Abstract PD13-12: PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study

Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. Preclinically, imlunestrant has favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1-mutant models, along with enhanced efficacy when combined with abemaciclib. In dose escalation (Phase 1a) and dose expansion (Phase 1b) in the EMBER study, imlunestrant monotherapy was well tolerated with favorable safety, PK and encouraging antitumor activity in heavily pre-treated ER+, HER2- advanced breast cancer (aBC) patients (Jhaveri, ASCO 2022); imlunestrant recommended phase 2 dose (RP2D) was determined as 400mg QD. Here, we present the phase 1b dose expansion of imlunestrant with abemaciclib ± aromatase inhibitor (AI) in EMBER (NCT04188548). Methods: Phase 1b enrolled patients with ER-positive (ER+), HER2-negative (HER2-) aBC [shown prior endocrine therapy (ET) sensitivity or untreated de novo aBC; ≤1 prior therapies for aBC but must not have received a prior CDK4/6 inhibitor]. Patients were randomized, based on menopausal status and presence of visceral metastases, to receive imlunestrant + abemaciclib OR imlunestrant + abemaciclib + AI. Men and premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included safety and tolerability, PK, objective response rate (ORR) per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease), and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of 26 May 2022, 85 patients have received imlunestrant [n=80 at 400 mg (RP2D); n=5 at 800 mg] in combination with abemaciclib (150mg twice daily) ± AI. Forty-eight (56%) patients had visceral disease and 9% had at least 1 ESR1 mutation detected in ctDNA at baseline. Patients were predominantly (75%) ET pre-treated, 51% with an AI; and 8% and 5%, respectively, had received prior chemotherapy or fulvestrant, for aBC. The most common treatment-emergent adverse events were diarrhea (87%), nausea (58%), fatigue (45%), neutropenia (39%) and abdominal pain (34%). The majority of treatment-related AEs (TRAEs) were Grade 1 or 2, with Grade ≥3 TRAEs occurring in 36% of patients. Most common TRAEs at RP2D (400mg) were diarrhea (81%), nausea (45%), fatigue (33%) and neutropenia (35%). No patient discontinued treatment due to an AE. Dose reductions were required of both imlunestrant and abemaciclib in 6 (7%) patients and of either imlunestrant in 3 (4%) or abemaciclib in 22 (26%) patients. Preliminary efficacy is presented in Table 1. Conclusion: Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting. The phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant + abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table 1. Preliminary efficacy in combination therapies in EMBER Citation Format: Komal Jhaveri, Hwei-Chung Wang, Cynthia Ma, Elgene Lim, Jessica J. Tao, Luis Manso, Jean-Yves Pierga, Ritesh Parajuli, Yolanda Jerez Gilarranz, Yen-Shen Lu, Muralidhar Beeram, Tim Larson, Ajay Dhakal, Roohi Ismail-Khan, Claudia Karacsonyi, Shanshan Cao, Cynthia Osborne, Shawn T. Estrem, Bastien Nguyen, Yujia Li, Eunice Yuen. PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study [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 PD13-12.