Skin Toxicities with Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Signals from Disproportionality Analysis of the FDA Adverse Event Reporting System

Background Cyclin-dependent kinase (CDK)-4/6 inhibitors have been associated with dermatologic reactions, especially alopecia, in pivotal trials. Objective We aimed to comprehensively describe skin toxicities with CDK4/6 inhibitors reported in the real world through the US FDA Adverse Event Reporting System (FAERS). Methods Cutaneous adverse events (AEs) were characterized in terms of spectrum and clinical features, including seriousness (with fatality proportion), latency, and discontinuation. Disproportionality analyses were performed through the reporting odds ratio (ROR) and 95% confidence interval (CI) by comparing CDK4/6 inhibitors with other anticancer drugs used in breast cancer. Results As of December 2020, a total of 7986 cutaneous events were reported with CDK4/6 inhibitors (15% of total AEs with CDK4/6 inhibitors), mainly by consumers (39.6%), with 43.5% classified as serious and 25% requiring discontinuation. In 49% of the cases, five or more noncutaneous events were co-reported. The most frequently reported cutaneous events were alopecia ( N = 3528), rash ( N = 1493), and pruritus ( N = 1211): rashes were recorded in the first month (median onset 28 days), whereas alopecia and nail alterations were recorded after a median of 67 and 112 days, respectively. Several cutaneous AEs were associated with increased reporting, including vitiligo ( N = 6; ROR 8.88; 95% CI 2.95–22.46) and bullous dermatitis with ribociclib ( N = 7; ROR 2.90; 95% CI 1.13–6.27); erythema multiforme with abemaciclib ( N = 9; ROR 5.80; 95% CI 2.57–11.48); onychoclasis ( N = 142, ROR 2.27; 95% CI 1.83–2.79) and trichorrhexis ( N = 22; ROR 3.27; 95% CI 1.78–5.93) with palbociclib. Conclusions Although causality cannot be demonstrated, a diverse reporting pattern of cutaneous AEs emerged from FAERS, including dermal/epidermal conditions, hair/nail disorders, and serious bullous conditions, with variable onsets and a remarkable proportion of discontinuations. The potential differential reporting among CDK4/6 inhibitors deserves further investigation.