Abstract CT517: Amcenestrant, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/HER2- advanced breast cancer (aBC): combined biomarker analyses from a Phase 1/2 study in postmenopausal women and a Phase 1 study in postmenopausal Japanese women
Authors: Iwata Hiroji , Bardia Aditya , Lord Simon , Linden Hannah M. , Campone Mario , Tamura Kenji , Yonemori Kan , Mukohara Toru , Combeau Cécile , Ternes Nils , Carene Dimitri , Ming Jeff , Lee Joon Sang , Celanovic Marina , Bauchet Anne-Laure , Bouaboula Monsif , Tanaka Tomoyuki , Kawabata Yumiko , Chandarlapaty Sarat 
Published: June 2022

Abstract
Background: Amcenestrant is an optimized oral SERD that has shown safety and clinical benefit in patients (pts) with wild-type (WT) and mutated ESR1 aBC. Here we provide a pooled analysis of biomarkers from two studies in heavily-pretreated, postmenopausal women with ER+/HER2- aBC.
Methods: Pooled analysis included study data from AMEERA-1 (NCT03284957), in which pts received single-agent amcenestrant in dose escalation (20-600 mg QD or 300 mg BID) and dose expansion (400 mg QD), and from AMEERA-2 (NCT03816839), in which Japanese pts received single-agent amcenestrant at 400 mg QD or 300 mg BID. Mutational profiling of plasma circulating cell-free DNA was conducted by droplet digital polymerase chain reaction (ddPCR) for 12 pathogenic ESR1 mutations at baseline (BL) and on treatment (OT; Cycle 2, Day 28), and by next-generation sequencing (NGS; 77-gene panel) at BL and end of treatment (EOT). Clinical benefit (CB; complete response + partial response [PR] + stable disease ≥ 24 weeks) was assessed in pooled pts who received amcenestrant≥ 150 mg QD or BID. In tumor tissue, ER, progesterone receptor (PgR), Ki67 and Bcl-2 expression levels over time were assessed by immunohistochemistry; functional ER pathway activity was assessed by gene set variation analysis with RNA-seq data (ER activity score).
Results: Among pts with data for ESR1 mutation status at BL (N = 80; ddPCR), 41 pts were WT and 39 pts had at least one ESR1 mutation, with D538G and Y537S the most prevalent. CB was observed in pts with both WT (13 pts) and mutated ESR1 (12 pts) at BL. The most frequent pathogenic mutations detected in pts (N = 79; NGS) at BL were ESR1 (49%), followed by PI3KCA (46%)and TP53 (33%). In response-evaluable pts with ESR1 mutational profiling at BL and OT (N = 40; ddPCR), 17 of 19 pts with ESR1 mutation at BL showed a decrease in ESR1 mutation allele frequency, independently of clinical benefit. Eight pts showed an increase (7/25 no CB and 1/15 CB). Among 17 pts with biopsies, pts with ER or PgR -/low (H-score: 0-3) at BL did not derive benefit from treatment. In the remaining patients with ER high (H-score ≥ 140), no difference between pts with and without CB was observed in ER, Bcl-2 or ER activity score, while pts with CB had a tendency for lower Ki67. ER and PgR decreased upon treatment independently of CB, while ER activity score and Ki67 mostly decreased in pts with CB and mostly increased in pts without CB.
Conclusions: In postmenopausal women with ER+/HER2- aBC treated with single-agent amcenestrant, low Ki67 at BL and the pharmacodynamic decrease of Ki67 and ER activation score by amcenestrant trended toward an association with CB, whereas increase in ESR1 mutation allele frequency on treatment trended toward an association with lack of CB. Clinical benefit was observed in both pts with WT and mutated ESR1 at BL.
Citation Format: Hiroji Iwata, Aditya Bardia, Simon Lord, Hannah M. Linden, Mario Campone, Kenji Tamura, Kan Yonemori, Toru Mukohara, Cécile Combeau, Nils Ternes, Dimitri Carene, Jeff Ming, Joon Sang Lee, Marina Celanovic, Anne-Laure Bauchet, Monsif Bouaboula, Tomoyuki Tanaka, Yumiko Kawabata, Sarat Chandarlapaty. Amcenestrant, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/HER2- advanced breast cancer (aBC): combined biomarker analyses from a Phase 1/2 study in postmenopausal women and a Phase 1 study in postmenopausal Japanese women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT517.