A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER plus ) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER.

1021 Background: Imlunestrant is a novel, orally bioavailable SERD with pure antagonistic properties that result in sustained inhibition of ER-dependent gene transcription and cell growth. In dose escalation, imlunestrant showed favorable safety, pharmacokinetics (PK) and preliminary efficacy in patients with ER+, HER2- aBC and ER+ EEC (Phase 1a EMBER, Jhaveri 2021). Here we present updated data from the dose escalation (Phase 1a) and dose expansion (Phase 1b) of imlunestrant monotherapy in EMBER (NCT04188548). Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior ET sensitivity; ≤3 prior therapies for aBC in Phase 1a following protocol amendment and ≤2 in Phase 1b) and ER+ EEC (prior platinum therapy; no prior fulvestrant or aromatase inhibitor). Premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included recommended phase 2 dose (RP2D) determination, safety and tolerability, PK, objective response rate per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease and ≥1 post-baseline tumor assessment or discontinued prior to tumor assessment, 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 January 14, 2022, 138 patients (n = 114 aBC, n = 24 EEC) received imlunestrant monotherapy at doses ranging from 200-1200 mg QD. Median age was 62.0 years (range 32-95). Median number of prior therapies for aBC and EEC was 2 (range 0-8) and 1 (0-5), respectively. aBC patients had received a prior ET (94.7%), CDK4/6 inhibitor (92.1%), fulvestrant (50.9%) and chemotherapy (26.3%). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were grade 1. At the RP2D (400 mg QD, n= 69), the most common all grade TEAE’s were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). Across all doses, the incidence of treatment-related grade 3 AEs was low (3.6%). No patient discontinued due to a TEAE. In evaluable aBC patients, ORR was 8.0% (6/75) and CBR was 40.4% (42/104). In evaluable EEC patients, ORR was 5.0% (1/20 had a PR- ongoing pending confirmation) and CBR was 47.1% (8/17). Clinical benefit was observed regardless of baseline ESR1 mutation status as determined by ctDNA sequencing. Additional biomarker analyses will be presented at the meeting. Conclusions: Imlunestrant continues to demonstrate a favorable side effect profile, with no cardiac or opthalmic safety signals, and has continued evidence of clinical activity in heavily pre-treated ER+ aBC and EEC patients. Clinical trial information: NCT04188548.