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 profi le, 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 tumorspecifi c 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-specifi c 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 fi rst selective inhibitor of CDK4 and CDK6 with a safety profi le allowing continuous dosing to achieve sustained target inhibition. This fi rst-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53.

CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer

“…In the subgroup of patients with GBM treated on this study, three patients achieved durable disease stabilization ( 4 ). Although this will need to be confi rmed in larger late-phase clinical trials, the potential effi cacy of abemaciclib for the treatment of GBM or even patients with brain metastases may possibly open up additional new drug applications.…”

“…In this issue, Patnaik and colleagues report data from the phase I trial of abemaciclib, which led in part to the FDA breakthrough therapy designation for refractory hormone receptor-positive (HR + ) advanced breast cancer ( 4 ). This study comprised a two-stage phase I trial design with dose escalation and expansion cohorts conducted in multiple a priori -determined tumor-specifi c groups.…”

“…The authors established the recommended phase II dose (RP2D) at 200 mg twice daily of abemaciclib and, importantly, observed antitumor activity in multiple solid tumors at this dose ( 4 ). Abemaciclib demonstrated a response rate of 23%, a clinical benefi t rate of 49%, and median progressionfree survival of 5.8 months in heavily pretreated patients with advanced breast cancers.…”

“…However, abemaciclib appears to have higher rates of fatigue (41% all grades; 3% grades 3-4) and diarrhea (63% all grades; 5% grades 3-4; ref. 4 ). Diarrhea prophylaxis with loperamide may reduce the rate of diarrhea, and this is being investigated in ongoing studies.…”

Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

“…The CDK4 pathway is associated with activating genomic alterations in 22%-78% of cases in cutaneous melanoma (23) and CDK4 inhibitor PD0332991 (also known as palbociclib) has demonstrated antitumor activity in NRAS-mutant melanomas in a preclinical mouse model (24), indicating the CDK4 pathway as a potential therapeutic target. Recently, a number of highly selective CDK4/6 inhibitors, such as PD0332991, LEE011 (also known as ribociclib), and LY2835219 (also known as abemaciclib), have been developed and entered clinical trials (25)(26)(27)(28)(29). Although the final outcomes of these clinical trials have not been completely evaluated at present, targeted therapies using CDK4/6 inhibitors are still expected for melanoma patients.…”