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. 2022 Mar 15:14:17588359221083956.
doi: 10.1177/17588359221083956. eCollection 2022.

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer

Aditya Bardia  1 , Javier Cortes  2 , Sara A Hurvitz  3 , Suzette Delaloge  4 , Hiroji Iwata  5 , Zhi-Ming Shao  6 , Dheepak Kanagavel  7 , Patrick Cohen  7 , Qianying Liu  8 , Sylvaine Cartot-Cotton  7 , Vasiliki Pelekanou  8 , Joyce O'Shaughnessy  9
Affiliations

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer

Aditya Bardia et al. Ther Adv Med Oncol. .

Abstract

Background: For estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2- ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2- breast cancer.

Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life.

Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2- ABC.

Clinicaltrials identifier: NCT04478266.

Keywords: ER-positive/HER2-negative; amcenestrant; endocrine therapy; metastatic breast cancer; selective estrogen receptor degrader.

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AB reports consulting or advisory roles at Biotheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech, Immunomedics, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Health, Sanofi, and Spectrum Pharmaceuticals; consulting or advisory roles (to his institution) with Genentech/Roche, Immunomedics, Innocrin Pharma, Novartis, Pfizer, and Radius Health; and research funding to his institution from AstraZeneca/Daiichi Sankyo, Genentech, Immunomedics, Merck, Novartis, Pfizer, Radius Health, and Sanofi. JC reports stock/ownership interest at MedSIR; honoraria from Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung; consulting or advisory role at AstraZeneca, Athenex, Bioasis, Biothera, Boehringer Ingelheim, Celgene, Cellestia Biotech, Clovis Oncology, Daiichi Sankyo, ERYTECH Pharma, GlaxoSmithKline, Kyowa Kyrin, Leuko, Lilly, Merck Sharp & Dohme, Merus, Polyphor, Roche, Seattle Genetics, and SERVIER; and research funding to his institution from ARIAD, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur, Puma Biotechnology, Queen Mary University of London, and Roche; and travel/accommodations/expenses from Daiichi Sankyo, Eisai, Novartis, Pfizer, and Roche. SAH reports stock/ownership interests at Ideal Implant and ROM Tech; research funding to her institution from Ambryx, Amgen, Arvinas, Bayer, Biomarin, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Merrimack, Novartis, OBI Pharma, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Sanofi, Seattle Genetics, and Zymeworks; and travel/accommodations/expenses from Lilly; and other relationships with Pfizer and Roche. SD reports consulting or advisory roles (to her institution) with AstraZeneca and Pierre Fabre; research funding to her institution from AstraZeneca, Exact Sciences, Lilly, Novartis, Pfizer, Puma Biotechnology, Roche/Genentech, and Sanofi; and travel/accommodations/expenses from AstraZeneca, Pfizer, and Roche. HI reports honoraria from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, Lilly Japan, Pfizer, and Taiho Pharmaceutical; consulting or advisory roles with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly Japan, Novartis, and Pfizer; and research funding to his institution from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly Japan, MSD, Nihonkayaku, Novartis, Pfizer, and Sanofi. ZMS reports no disclosures. DK, PC, QL, and SCC are employees of Sanofi and may hold shares and/or stock options in the company. VP is a former employee of Sanofi and a current employee of Bayer. JO discloses honoraria from AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Genentech, Genomic Health, GRAIL, HERON, Immunomedics, Ipsen, Jounce Therapeutics, Lilly, Merck, Myriad Pharmaceuticals, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Samsung, Sanofi, Seattle Genetics, and Syndax; consulting or advisory roles with AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Genentech, Genomic Health, GRAIL, HERON, Immunomedics, Ipsen, Jounce Therapeutics, Lilly, Merck, Myriad Pharmaceuticals, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Samsung, Sanofi, Seattle Genetics, and Syndax; speakers’ bureau fees from AstraZeneca, Lilly, Novartis, and Pfizer; research funding to her institution from Seattle Genetics; and travel/accommodations/expenses from AbbVie, Agendia, Amgen, AstraZeneca, Celgene, Eisai, Genomic Health, GRAIL, Ipsen, Jounce Therapeutics, Lilly, Myriad Pharmaceuticals, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, and Seattle Genetics.

Figures

Figure 1.
Figure 1.
(a) Amcenestrant, an oral SERD, antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway and (b) amcenestrant structure. E, estrogen; ER, estrogen receptor; SERD, selective estrogen receptor degrader; SERM, selective estrogen receptor modulator.
Figure 2.
Figure 2.
AMEERA-5 study design. Randomization will be stratified by de novo metastatic disease (yes or no), menopausal status (yes or no), and visceral metastasis defined by at least one of the following: liver, lung, or brain metastasis or pleural or peritoneal involvement (yes or no). PO, oral; QD, once daily; SQ, subcutaneous. aArchived tissue or fresh sample obtained between screening and cycle 1 day 1. bPre-/perimenopausal women and men will receive a subcutaneous goserelin implant (3.6 mg) on day 1 of every 28-day cycle.
Figure 3.
Figure 3.
Countries with AMEERA-5 planned enrollment sites.
See this image and copyright information in PMC

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