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

UNLABELLED:

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.

SIGNIFICANCE:

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: Amita Patnaik, Lee S Rosen, Sara M Tolaney, Anthony W Tolcher, Jonathan W Goldman, Leena Gandhi, Kyriakos P Papadopoulos, Muralidhar Beeram, Drew W Rasco, John F Hilton, Aejaz Nasir, Richard P Beckmann, Andrew E Schade, Angie D Fulford, Tuan S Nguyen, Ricardo Martinez, Palaniappan Kulanthaivel, Lily Q Li, Martin Frenzel, Damien M Cronier, Edward M Chan, Keith T Flaherty, Patrick Y Wen, Geoffrey I Shapiro
• Journal: Cancer discovery (Cancer Discov) Vol. 6 Issue 7 Pg. 740-53 (07 2016) ISSN: 2159-8290 [Electronic] United States
• PMID: 27217383 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Benzimidazoles
• abemaciclib
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Aminopyridines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Breast Neoplasms (diagnosis, drug therapy)
• Carcinoma, Non-Small-Cell Lung (diagnosis, drug therapy)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Disease Models, Animal
• Drug Monitoring
• Female
• Humans
• Lung Neoplasms (diagnosis, drug therapy)
• Male
• Mice
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms (diagnosis, drug therapy, mortality)
• Tomography, X-Ray Computed
• Treatment Outcome
• Xenograft Model Antitumor Assays