amcenestrant (SAR439859)

Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies.

The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.

Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy.

P2, N=367, Active, not recruiting, Sanofi | Trial completion date: Mar 2024 --> Sep 2024

Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice...Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

P2, N=367, Active, not recruiting, Sanofi | Trial completion date: Dec 2023 --> Mar 2024

P1, N=10, Active, not recruiting, Sanofi | Trial completion date: Nov 2023 --> Nov 2024

Both amcenestrant and letrozole demonstrated antiproliferative activity in postmenopausal women with previously untreated, operable ER+/HER2- breast cancer and had good overall tolerability.

P2, N=290, Active, not recruiting, Sanofi | Trial completion date: Sep 2023 --> Dec 2023

AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.

SERD plus Palbociclib resulted in higher rates of AEs (p<0.01). Table: 481P Characterization of ESR1mut and response to SERD (Amcenestrant, Elacestrant, and Camizestrant) Conclusions Our study supports the favorable safety profile of the new generation oral SERD and presents its efficacy according to ESR1mut. Further studies shall assess the potential biomarker role of individual ESR1mut.

P1, N=10, Active, not recruiting, Sanofi | Trial completion date: May 2023 --> Nov 2023

P3, N=1068, Terminated, Sanofi | Active, not recruiting --> Terminated; The study was terminated based on the review by an independent data monitoring committee of the prespecified interim analysis of the Phase 3 AMEERA-5 efficacy data. No new safety signals were observed.

P3, N=1068, Active, not recruiting, Sanofi | Trial completion date: Dec 2023 --> May 2023

Amcenestrant revealed no significant PFS difference in the ESR1wt population (HR 1.197, 95% CI 0.857-1.670, p=0.291) when compared to ET. Additionally, a separate analysis of EMERALD was performed using KMSubtraction to derive survival data of the ESR1wt subgroup comparing Elacestrant vs Fulvestrant... Our results suggest that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup. These findings are in line with the recent FDA approval of Elacestrant for patients with ESR1mt tumours. >

Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.

The only FDA-approved selective estrogen receptor degrader (SERD) fulvestrant has been used in the second line treatment to overcome aromatase inhibitor- or tamoxifen-resistance. However, fulvestrant has poor pharmacokinetic properties, which has inspired the development of a new generation of oral SERDs including amcenestrant and giredestrant...Pathway analysis of ELF3-targeted genes reveals that ELF3 may regulate cell metabolism specifically in SERD resistant cells but not in parental cells. Our study suggests that ELF3 may be a novel driver of acquired resistance to SERDs in ER+ breast cancer.

P1/2, N=136, Active, not recruiting, Sanofi | Trial completion date: Dec 2023 --> Dec 2027 | Trial primary completion date: Dec 2023 --> Dec 2027

P1, N=10, Active, not recruiting, Sanofi | Trial completion date: Nov 2022 --> May 2023

Promising results from early-phase trials are not translating into sufficient clinical benefit in pivotal trials of main oral SERDs in monotherapy, except for elacestrant. Whether oral SERDs might become the backbone for combination strategies in MBC or the preferred (neo)adjuvant endocrine agents is under evaluation.

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The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2- negative breast cancer. Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact.

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No abstract available

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.

The Endocrine Optimization Protocol (EOP) is a sub-study of the ongoing I-SPY 2 TRIAL testing amcenestrant (an oral selective estrogen receptor degrader [SERD]), with or without addition of abemaciclib (a CDK4/6 inhibitor) or letrozole (an aromatase inhibitor) in patients with stage 2/3, MammaPrint (MP) low-risk (index 0 to 1) or high-risk 1 (index -0.57 to 0), HR+/HER2- negative breast cancer. Radiology 263:663–672, 2012 3. Radiology 279:44–55, 2016

P3, N=1068, Active, not recruiting, Sanofi | Trial completion date: Jun 2027 --> Dec 2023

P1/2, N=136, Active, not recruiting, Sanofi | Trial completion date: Aug 2024 --> Dec 2023 | Trial primary completion date: Aug 2024 --> Dec 2023

P3, N=1068, Active, not recruiting, Sanofi | Trial primary completion date: Jan 2024 --> Jun 2022

P1/2, N=136, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | N=251 --> 136

Pts were randomized 1:1 to AMC 400 mg QD (4 x 100 mg capsules) or single agent TPC (fulvestrant, aromatase inhibitor, or tamoxifen) and stratified for the presence of visceral metastasis, prior CDK4/6 inhibitor (i), and ECOG performance status 0 or 1. The safety profile of AMC was consistent with earlier studies. Clinical development of AMC continues, with a focus on earlier-line breast cancer indications for pts with endocrine-sensitive disease in AMEERA-5 and -6.

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). 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.

P2, N=264, Not yet recruiting, Stanford University | Initiation date: Mar 2022 --> Jan 2023

P2, N=367, Active, not recruiting, Sanofi | Trial completion date: Nov 2025 --> Sep 2023

P1/2, N=251, Recruiting, Sanofi | Trial completion date: May 2024 --> Aug 2024 | Trial primary completion date: May 2024 --> Aug 2024

Background: Amcenestrant is an optimized oral selective ER degrader (SERD) that antagonizes and degrades the ER and has demonstrated favorable preliminary safety and antitumor activity as monotherapy and in combination with palbociclib in postmenopausal patients with ER+/HER2− advanced breast cancer, irrespective of baseline (BL) ESR1 mutation status. Both doses of amcenestrant demonstrated robust Ki67 reductions, strongly engaged the ER target, and continued to show a favorable safety profile in an early breast cancer population, consistent with previous published reports. Based on PD activity and safety, and emerging results from other ongoing amcenestrant trials, the 200 mg QD dose of amcenestrant was selected for our ongoing study in the adjuvant setting; AMEERA-6 (NCT05128773).

P1, N=10, Active, not recruiting, Sanofi | Trial completion date: May 2022 --> Nov 2022

Pre-/perimenopausal women and men receive goserelin subcutaneously. 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. NCT04478266.

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.

P2, N=367, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting