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

TLDR

The study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of orally administered abemaciclib in a multicenter phase I dose‑escalation followed by tumor‑specific cohorts for breast cancer, NSCLC, glioblastoma, melanoma, and colorectal cancer. The trial enrolled 225 patients, with 33 in dose‑escalation and 192 in tumor‑specific cohorts. Dose‑limiting toxicity was grade 3 fatigue, with a maximum tolerated dose of 200 mg every 12 h; common adverse events included fatigue, gastrointestinal, renal, and hematopoietic effects; plasma levels rose with dose and showed pharmacodynamic activity in proliferating keratinocytes and tumors; radiographic responses were observed in previously treated breast cancer, NSCLC, and melanoma patients, with a 31 % overall response rate and 61 % achieving response or stable disease ≥6 months in hormone‑receptor‑positive breast cancer, demonstrating single‑agent activity of abemaciclib across these solid tumors. Published in Cancer Discovery 6(7):740‑753, ©2016 AACR.

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.