Efficacy and Safety of Ribociclib for the Treatment of Advanced Breast Cancer: A Review of Subgroup Analyses from the Phase 3 Trial MONALEESA-2

Background: Endocrine therapy is recommended for patients with hormone receptor–positive (HR+) advanced and metastatic breast cancer without visceral crisis (symptomatic visceral disease). Ribociclib is an orally bioavailable inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) approved for use in combination with an aromatase inhibitor for the treatment of HR+, human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer. In the MONALEESA-2 study, first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) compared with placebo + letrozole in patients with HR+/HER2− advanced breast cancer.

Objectives: To discuss updated PFS data from the MONALEESA-2 study and to provide a summarized analysis of efficacy and safety results from the available subgroups in the study at the initial interim data cutoff (January 29, 2016).

Methods: MONALEESA-2 is an international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT01958021) in postmenopausal women with locally advanced or metastatic HR+/HER2− breast cancer randomly assigned 1:1 to receive oral ribociclib 600 mg or placebo on a 3-weeks-on, 1-week-off schedule, plus letrozole 2.5 mg/day (continuous schedule). Randomization was stratified by disease site (presence or absence of liver or lung metastases). Patients with any prior systemic therapy for advanced breast cancer, inflammatory breast cancer, active cardiac disease, or history of cardiac dysfunction (QTcF >450 msec) were excluded. The primary end point was PFS.

Results: At the initial interim analysis of the MONALEESA-2 trial (N = 668), median PFS occurred at 14.7 months in the placebo group but was not reached in the ribociclib group (hazard ratio [HR], 0.56; 95% CI, 0.43-0.72; P = 3.29×10⁻⁶). Results from a second overall survival interim analysis (data cutoff, January 2, 2017) showed that the median PFS for the ribociclib group was 25.3 months versus 16.0 months for the placebo group (HR, 0.568; 95% CI, 0.457-0.704; P = 9.63×10^–8). Further analysis of data from the initial analysis showed that PFS benefit was maintained across all of the following assessed subgroups: patients ≥65 years (HR, 0.608; 95% CI, 0.394-0.937); <65 years (HR, 0.523; 95% CI, 0.378-0.723); with <3 visceral metastases (HR, 0.607; 95% CI, 0.437-0.845); with ≥3 visceral metastases (HR, 0.456; 95% CI, 0.298-0.700); with bone-only disease (HR, 0.690; 95% CI, 0.381-1.249); with de novo disease (HR, 0.448; 95% CI, 0.267-0.750); with prior (neo)adjuvant chemotherapy (HR, 0.548; 95% CI, 0.384-0.780) or endocrine therapy (HR, 0.538; 95% CI, 0.384-0.754); and without prior (neo)adjuvant chemotherapy (HR, 0.548; 95% CI, 0.373-0.806) or endocrine therapy (HR, 0.570; 95% CI, 0.380-0.854). The adverse event (AE) profile was consistent across the ribociclib + letrozole subgroups; the most frequent AEs included neutropenia, leukopenia, alopecia, nausea, diarrhea, and fatigue. Discontinuation due to AEs occurred in 4% to 10% of patients in the ribociclib + letrozole subgroups and 1% to 3% of patients in the placebo + letrozole subgroups.

Conclusions: The consistent efficacy data and tolerable safety profile across patient subsets of the MONALEESA-2 trial support the use of ribociclib + letrozole for first-line treatment of postmenopausal women with advanced breast cancer, regardless of age, sites of metastases, or prior adjuvant therapy.

Disclosures: Support for this study was provided by Novartis Pharmaceuticals Corporation. Assistance with preparation of this abstract was provided under the direction of the author by MedThink SciCom (Cary, NC) with support from Novartis Pharmaceuticals Corporation.