Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study

Kan Yonemori; Valentina Boni; Kim Gun Min; Tarek M Meniawy; Janine Lombard; Peter A Kaufman; Debra L Richardson; Laura Bender; Meena Okera; Koji Matsumoto; Karthik V Giridhar; José Angel García-Sáenz; Hans Prenen; Bernard Doger de Speville Uribe; Don S Dizon; Javier Garcia-Corbacho; Els Van Nieuwenhuysen; Yujia Li; Shawn T Estrem; Bastien Nguyen; Francesca Bacchion; Roohi Ismail-Khan; Komal Jhaveri; Kalyan Banda

doi:10.1016/j.ygyno.2024.10.006

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Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study

Authors: Kan Yonemori ; Valentina Boni ; Kim Gun Min ; Tarek M Meniawy ; Janine Lombard ; Peter A Kaufman ; Debra L Richardson ; Laura Bender ; Meena Okera ; Koji Matsumoto ; Karthik V Giridhar ; José Angel García-Sáenz ; Hans Prenen ; Bernard Doger de Speville Uribe ; Don S Dizon ; Javier Garcia-Corbacho ; Els Van Nieuwenhuysen ; Yujia Li ; Shawn T Estrem ; Bastien Nguyen ; Francesca Bacchion ; Roohi Ismail-Khan ; Komal Jhaveri ; Kalyan Banda

Citation: GYNECOLOGIC ONCOLOGY, Vol.191 : 172-181, 2024-12

Journal Title: GYNECOLOGIC ONCOLOGY

ISSN: 0090-8258

Issue Date: 2024-12

MeSH: Adult ; Aged ; Aged, 80 and over ; Aminopyridines* / administration & dosage ; Aminopyridines* / adverse effects ; Aminopyridines* / pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols* / administration & dosage ; Antineoplastic Combined Chemotherapy Protocols* / adverse effects ; Antineoplastic Combined Chemotherapy Protocols* / therapeutic use ; Benzimidazoles* / administration & dosage ; Benzimidazoles* / adverse effects ; Benzimidazoles* / pharmacokinetics ; Carcinoma, Endometrioid / drug therapy ; Carcinoma, Endometrioid / metabolism ; Carcinoma, Endometrioid / pathology ; Endometrial Neoplasms* / drug therapy ; Endometrial Neoplasms* / metabolism ; Endometrial Neoplasms* / pathology ; Female ; Humans ; Middle Aged ; Neoplasm Recurrence, Local / drug therapy ; Receptors, Estrogen / metabolism

Keywords: CDK4/6 inhibitors ; SERD ; Uterine cancer

Abstract: Objective: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC.

Methods: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity.

Results: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12).

Conclusion: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.