Exploratory Biomarkers in MONARCH 1: A Phase 2 Study of Abemaciclib Monotherapy in HR+/HER2– Metastatic Breast Cancer

Abemaciclib is a selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 that prevents completion of the cell cycle in a number of cancer cell lines, and has shown efficacy in treating patients with breast cancer. In the phase 2 MONARCH 1 study (NCT02102490), which included women with advanced hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) breast cancer that had disease progression following antiestrogen therapy, abemaciclib monotherapy showed antitumor activity with an objective response rate of 19.7% and a clinical benefit rate (CBR; defined as partial response [PR] plus stable disease [SD] of ≥6 months) of 42.4%.

In this post-hoc analysis of the MONARCH 1 study, exploratory biomarkers were investigated by comparison of paired pre- and on-treatment blood exosomes and formalin-fixed paraffin-embedded (FFPE) archival tumor tissues. “Biopsied tissue is the ‘gold standard’ in biomarker analysis,” noted Dr Caroline Dive of Manchester, UK, who was unaffiliated with the study, “but exosome analysis is a very exciting, emergent new field.” Exosome samples at baseline (n = 68), after 15 days of the first treatment (n = 68), and following treatment discontinuation (n = 59) were analyzed using an automated multimodal multiplexed platform (Modaplex, QIAGEN). FFPE tumor samples (n = 77) were also analyzed for mRNA expression of cell-cycle–related genes and compared with normal reduction mammoplasty tissues (n = 19).

In the exosome analysis, samples from day 15 of treatment showed several changes in mRNA levels of cell-cycle–related genes, including decreases in the E2F1-4 transcription factors that are associated with cell proliferation, and an increase in CCND1, which is a marker for cell-cycle arrest. Discontinuation of treatment was associated with a reversion to baseline levels in the exosome analysis. mRNA expression profiles of cell-cycle–related genes were distinct in FFPE tumors of metastatic breast cancer patients compared with normal breast tissues, and differences were also observed in some mRNAs when compared with baseline exosome samples. In single-marker analysis of tumors, higher mRNA levels of retinoblastoma (RB) correlated with specific efficacy outcomes, including disease control rate (DCR; defined as PR plus SD), CBR, progression-free survival (PFS), and treatment duration (all P <0.05). In a multimarker analysis, mRNA levels of RB1, CCND1, CCNE1, cMYC, and CDK2 further identified response subgroups.

The changes in the mRNA profiles of cell proliferation genes that were seen at day 15 of treatment confirm abemaciclib’s mechanism of action in inhibiting CDKs 4 and 6. Notably, the cessation of treatment resulted in a reversion of these profiles to baseline levels. Higher tissue levels of RB mRNA correlated with DCR, CBR, PFS, and treatment duration, suggesting that this biomarker may be a prognostic indicator in abemaciclib treatment. “The question,” posed Dr Dive, “is how are these exploratory biomarkers going to be targeted and qualified in the future?”

Tolaney S, et al. ESMO 2016. Abstract LBA12.