biomarkers Exploratory biomarkers in MONARCH 1, a phase II study of abemaciclib monotherapy in hormone-receptor positive (HR ) HER2- metastatic breast cancer (MBC)

Abstract

Background: Abemaciclib is a selective inhibitor of CDK4 & 6 that is dosed orally on a continuous schedule. In the MONARCH 1 phase II study (NCT02102490), abemaciclib monotherapy demonstrated antitumor activity with an objective response rate of 19.7% and a clinical benefit rate (CBR = PR + SD > 6 months) of 42.4% in women with previously treated HR+ HER2- MBC whose disease had progressed on or after prior endocrine therapy and who had received 1-2 prior chemotherapies in the metastatic setting. Methods: Exploratory biomarker analyses of paired pre- and on-treatment blood exosomes and formalin-fixed paraffin-embedded (FFPE) archival tumor tissues from patients in MONARCH 1 were performed. Exosomal preparations from baseline samples (n = 68), day 15 of cycle 1 (C1D15) treatment (n = 68), and samples following treatment discontinuation (n = 59) were analyzed as a novel "liquid biopsy" using an automated multi-modal multiplexed platform (Modaplex, QIAGEN). FFPE tumors (n = 77) were also analyzed for mRNA expression of cell cycle related genes as well as normal reduction mammoplasty tissues (n = 19) for comparison. Results: In blood, analysis at C1D15 revealed several changes in mRNA levels of cell-cycle related genes, including decreases in E2F1-4, and an increase in CCND1; these changes reverted following treatment discontinuation. For baseline exosome samples, notable differences were observed in some mRNAs compared to archival tumor. Cell cycle mRNA expression profiles were distinct in FFPE tumors of MBC patients compared to normal breast tissues. In single marker analysis of tumors, higher mRNA levels of retinoblastoma (RB) correlated with specific efficacy outcomes including disease control rate (DCR = PR + SD), CBR, PFS, and treatment duration (p < 0.05); some associations were also observed for other genes. In multi-marker analysis, mRNA levels of RB1, CCND1, CCNE1, cMYC, and CDK2 further identified response sub-groups. Conclusions: Changes in mRNAs by C1D15 included inhibition of proliferation genes; cessation of treatment resulted in a reversal. Higher tissue levels of RB mRNAs correlated with DCR, CBR, PFS, and treatment duration.