Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: Preliminary data from ELECTRA, an open-label, multicenter, phase 1b/2 study.
Authors: Ibrahim Nuhad K. , Hamilton Erika P. , Kim Sung-Bae , Im Young-Hyuck , Seguí Elia , García-Sáenz Jose A. , Di Sanzo Alessandro , Vallespir Bartomeu Pizà , Domínguez Lizarbe Manuel , Wasserman Tomer , Theall Kathy Puyana , Ciruelos Eva 
Published: June 2024

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Background: Endocrine therapy plus a CDK4/6 inhibitor (ET+CDK4/6i) is the mainstay in first-line ER+, HER2- mBC; however, tumors develop resistance to ET. In EMERALD, single-agent elacestrant was associated with significantly prolonged progression-free survival (PFS) and a manageable safety profile vs standard-of-care (SOC) ET in pts with ER+, HER2-, estrogen receptor 1 mutated ( ESR1-mut) mBC previously treated with ET+CDK4/6i, resulting in the first oral SERD approved. Pts in the elacestrant arm had a 45% reduction in the risk of progression or death vs SOC ET (HR = 0.55; 95% CI, 0.39 to 0.77; p = 0.0005) (1). In those pts with ≥12 months’ prior ET+CDK4/6i, median PFS with elacestrant was 8.6 mo vs 1.9 mo with SOC ET (SABCS 2022). To address additional resistance mechanisms and enable an oral-oral combination, ELECTRA (NCT05386108) phase 1b is evaluating the safety of elacestrant + abemaciclib in pts regardless of metastases site and ESR1 status. Phase 2 will evaluate efficacy and safety of the combination in pts with brain metastases since both compounds cross the blood-brain barrier (2,3). Methods: Eligible pts have ER+, HER2- mBC. For phase 1b, brain metastases are not required for eligibility. For phase 2, presence of ≥1 active and measurable brain metastases per RECIST v1.1 is required. In the mBC setting, pts must have previously received ≥1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The phase 1b primary objective is to determine the recommended phase 2 dose (RP2D) of elacestrant + abemaciclib. For this analysis, RP2D, updated adverse events (AEs) and preliminary efficacy for the combination from the phase 1b portion will be presented. Results: As of January 2024, 26 pts were enrolled in the phase 1b elacestrant + abemaciclib cohorts, none with brain metastases. No dose-limiting toxicities were observed. RP2D of elacestrant with abemaciclib will be reported. The most common all-grade (Gr) AEs were diarrhea (n=21, 81%; 0 Gr3), nausea (n=16, 62%; 0 Gr3), and decreased neutrophils/neutropenia (n=13, 50%; n=10, 38% Gr 3). No Gr4 AEs or Gr3 diarrhea were observed. In 21 evaluable pts, 6 had partial response (1 unconfirmed) and 9 had stable disease (2 unconfirmed) as best tumor response. To date, up to 11 cycles of the combination have been administered. Updated safety, PK, and preliminary efficacy will be reported. Conclusions: The RP2D for elacestrant + abemaciclib will be reported; the combinationdemonstrated a manageable and predictable safety profile. Preliminary efficacy data showed encouraging antitumor activity. Elacestrant has the potential to become the ET backbone for combination regimens. 1. Bidard, 2022. 2.Conlan, 2020. 3.Tolaney, 2020. Clinical trial information: NCT05386108 .