Ribociclib (LEE011) is a selective cyclin-dependent kinase inhibitor. It helps slow the progression of cancer by inhibiting two proteins, the cyclin-dependent kinase 4 and 6 (CDK 4/6), which interact with cyclin D1. Thereby, the retinoblastoma (Rb) protein phosphorylation is inhibited and CDK-mediated G1 to S phase transitions are prevented. As a consequence, the cell cycle in the G1 phase is arrested, which stops the cancer cell growth. Ribociclib has not yet been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

This report is based on the interim analysis of the randomised, double-blind, placebo-controlled MONALEESA-2 phase III study, which assessed the safety and efficacy of ribociclib in combination with letrozole for postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor 2 negative recurrent or metastatic breast cancer. A total of 668 patients were randomly assigned in a 1:1 ratio to either receive ribociclib or placebo in combination with letrozole. The stratification of randomisation was based on the presence or absence of liver or lung metastases. The results of the interim analysis were reported after disease progression or death had occurred in 243 patients. The primary endpoint of the MONALEESA-2 trial was locally assessed progression-free survival (PFS), according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. The 12-month as well as the 18-month PFS rates were improved in the ribociclib group. In contrast, no data on median overall survival (OS), median PFS and quality of life (QoL) were available at the time of data cut-off. In terms of safety, ≥3 grade adverse events (AEs) could be observed more often in the ribociclib group than in the placebo group. The most common AEs of any grade in the ribociclib group were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue (36.5%) and diarrhoea (35.0%).

Overall, even if the addition of ribociclib to letrozole increases the rate of toxicity significantly, there may be a benefit gained from adding it, since ribociclib increased the PFS rate by 11.9% and 20.8% (12-months vs. 18-months analysis). However, no evidence regarding the comparative OS advantage of ribociclib in combination with letrozole and no median PFS data were reported. Nevertheless, it might be crucial to investigate the impact of the treatment with CDK 4/6 inhibitors on the endocrine sensitivity of subsequent therapies. In addition, the effectiveness of ribociclib has not been supported by QoL outcomes. These and the lack of potential biomarkers highlight the necessity for further studies in order to identify those patients who would benefit the most from the treatment with ribociclib.