title: Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.
abstract: We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.
  
  
  
  Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas. amita.patnaik@start.stoh.com geoffrey_shapiro@dfci.harvard.edu.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: University of California, Los Angeles, California.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Tolaney
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: University of California, Los Angeles, California.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, Texas.
authors.forename: Drew W
authors.initials: DW
authors.lastname: Rasco
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: John F
authors.initials: JF
authors.lastname: Hilton
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beckmann
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Schade
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Angie D
authors.initials: AD
authors.lastname: Fulford
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Tuan S
authors.initials: TS
authors.lastname: Nguyen
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Kulanthaivel
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Li
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Martin
authors.initials: M
authors.lastname: Frenzel
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Damien M
authors.initials: DM
authors.lastname: Cronier
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. amita.patnaik@start.stoh.com geoffrey_shapiro@dfci.harvard.edu.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C000590451:abemaciclib; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6