Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET
Authors: Jhaveri Komal , O’Shaughnessy Joyce , Andre Fabrice , Goetz Matthew P. , Harbeck Nadia , Martín Miguel , Bidard Francois-Clement , Thomas Zachary M. , Young Suzanne , Ismail-Khan Roohi , Smyth Lillian M. , Gnant Michael 
Published: March 2023

Abstract
Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022.
Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-02.