Abstract PS7-06: Elacestrant combinations in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase 1b/2, open-label, umbrella study

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Abstract Background: Endocrine therapy (ET) + CDK4/6i is the mainstay in 1L ER+/HER2- mBC; however, ET resistance develops. Intrinsic resistance mechanisms include PI3K/AKT/mTOR or cell cycle pathway alterations; acquired resistance mechanisms include ESR1-mut during ET in mBC. In EMERALD, single-agent elacestrant significantly improved PFS vs standard of care (SOC) ET (ESR1-mut tumors: HR = 0.55; 95% CI, 0.39-0.77; P = 0.0005; all patients: HR = 0.70; 95% CI, 0.55-0.88; P = 0.0018) with manageable safety in patients with ER+/HER2- mBC previously treated with ET+CDK4/6i (Bidard 2022). In those with prior ET+CDK4/6i ≥12 months and ESR1-mut tumors, median PFS (mPFS) with elacestrant was 8.6 vs 1.9 months (HR = 0.41; 95% CI, 0.26-0.63) with SOC ET (Bardia 2022). To address various resistance mechanisms, ELEVATE (NCT05563220) evaluates elacestrant in combination with everolimus, alpelisib, capivasertib, ribociclib, palbociclib, or abemaciclib. Methods: Eligible patients have ER+/HER2- mBC. Phase 1b objective is to identify the recommended phase 2 dose (RP2D) of each combination. ELECTRA (NCT05386108) evaluated the RP2D of elacestrant + abemaciclib. Phase 2 primary objective is to evaluate PFS in patients receiving elacestrant combined with each of the other study drugs at the RP2D. This analysis reports updated safety from the phase 1b portion for the following combinations: everolimus, alpelisib, ribociclib, and palbociclib. Preliminary phase 1b efficacy is reported for the elacestrant + everolimus combination; efficacy evaluation for additional combinations is ongoing. Results: As of July 2024, 23 patients have been enrolled in the elacestrant (258-345 mg) + everolimus (5-10 mg) cohorts. The most common (≥30%) treatment-emergent AEs (TEAEs) were nausea (n=13, 57%; 4% Gr ≥3), stomatitis (n=12, 52%; 9% Gr ≥3), diarrhea (n=10, 43%; 9% Gr ≥3), and fatigue (n=10, 43%; 9% Gr ≥3). mPFS was not yet reached after a median 0.8 to 12.3 months of follow-up across cohorts. Preliminary efficacy in response evaluable patients (n=16) for the elacestrant + everolimus combination demonstrated a CBR at 24 weeks of 81% and ORR of 25%. The elacestrant (258 mg) + alpelisib (250-200 mg) cohort enrolled 9 patients. The most common TEAEs (≥30%) were nausea (n=8, 89%; 11% Gr ≥3), rash (n=4, 44%; 22% Gr ≥3), vomiting (n=4, 44%; 0 ≥G3), dry mouth, stomatitis, and dizziness (n=3, 33%; 0 Gr ≥3). Elacestrant (86-258 mg) + ribociclib (400-600 mg) cohorts enrolled 18 patients. The most common (≥30%) TEAE was neutropenia (n=7, 39%; 28% Gr ≥3). Elacestrant (258-345 mg) + palbociclib (100 mg) cohorts enrolled 12 patients. The most common (≥30%) TEAEs were neutropenia (n=5, 42%; 17% Gr ≥3) and nausea (n=4, 33%; 0 Gr ≥3). Phase 1b of the capivasertib combination is currently ongoing to determine the RP2D. Updated data will be presented. Conclusion: The phase 1b combinations of elacestrant with either everolimus, ribociclib, or palbociclib demonstrated a manageable safety profile consistent with previously reported data for each compound. The elacestrant + everolimus combination shows favorable efficacy. The phase 1b combinations with ribociclib, palbociclib, or capivasertib are ongoing. The phase 1b combination with alpelisib is under evaluation. The elacestrant + everolimus and elacestrant 345 mg QD + abemaciclib 150 mg BID (RP2D determined in ELECTRA trial) combinations are currently enrolling patients in phase 2. Elacestrant has the potential to become the ET backbone with targeted therapies, to enable all-oral combinations as a treatment option that can replace fulvestrant-based combinations and delay chemotherapy or ADC-based regimens. Citation Format: Hope S. Rugo, Sara M. Tolaney, Nancy Chan, Erika Hamilton, Marina N. Sharifi, Kristine J. Rinn, Wassim McHayleh, Rinat Yerushalmi, Neelima Vidula, Joyce O’Shaughnessy, Giuseppe Curigliano, Javier Cortés, Paula Muñoz Romero, Bartomeu Piza Vallespir, Kathy Puyana Theall, Alessandro Paoli, Monica Binaschi, Tomer Wasserman, Virginia Kaklamani. Elacestrant combinations in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase 1b/2, open-label, umbrella study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS7-06.

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