Elacestrant (Ela) combinations with ribociclib (Ribo) and everolimus (Eve) in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study.

Abstract

1070 Background: Progression of ER+/HER2- mBC on 1L endocrine therapy (ET) + CDK4/6i is associated with several mechanisms of resistance that impact efficacy and subsequent therapy. Treatment options include endocrine monotherapy, continuing ET+CDK4/6i, or PI3K/AKT/mTOR pathway–ET combination regimens. Acquired ESR1 mutations emerge in up to 50% of patients and continuing SOC ET is limited by resistance to ET due to these mutations. Several trials have shown improved mPFS with the addition of Eve: 3.6-6.8 mo (Cook 2021, Vasseur 2024) or switch in CDK4/6i: 5.3 mo (Kalinsky 2023). In the Ph 3 EMERALD trial, single-agent Ela significantly improved PFS vs SOC ET ( ESR1 -mut tumors HR 0.55; 95% CI 0.39-0.77; P=0.0005; all pts HR 0.70; 95% CI 0.55-0.88; P=0.0018) with manageable safety in pts with ER+/HER2- mBC who had prior ET+CDK4/6i (Bidard 2022). This analysis reports updated safety and preliminary efficacy for Ela in combination with Ribo or Eve. Methods: ELEVATE evaluates Ela in combination with everolimus (Eve), alpelisib (Alp), capivasertib (Capi), ribociclib (Ribo), palbociclib (Palbo), or abemaciclib (Abema) to address different resistance mechanisms. Pts with ER+/HER2- mBC and 1-2L of prior ET are eligible regardless of ESR1 -mut status. Objectives are to identify the RP2D (Ph 1b) and evaluate PFS (Ph 2) with each combination. Results: Elacestrant combinations with Ribo or Eve showed safety consistent with the known profiles of each drug + SOC ET. The most common AEs (≥30%) with Ela + Ribo (n=32) from Ph 1b were neutropenia (38%; 25% ≥Gr3) and nausea (31%; 0 ≥Gr3). The most common AEs for Ela + Eve (n=72) from Ph 1b + Ph 2 were nausea (54%; 6% ≥Gr3), diarrhea (43%; 7% ≥Gr3), stomatitis (38%; 3% ≥Gr3), and fatigue (32%; 6% ≥Gr3). Median PFS for Ela + Ribo was 7.2 months, while for Ela + Eve was 8.5 months. Table 1 summarizes mPFS from Ph 1b in efficacy-evaluable pts who received prior ET+CDK4/6i, as of Dec 2024. Updated data will be presented. Conclusions: Elacestrant plus Ribo or Eve demonstrates promising Ph 1b efficacy in pts with ER+/HER2- mBC with progressive disease after ET+CDK4/6i in all patients. Ela 345 mg + Ribo 400 mg QD was determined as the RP2D. Previously, Ela 345 mg + Eve 7.5 mg was identified as the RP2D. Elacestrant has the potential to become an ET backbone for various targeted agents, offering an all-oral treatment regimen in pts with ER+/HER2- mBC, delaying chemo or ADC-based regimens. Clinical trial information: NCT05563220 . Ph 1b mPFS in prior ET+CDK4/6i, efficacy-evaluable population. N Ela (86-345 mg) + Ribo (400-600 mg) N Ela (258-345 mg) + Eve (5-10 mg) mPFS, mo (95% CI) 32 7.2 (3.52 - 12.78) 22 8.5 (7.23 - 16.07)