Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study

Abstract

Purpose: Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1-mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2-negative (HER2-) ABC experience is reported here.

Methods: An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label.

Results: Overall, 262 patients with ER+/HER2- ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of ESR1 mutation status.

Conclusion: Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.

Trial registration: ClinicalTrials.gov NCT04188548.

FIG 1.

CONSORT diagram. ABC, advanced breast cancer; EEC, endometrial endometrioid cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

FIG 2.

Imlunestrant plasma concentration in patients who received imlunestrant monotherapy or in combination with targeted therapy. Patients with ABC and EEC were included together in the PK summaries since no PK differences existed between these patients. (A) Imlunestrant plasma concentration-time profiles on day 15 after multiple oral imlunestrant doses of 200-1,200 mg once daily in patients with intensive PK sampling who received monotherapy during phase Ia or Ib. (B) Steady-state average total plasma concentrations of imlunestrant trough concentrations across different cohorts. The shaded area represents the EC₈₀ range (18-38 ng/mL) derived from preclinical breast cancer xenograft studies. The dotted black line represents the fulvestrant steady-state total C_max of 28 ng/mL and unbound C_max of 0.0056 ng/mL. ABC, advanced breast cancer; AI, aromatase inhibitor; C_max, maximum plasma concentration; EC, effective concentration; EEC, endometrial endometrioid cancer; PK, pharmacokinetics; RP2D, recommended phase II dose.

FIG 3.

Tumor response in patients with ER+/HER2– ABC who received imlunestrant monotherapy at the RP2D or in combination with abemaciclib with or without AI. Waterfall plot for best percentage change in tumor size in patients with measurable disease who received imlunestrant monotherapy at the RP2D (n = 34), imlunestrant + abemaciclib (n = 28), and imlunestrant + abemaciclib + AI (n = 34). Each bar represents one patient. ABC, advanced breast cancer; AI, aromatase inhibitor; ER, estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; RP2D, recommended phase II dose.

FIG 4.

Circulating tumor DNA dynamics in patients with ER+/HER2– ABC who received imlunestrant monotherapy (all dose levels) or in combination with abemaciclib with or without AI. Mean VAF % change of all somatic mutations at C2D1 compared with baseline according to the clinical benefit and best overall response in patients who received (A) imlunestrant (n = 89) or (B) imlunestrant + abemaciclib with or without AI (n = 41). (C and D) PFS according to MR (≥50% decline in VAF at C2D1) or no MR (<50%-0% decline in VAF at C2D1). (E) Landscape of ESR1 mutations detected at baseline. (F) Dynamic change in ESR1 mutations at baseline and at C2D1 in response to imlunestrant (n = 45) and imlunestrant + abemaciclib with or without AI (n = 5). Multiple ESR1 mutations (n = 97) were observed per patient. The Guardant360 assay was used to perform ctDNA somatic mutation analysis. ABC, advanced breast cancer; AI, aromatase inhibitor; C2D1, cycle 2 day 1; CB, clinical benefit; CR, complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; MR, molecular response; ND, not detected; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VAF, variant allele frequency.