On 13 March 2017, the United States Food and Drug Administration (FDA) approved the second selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor ribociclib (Kisqali®, Novartis) for use in combination with an aromatase inhibitor as initial treatment for postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.
The approval was based on an interim analysis of the phase III MONALEESA-2 trial, published in The New England Journal of Medicine in October 2016. This trial compared ribociclib plus the aromatase inhibitor letrozole versus letrozole alone in 668 postmenopausal women who had received no prior systemic therapy for their advanced breast cancer. At 15.3 months follow-up, the combination of ribociclib and letrozole had significantly improved progression-free survival (PFS) compared to letrozole alone (PFS not reached vs 14.7 months; HR 0.556, P<.0001) with the benefit seen across all patient subgroups. Objective response rate was also improved with the combination (52.7% vs 37.1%). According to a company statement, subsequent analysis at 26.3 months follow-up demonstrated median PFS of 25.3 months with ribociclib combination, compared with 16.0 months for letrozole alone; overall survival data are not yet mature.
The most common grade 3/4 adverse events seen with the ribociclib/letrozole combination were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase (9% vs 1%). Ribociclib is accompanied by warnings about QT interval prolongation and hepatobiliary toxicity; clinicians are advised to monitor electrocardiograms and liver function tests.
Approval of ribociclib provides further support for the role of CDK4/6 inhibitors in HR-positive advanced breast cancer. The first drug in this class, palbociclib, was approved in February 2015 and has since become a standard of care in combination with an aromatase inhibitor for first-line treatment of patients with HR-positive/HER2-negative advanced breast cancer. Based on confirmatory results from phase III PALOMA 2 trial FDA on 31 March 2017 converted accelerated approval to full approval. Palbociclib is also approved in combination with fulvestrant for patients with metastatic disease progressing on initial endocrine therapy.