LAUSR

Background: Cyclin D-cyclin-dependent kinase (CDK) 4/6 complexes promote cell proliferation through phosphorylation of retinoblastoma protein (Rb). In breast cancer, cyclin D-CDK4/6 activity can be increased through cyclin D gene (CCND1) amplification or loss of the CDK4/6 negative regulator p16. Here we present efficacy data from the Phase III MONALEESA-2 study of ribociclib (CDK4/6 inhibitor) + letrozole vs. placebo + letrozole for first-line treatment of HR+, HER2- ABC, assessed in baseline tumors by protein levels of Rb, p16, the cell proliferation marker Ki67, and by gene expression levels of CDKN2A (p16) and CCND1. Methods: Postmenopausal women with HR+, HER2- ABC with no prior systemic therapy for advanced disease were randomized 1:1 to receive ribociclib or placebo (600 mg/day 3-weeks-on/1-week-off) + letrozole (2.5 mg/day continuous). The primary endpoint was investigator-assessed progression-free survival (PFS). Provision of a representative baseline tumor biopsy or archival tissue at screening was mandatory if available. Baseline tumor tissue was evaluated for protein biomarkers (immunohistochemistry) and gene expression (NanoString nCounter® Human Cancer Reference panel). Results: Of 668 patients randomized, 479 were evaluable for total Rb, and 416 (87%) displayed high levels (H-score ≥100). p16 protein levels were evaluable in 405 patients; 165 (41%) had low (H-score 14% of cells in 247 (53%) patients. The median messenger RNA expression level was used as the cut-off to define patients with low or high baseline CDKN2A and CCND1 gene expression. An improved PFS was observed by the addition of ribociclib to letrozole in all the above patient subgroups, with hazard ratios ranging from 0.40 (high p16 by H-score; 95% confidence interval [CI] 0.16-1.0; p=0.06) to 0.64 (≤14% Ki67-positive cells; 95% CI 0.39-1.0; p=0.07). Patients with less or greater than 14% Ki67-positive cells, lower or higher p16 levels, Rb levels, or CDKN2A or CCND1 gene expression benefitted from the addition of ribociclib to letrozole to a similar extent. Conclusions: A consistent benefit from ribociclib + letrozole vs. placebo + letrozole was observed irrespective of baseline Rb, p16, and Ki67 levels or CDKN2A and CCND1 gene expression levels. Hormone receptor positivity remains the only established biomarker of response to CDK4/6 inhibitors. Citation Format: Fabrice Andre, Salomon M. Stemmer, Mario Campone, Katarina Petrakova, Shani Paluch-Shimon, Yoon-Sim Yap, Norbert Marschner, Arlene Chan, Cristian Villanueva, Lowell L. Hart, Carlos L. Arteaga, Gabe S. Sonke, Eva-Maria Grischke, Emilio Alba, Arnd Nusch, Denise A. Yardley, Erik Jakobsen, Sibel Blau, Sara M. Tolaney, Faye Su, Wei He, Caroline Germa, Gabriel N. Hortobagyi. Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT045. doi:10.1158/1538-7445.AM2017-CT045