369P - Elacestrant combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): Preliminary data from ELEVATE, a phase Ib/II, open-label, umbrella study

Background

Endocrine therapy (ET) + CDK4/6i is the mainstay in 1L ER+, HER2- mBC; however, resistance to ET emerges. De novo resistance mechanisms include alterations in PI3K/AKT/mTOR or cell cycle pathways; acquired resistance mechanisms include ESR1-mut during ET in mBC. In EMERALD, single-agent elacestrant significantly improved PFS vs standard of care (SOC) ET with manageable safety in pts with ER+/HER2-, ESR1-mut mBC previously treated with ET+CDK4/6i, leading to the first oral SERD approved. Pts had a 45% reduction in risk of progression or death with elacestrant vs SOC (HR = 0.55; 95% CI: 0.39-0.77; P = 0.0005) (Bidard 2022). To address other resistance mechanisms, ELEVATE (NCT05563220) evaluates elacestrant in combination with everolimus, alpelisib, capivasertib, palbociclib, ribociclib, or abemaciclib.

Methods

Eligible pts have ER+, HER2− mBC. Phase 1b objective is to identify the recommended phase 2 dose (RP2D) of each combination. Study design was amended to include a combination arm with capivasertib. The ELECTRA study (NCT05386108) evaluated the RP2D of the elacestrant + abemaciclib combination.

Results

As of April 2024, the most common (≥30%) all-grade AEs from phase 1b were consistent with known safety profiles for everolimus, palbociclib, and ribociclib + SOC ET (Table). The elacestrant + alpelisib combination is under evaluation. Elacestrant 345 mg + everolimus 7.5 mg QD was identified as the RP2D for the combination. The study is currently enrolling elacestrant 345 mg QD + abemaciclib 150 mg BID (RP2D from ELECTRA) in phase 2. Updated safety will be presented. Table: 369P

Treatment-Emergent AEs (≥30%), n (%)

^∗Combined terms

Conclusions

Elacestrant has the potential to become the ET backbone with targeted therapies, enabling all-oral combinations. Phase 2 for elacestrant + abemaciclib and elacestrant + everolimus are currently enrolling.

Clinical trial identification

NCT05563220.

Editorial acknowledgement

Editorial assistance was provided by Mark Phillips, PharmD, MBA, of The Phillips Group Oncology Communications, Inc.

Legal entity responsible for the study

Menarini Group.

Funding

Menarini Group.

Disclosure

H.S. Rugo: Financial Interests, Personal, Advisory Board, Consultancy/advisory support: NAPO; Financial Interests, Personal, Invited Speaker, Honoraria: Mylan/Viatris, Chugai; Financial Interests, Personal, Advisory Board, Advisory/Consultancy: PUMA, Sanofi; Financial Interests, Institutional, Local PI: Novartis, Lilly, Pfizer, Daiichi, AstraZeneca, Gilead Sciences, Inc.; Financial Interests, Institutional, Coordinating PI: OBI Pharma, F. Hoffmann-La Roche AG/Genentech, Inc., Merck; Financial Interests, Institutional, Research Grant: Stemline Therapeutics, Ambryx. J. 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