Young, Suzanne R.L.

1001 Background: Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who had disease progression on or after aromatase inhibitor-based therapy, showed significant progression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrant or exemestane) in pts with ESR1 mutations ( ESR1 m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1 m. Exploratory PRO analyses are presented here. Methods: EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and ≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting 0 (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE. Results: In pts with ESR1 m, imlu monotherapy was associated with many improved or maintained EORTC QLQ-C30 scores, whereas scores with SOC were declined or maintained. Specifically, pts with ESR1 m on imlu had improved global health status (GHS)/quality of life (QOL) and physical function (PF) scores, while scores with SOC declined (mean change differences between treatments: 9.9 [0.1, 19.7] and 6.2 [-0.8, 13.1], respectively). These PRO findings mirror the PFS findings in this group. In the overall population, GHS/QOL scores declined similarly with imlu vs SOC (mean change differences: 0.5 [-4.7, 5.7]), while PF scores were maintained with imlu vs a slight decline with SOC (mean change difference: 2.5 [-1.1, 6.1]). Most fulvestrant recipients (72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2], respectively). Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%). Conclusions: PROs from EMBER-3 demonstrated that patients with ESR1 m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC. Clinical trial information: NCT04975308 .

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.