Ribociclib as First Line Therapy for HR Positive, Advanced Breast Cancer.
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<1.29x10 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=3.29x10 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
The New England journal of medicine