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N Engl J Med. 2016 Nov 3;375(18):1738-1748. Epub 2016 Oct 7.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

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From the University of Texas M.D. Anderson Cancer Center, Houston (G.N.H.), and Texas Oncology-Baylor Charles A. Sammons Cancer Center and the U.S. Oncology Network, Dallas (J.O.) - all in Texas; Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv (S.M.S.), and Sheba Medical Center, Ramat Gan (S.P.-S.) - both in Israel; the Sarah Cannon Research Institute (H.A.B., D.Y.), Vanderbilt-Ingram Cancer Center (C.L.A.), and Tennessee Oncology (D.Y.) - all in Nashville; National Cancer Center Singapore, Singapore (Y.-S.Y.); Netherlands Cancer Institute and BOOG Study Center, Amsterdam (G.S.S.); Institut de Cancérologie de l'Ouest/René Gauducheau, Saint-Herblain (M.C.), Institut Gustave Roussy, Université Paris Sud, Villejuif (F.A.), University Hospital of Besançon, Besançon (C.V.), and Centre Léon Bérard, Lyon (T.B.) - all in France; Duke University Medical Center, Durham, NC (K.L.B.); Dana-Farber Cancer Institute, Boston (E.P.W.); University of Ulm, Ulm (W.J.), Onkologische Praxis, Velbert (A.N.), University of Tübingen, Tübingen (E.-M.G.), and Joint Practice for Interdisciplinary Oncology and Hematology, Freiburg (N.M.) - all in Germany; Tom Baker Cancer Centre, Calgary, AB, Canada (S.V.); University of Padua and Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy (P.C.); Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh (D.A.C.); Masaryk Memorial Cancer Institute, Brno, Czech Republic (K.P.); Florida Cancer Specialists-Sarah Cannon Research Institute, Fort Myers (L.L.H.); Breast Cancer Research Centre-Western Australia and Curtin University, Perth, Australia (A.C.); Department of Oncology, Vejle Hospital, Vejle, Denmark (E.J.); Arkhangelsk Clinical Oncology Dispensary, Arkhangelsk, Russia (O.B.); Hospital Universitario Virgen de la Victoria, Institute of Biomedical Research in Málaga, Málaga, Spain (E.A.); Oslo University Hospital, Oslo (E.W.); Virginia Cancer Specialists, Arlington (A.M.F.); Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan (L.-M.T.); Rainier Hematology-Oncology, Northwest Medical Specialties, Puyallup, WA (S.B.); Novartis Pharmaceuticals, East Hanover, NJ (F.X., M.M., C.G., S.H.); and Novartis Pharma, Basel, Switzerland (F.S.).



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).


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.


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.


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; number, NCT01958021 .).

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