G Curigliano1, P Gómez Pardo2, F Meric-Bernstam3, P Conte4, M P Lolkema5, J T Beck6, A Bardia7, M Martínez García8, F Penault-Llorca9, S Dhuria10, Z Tang10, N Solovieff11, M Miller10, E Di Tomaso11, S A Hurvitz12. 1. Istituto Europeo di Oncologia, via Ripamonti 435, 20141, Milan, Italy. Electronic address: giuseppe.curigliano@ieo.it. 2. Servicio Oncologia Médica, Vall d'Hebron University Hospital, Vall d'Hebron 119-129, 08035, Barcelona, Spain. 3. The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX, 77030, USA. 4. Istituto Oncologico Veneto, Via Gattamelata 64, 35128, Padua, Italy; University of Padova, Via Giustiniani 22, 35121, Padua, Italy. 5. University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands; Erasmus Medical Center Cancer Institute, Erasmus Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. 6. Highlands Oncology Group, 3232 N North Hills Blvd, Fayetteville, AR, 72703, USA. 7. Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. 8. Oncología Médica, Hospital del Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain. 9. Centre Jean Perrin, Unicancer and EA 4677 Université d'Auvergne, 58 rue Montalembert, 63011, Clermont-Ferrand, France. 10. Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA. 11. Novartis Institutes for BioMedical Research, 230 Massachusetts Avenue, Cambridge, MA, 02139, USA. 12. University of California, Los Angeles, 2825 Santa Monica Blvd, Suite 211, Santa Monica, CA, 90404, USA.
Abstract
OBJECTIVES:Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS:Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).
RCT Entities:
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).
Authors: Cynthia X Ma; Feng Gao; Jingqin Luo; Donald W Northfelt; Matthew Goetz; Andres Forero; Jeremy Hoog; Michael Naughton; Foluso Ademuyiwa; Rama Suresh; Karen S Anderson; Julie Margenthaler; Rebecca Aft; Timothy Hobday; Timothy Moynihan; William Gillanders; Amy Cyr; Timothy J Eberlein; Tina Hieken; Helen Krontiras; Zhanfang Guo; Michelle V Lee; Nicholas C Spies; Zachary L Skidmore; Obi L Griffith; Malachi Griffith; Shana Thomas; Caroline Bumb; Kiran Vij; Cynthia Huang Bartlett; Maria Koehler; Hussam Al-Kateb; Souzan Sanati; Matthew J Ellis Journal: Clin Cancer Res Date: 2017-03-07 Impact factor: 12.531
Authors: G Curigliano; H J Burstein; E P Winer; M Gnant; P Dubsky; S Loibl; M Colleoni; M M Regan; M Piccart-Gebhart; H-J Senn; B Thürlimann; F André; J Baselga; J Bergh; H Bonnefoi; S Y Brucker; F Cardoso; L Carey; E Ciruelos; J Cuzick; C Denkert; A Di Leo; B Ejlertsen; P Francis; V Galimberti; J Garber; B Gulluoglu; P Goodwin; N Harbeck; D F Hayes; C-S Huang; J Huober; K Hussein; J Jassem; Z Jiang; P Karlsson; M Morrow; R Orecchia; K C Osborne; O Pagani; A H Partridge; K Pritchard; J Ro; E J T Rutgers; F Sedlmayer; V Semiglazov; Z Shao; I Smith; M Toi; A Tutt; G Viale; T Watanabe; T J Whelan; B Xu Journal: Ann Oncol Date: 2017-08-01 Impact factor: 32.976