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

Komal L Jhaveri; Elgene Lim; Rinath Jeselsohn; Cynthia X Ma; Erika P Hamilton; Cynthia Osborne; Manali Bhave; Peter A Kaufman; J Thaddeus Beck; Luis Manso Sanchez; Ritesh Parajuli; Hwei-Chung Wang; Jessica J Tao; Seock-Ah Im; Kathleen Harnden; Kan Yonemori; Ajay Dhakal; Patrick Neven; Philippe Aftimos; Jean-Yves Pierga; Yen-Shen Lu; Timothy Larson; Yolanda Jerez; Kostandinos Sideras; Joohyuk Sohn; Sung-Bae Kim; Cristina Saura; Aditya Bardia; Sarah L Sammons; Francesca Bacchion; Yujia Li; Eunice Yuen; Shawn T Estrem; Vanessa Rodrik-Outmezguine; Bastien Nguyen; Roohi Ismail-Khan; Lillian Smyth; Muralidhar Beeram

doi:10.1200/JCO.23.02733

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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

Authors: Komal L Jhaveri ; Elgene Lim ; Rinath Jeselsohn ; Cynthia X Ma ; Erika P Hamilton ; Cynthia Osborne ; Manali Bhave ; Peter A Kaufman ; J Thaddeus Beck ; Luis Manso Sanchez ; Ritesh Parajuli ; Hwei-Chung Wang ; Jessica J Tao ; Seock-Ah Im ; Kathleen Harnden ; Kan Yonemori ; Ajay Dhakal ; Patrick Neven ; Philippe Aftimos ; Jean-Yves Pierga ; Yen-Shen Lu ; Timothy Larson ; Yolanda Jerez ; Kostandinos Sideras ; Joohyuk Sohn ; Sung-Bae Kim ; Cristina Saura ; Aditya Bardia ; Sarah L Sammons ; Francesca Bacchion ; Yujia Li ; Eunice Yuen ; Shawn T Estrem ; Vanessa Rodrik-Outmezguine ; Bastien Nguyen ; Roohi Ismail-Khan ; Lillian Smyth ; Muralidhar Beeram

Citation: JOURNAL OF CLINICAL ONCOLOGY, Vol.42(35) : 4173-4186, 2024-12

Journal Title: JOURNAL OF CLINICAL ONCOLOGY

ISSN: 0732-183X

Issue Date: 2024-12

MeSH: Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Aminopyridines* / administration & dosage ; Aminopyridines* / adverse effects ; Aminopyridines* / therapeutic use ; Antineoplastic Combined Chemotherapy Protocols* / adverse effects ; Antineoplastic Combined Chemotherapy Protocols* / therapeutic use ; Aromatase Inhibitors / administration & dosage ; Aromatase Inhibitors / adverse effects ; Aromatase Inhibitors / therapeutic use ; Benzimidazoles* / administration & dosage ; Benzimidazoles* / adverse effects ; Benzimidazoles* / therapeutic use ; Breast Neoplasms* / drug therapy ; Breast Neoplasms* / genetics ; Breast Neoplasms* / metabolism ; Breast Neoplasms* / pathology ; Cyclin-Dependent Kinase 4 / antagonists & inhibitors ; Everolimus* / administration & dosage ; Everolimus* / adverse effects ; Everolimus* / therapeutic use ; Female ; Humans ; Middle Aged ; Molecular Targeted Therapy ; Progression-Free Survival ; Receptor, ErbB-2* / metabolism ; Receptors, Estrogen* / metabolism ; Thiazoles / administration & dosage ; Thiazoles / adverse effects ; Thiazoles / therapeutic use

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.