Abstract OT-09-03: EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer
Authors: Lim Elgene , Beeram Murali , Prawira Amy , Patnaik Amita , Wang Xuejing A , Young Suzanne RL , Smyth Lillian M , Hamilton Erika P. 
Published: February 2021

Abstract
Background: Estrogen receptor (ER) is the key therapeutic target for the most common breast cancer (BC) subtype affecting patients worldwide. Novel degraders and antagonists of ER are under evaluation, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant (fulv), the only approved SERD. ER is also overexpressed in approximately 80% of endometroid endometrial cancers and endocrine therapy (ET) is a standard of care (SOC) option for this disease, though no ER-directed therapies are specifically approved in this setting. LY3484356 is a novel, orally bioavailable SERD with pure antagonistic properties which results in sustained inhibition of ER-dependent gene transcription and -cell growth. Preclinically, LY3484356 monotherapy shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants, along with enhanced antitumor efficacy when combined with abemaciclib, everolimus, or alpelisib. This trial investigates LY3484356 alone and in combination with other SOC anticancer therapies, in women with ER+ advanced BC and ER+ endometroid endometrial cancer. Trial Design: This global first-in-human phase 1a/b, study of LY3484356, includes dose escalation of LY3484356 monotherapy (n=100), followed by dose expansion (n=360) at the recommended phase 2 dose (RP2D) of LY3484356 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using an interval 3+3 design. In dose expansion (Parts A-D), each combination cohort will include a safety lead-in of 3-6 patients. Premenopausal women must receive concomitant treatment with a GnRH agonist. Eligibility criteria: Eligible patients must have pre- or post-menopausal ER+, HER2- or HER2+, advanced BC or ER+ endometroid endometrial cancer. ER+, HER2- BC patients must have either untreated de novo disease or prior ET sensitivity. In dose escalation, BC patients may have received up to 3 prior therapies for metastatic disease. In dose expansion, prior therapy requirements are outlined in the Table below. ER+ endometroid endometrial cancer patients must have progressed on platinum-based therapy. Key Study endpoints: Recommended phase 2 dose determination; safety and tolerability assessment, PK evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment for the EMBER study is ongoing (NCT04188548).
Table. Dose Expansion (Phase 1b)Patient SubgroupKey EligibilityStudy DrugsER+, HER2- BC Randomized (Part A)-≤1 prior metastatic therapy-LY3484356 + Abemaciclib-No prior CDK4 & 6 inhibitor-LY3484356 + Abemaciclib + Physician’s Choice AI*ER+, HER2- BC (Part B)-≤2 prior metastatic therapies (≤1 prior ET)-LY3484356 monotherapy-Prior CDK4 & 6 inhibitor required-LY3484356 + Everolimus-No prior Everolimus/Alpelisib-LY3484356 + Alpelisib-PIK3CA mutation required for AlpelisibER+, HER2+ BC Randomized (Part C)-≥2 prior HER2 therapies-LY3484356 + Trastuzumab-No prior fulv or CDK4 & 6 inhibitor-LY3484356 + Trastuzumab + AbemaciclibER+ endometroid endometrial cancer Randomized (Part D)-Progressed on platinum-based therapy-LY3484356 monotherapy-No prior AI or fulv-LY3484356 + Abemaciclib* anastrozole, letrozole, or exemestane
Citation Format: Elgene Lim, Murali Beeram, Amy Prawira, Amita Patnaik, Xuejing A Wang, Suzanne RL Young, Lillian M Smyth, Erika P. Hamilton. EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-03.