Abstract OT1-04-01: AMEERA-6: Phase 3 Study of Adjuvant Amcenestrant Versus Tamoxifen for Patients With Hormone Receptor-Positive Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity

Abstract Background: About 30% of patients (pts) with hormone receptor (HR)-positive early breast cancer (EBC) on adjuvant aromatase inhibitor (AI) therapy discontinue due to toxicity with 22% of pts discontinuing during the first year (Henry et al. JCO 2012). For these patients who struggle with adjuvant AIs, there are limited alternatives including switch to a different AI which may have similar side effects, tamoxifen, or observation. This paucity of effective and tolerable options may contribute to poor adherence and/or early discontinuation of adjuvant endocrine therapy, which is associated with worse outcomes. Amcenestrant (SAR439859) is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 first-in-human trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer. The phase 2 window-of-opportunity study AMEERA-4 evaluating two doses of amcenestrant demonstrated robust Ki67 reductions, strong engagement of the ER target, and continued to show a favorable safety profile in an early breast cancer population. Based on pharmacodynamic activity, safety, and emerging results from other ongoing amcenestrant trials, the 200 mg daily dose of amcenestrant was selected for the AMEERA-6 study. Trial Design: This is a prospective, randomized, international, double-blind, double-dummy, phase 3 superiority study of amcenestrant versus tamoxifen. Eligible pts are men and women with any menopausal status with HR+ stage IIB/III breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status. If neoadjuvant systemic therapy was administered, pts must have residual nodal disease after definitive breast surgery (ypN1-3). Pts will be centrally assessed to have ER-positive and/or progesterone receptor-positive (≥10% positive stained cells) status by immunohistochemistry assay. Pts must have received at least 6 months of adjuvant AIs (≥3 months in the adjuvant setting if they received prior neoadjuvant AI) and discontinued within 30 months of initiation due to AI-related toxicity. Pts may have been treated with more than one AI. All adjuvant therapies including chemotherapy, anti-HER2 treatment, cyclin-dependent kinase (CDK) 4/6 inhibitor, and/or poly (ADP-ribose) polymerase (PARP) inhibitors must be completed or stopped prior to randomization. 3738 pts will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily for 5 years and will be followed for 10 years from randomization. Men and pre/peri-menopausal women will also receive a GnRH analog. Extended adjuvant endocrine therapy upon completion of study treatment is allowed per investigator discretion. Stratification factors include duration of prior AI therapy, HER2 status and prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. The primary endpoint is invasive breast cancer-free survival (IBCFS) based on STEEP criteria version 2.0 defined as occurrence of first recurrence of the disease: ipsilateral or regional invasive, distant recurrence, contralateral invasive breast cancer and death. Key secondary endpoint is invasive disease-free survival (IDFS) and other secondary endpoints include overall survival, safety, patient reported outcomes, and pharmacokinetics of amcenestrant. Adherence to treatment and biomarkers are exploratory endpoints. AMEERA-6 recruited the first patient in March 2022 and is being conducted in partnership with AFT, BIG, EORTC, and Sanofi. Clinical trial information: NCT05128773 Citation Format: Otto Metzger, Christina Herold, Coralie Poncet, Heidi De Swert, Jose Casas-Martin, Ann Partridge, Samia Guita, Lisa Carey, Eva Schumacher, Theodora Goulioti, Thomas Meyskens, Joseph Gannon, Khadija Benlhassan, Giovanna Rossi, Eleni Xenophontos, Amal Arahmani, Amylou C. Dueck, Gautier Paux, Etienne Brain, David A. Cameron. AMEERA-6: Phase 3 Study of Adjuvant Amcenestrant Versus Tamoxifen for Patients With Hormone Receptor-Positive Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-04-01.