Imlunestrant, an oral selective estrogen receptor degrader (SERD), in combination with human epidermal growth factor receptor 2 (HER2) directed therapy, with or without abemaciclib, in estrogen receptor (ER) positive, HER2 positive advanced breast cancer (aBC): EMBER phase 1a/1b study.

person Manali A. Bhave Emory University School of Medicine, Atlanta, GA info_outline Manali A. Bhave, Komal L. Jhaveri, Peter A. Kaufman, Philippe Georges Aftimos, Janine Margaret Lombard, Kostandinos Sideras, Seock-Ah Im, Cynthia X. Ma, Kuo-Ting Lee, Sung-Bae Kim, Yujia Li, Eunice Yuen, Shawn T. Estrem, Bastien Nguyen, Francesca Bacchion, Roohi Ismail-Khan, Muralidhar Beeram, Joohyuk Sohn

Authors person Manali A. Bhave Emory University School of Medicine, Atlanta, GA info_outline Manali A. Bhave, Komal L. Jhaveri, Peter A. Kaufman, Philippe Georges Aftimos, Janine Margaret Lombard, Kostandinos Sideras, Seock-Ah Im, Cynthia X. Ma, Kuo-Ting Lee, Sung-Bae Kim, Yujia Li, Eunice Yuen, Shawn T. Estrem, Bastien Nguyen, Francesca Bacchion, Roohi Ismail-Khan, Muralidhar Beeram, Joohyuk Sohn Organizations Emory University School of Medicine, Atlanta, GA, Memorial Sloan Kettering Cancer Center, New York, NY, University of Vermont Cancer Center, Burlington, VT, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Institut Jules Bordet, Brussels, Belgium, Medical Oncology Department, Calvary Mater Hospital Newcastle, Newcastle, NSW, Australia, Mayo Clinic Florida, Jacksonville, FL, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, South Korea, Washington University School of Medicine, St. Louis, MO, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Eli Lilly and Company, Indiananapolis, IN, Eil Lilly and Company, Indianapolis, IN, Eli Lilly and Company, Indianapolis, IN, START Center for Cancer Care, San Antonio, TX, Severance Hospital, Yonsei University Health System, Seoul, South Korea Abstract Disclosures Research Funding Eli Lilly and Company Background: Imlunestrant is a next-generation, oral SERD designed to deliver continuous ER-target inhibition. In the first-in-human Phase 1a/b EMBER study (NCT04188548), imlunestrant demonstrated favourable safety, PK, and clinical benefit when administered as monotherapy or with targeted therapy in ER+, HER2- aBC. Here we present clinical data of imlunestrant with HER2 targeted therapy, in patients (pts) with ER+, HER2+ aBC enrolled in EMBER. Methods: Pts were randomized to imlunestrant (400mg po daily) + trastuzumab (H), with or without (±) abemaciclib (Part C) or received maintenance treatment with imlunestrant + H + pertuzumab (P) (Part E), at standard doses in 21-day cycles. Key eligibility (Part C): ≥ 2 prior HER2 directed regimens, no prior CDK4/6i or fulvestrant; (Part E): received 1st line induction taxane chemotherapy (any duration) + H + P, without disease progression and ≤1 prior therapy for aBC. Key endpoints included safety, PK, ORR, CBR and PFS. Results: Overall, 45 pts with ER+/HER2+ aBC received the following combinations: imlunestrant + H (n=18), imlunestrant + H + abemaciclib (n=21; 1 pt received 800 mg imlunestrant), and imlunestrant + H + P (n=6). Baseline characteristics, safety, and preliminary efficacy are presented below (Table). Most TEAEs were grade 1-2. Common TEAEs with imlunestrant + H were fatigue (33%) and nausea (28%); with imlunestrant + H + abemaciclib were diarrhea (100%), neutropenia (57%), fatigue (52%) and nausea (48%); and with imlunestrant + H + P were diarrhea (50%) and arthralgia (50%). Imlunestrant PK was consistent with those previously reported with no drug-drug interactions observed with the combinations. From Part C, sequencing of baseline plasma ctDNA samples (n=37) identified prevalent mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Clinical activity of imlunestrant in this ER+/HER2+ population, while based on small numbers, is promising. Conclusions: Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab was well tolerated, showed no drug-drug interactions, and demonstrated preliminary antitumor activity in pts with ER+/HER2+ aBC. Clinical trial information: NCT04188548. Part C Part E (maintenance) Imlunestrant + trastuzumab (H) N=18 Imlunestrant + H + abemaciclib N=21 Imlunestrant + H + P N=6 Prior therapies for aBC, median (range) 4 (1-10) 3 (1-7) 1 (1-1) All-grade/ Grade ≥3 TEAEs, % 17 (94)/6 (33) 21 (100)/11 (52) 6 (100)/1 (17) Grade ≥3 TRAEs, % 1 (6) 9 (43) 0 Dose reductions due to TRAEs, % 0 8 (38) 0 Discontinuations due to TRAEs, % 0 1(5) 0 ORR (CR+PR), n (%) 1/14 (7) 5/20 (25) 1/3 (33) CBR (CR or PR or SD≥24 wks), n (%) 8 (44) 10 (48) 6 (100) Median PFS, mo (95% CI) 5.3 (1.9, 6.6) 6.7 (2.7, 12.4) 15.8 (8.3, NA)