BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could 
potentially overcome or delay resistance to endocrine therapy in advanced breast 
cancer that is positive for hormone receptor (HR) and negative for human 
epidermal growth factor receptor 2 (HER2).
METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the 
efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with 
letrozole for first-line treatment in 668 postmenopausal women with HR-positive, 
HER2-negative recurrent or metastatic breast cancer who had not received 
previous systemic therapy for advanced disease. We randomly assigned the 
patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 
1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. 
The primary end point was investigator-assessed progression-free survival. 
Secondary end points included overall survival, overall response rate, and 
safety. A preplanned interim analysis was performed on January 29, 2016, after 
243 patients had disease progression or died. Prespecified criteria for 
superiority required a hazard ratio of 0.56 or less with P<1.29×10-5.
RESULTS: The duration of progression-free survival was significantly longer in 
the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 
to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 
months. After 18 months, the progression-free survival rate was 63.0% (95% 
confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% 
CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at 
baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). 
Common grade 3 or 4 adverse events that were reported in more than 10% of the 
patients in either group were neutropenia (59.3% in the ribociclib group vs. 
0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of 
discontinuation because of adverse events were 7.5% and 2.1%, respectively.
CONCLUSIONS: Among patients receiving initial systemic treatment for 
HR-positive, HER2-negative advanced breast cancer, the duration of 
progression-free survival was significantly longer among those receiving 
ribociclib plus letrozole than among those receiving placebo plus letrozole, 
with a higher rate of myelosuppression in the ribociclib group. (Funded by 
Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).