechnology, Pfizer, Roche DiagnosticsResearch Funding: Acerta PharmaTravel, Accommodations, Expenses: Puma Biotechnology, Pfizer, Roche Diagnostics Meghan KaruturiConsulting or Advisory Role: Pfizer, MD Anderson Physician's Network Paul ConklingEmployment: Virginia Oncology AssociatesResearch Funding: Bristol-Myers Squibb, EMD Serono, Arcus Biosciences, Aptose Biosciences, Janssen, Pfizer, Bayer, Astex Pharmaceuticals Rebecca G. BagleyEmployment: Radius Health, Inc. Yamei WangEmployment: Radius Health, Inc.Stock and Other Ownership Interests: RDUS Maureen G. ConlanEmployment: Radius Health, Inc.Stock and Other Ownership Interests: Radius Health, Inc. Peter KabosConsulting or Advisory Role: LillyResearch Funding: Radius Health, Inc., Lilly, Pfizer, AstraZeneca, Sanofi, Genentech, AngiochemNo other potential conflicts of interest were reported.
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Source: PubMed