Abstract 41P
Background
BM can be an important cause of morbidity and mortality in breast cancer. In addition to mechanisms of endocrine therapy resistance, like ESR1 mutations, BM have other causes of resistance such as inherent resistance to systemic therapy and limited drug tissue penetration. We have shown imlunestrant has activity in ER-dependent cell lines and in vivo models. Herein we describe a more comprehensive evaluation across a panel of breast cancer cell lines as well as multiple in vivo models and, for the first time, describe CNS penetrance and in vivo CNS activity in a BM model.
Methods
ER+ breast cancer cell lines and mouse models with ESR1 wild-type or mutant tumors were treated with imlunestrant alone or with abemaciclib, alpelisib or everolimus. Effects on ER degradation, ER-mediated gene expression, cell proliferation and viability were examined in vitro. In vivo drug exposure, target inhibition, and efficacy were analyzed, as well as overall survival in a brain orthotopic model (MCF7).
Results
Across cell lines, imlunestrant degraded ER and decreased ER-mediated gene expression. In addition, cell proliferation and tumor growth in ESR1-wild type and mutant models was significantly inhibited by imlunestrant. Combination of imlunestrant with abemaciclib, alpelisib or everolimus further enhanced the efficacy across cell lines and in vivo models, regardless of ER mutation status. Imlunestrant also showed sustained exposure in mouse tumor and brain up to 7 days after last dose, which correlated with robust tumor target inhibition measured by PGR expression. In a brain orthotopic tumor model, imlunestrant prolonged survival compared to either vehicle or fulvestrant (60%, 0% and 10% alive at 68 days, respectively).
Conclusions
Imlunestrant, a novel potent and orally available SERD, demonstrated activity across a panel of breast cancer cell lines and decreased tumor burden in both ESR1-wild type and mutant xenograft and PDX models. Imlunestrant also demonstrated CNS penetrance and improved survival in a brain orthotopic model. Imlunestrant is being evaluated in multiple global phase III clinical trials in metastatic and early breast cancer.
Drs. Cecilia Mur and Matthew VandeKopple have equally contributed to the study.
Legal entity responsible for the study
Eli Lilly and Company.
Funding
Eli Lilly and Company.
Disclosure
M. VandeKopple, A. Capen, L. Huber, N. Pulliam, M. Dowless, X. Gong: Financial Interests, Personal, Full or part-time Employment: Loxo Oncology at Lilly; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. C. Mur, W. Shen, C. Marugan, M.A. Castanares, D. Garcia-Tapia, B. Mattioni, J. Bastian, J. Manro, M.J. Ortiz Ruiz, M.J. Lallena, A. De Dios: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company.