An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer—A Systematic Review of Randomized Phase II and III Clinical Trials

Abstract

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.

A Canadian real world prospective observational study assessing the impact of hormone therapy ± targeted therapy in the treatment of HR+ HER2- advanced breast cancer

“…The absolute numbers favored ET + TT vs ET independent of the line of therapy, with statistical signi cant bene t in 1st line. These results are consistent with the ones reported from other studies, suggesting that the increased understanding of endocrine resistance and its targeted approaches may positively impact the outcomes of patients with HR+/HER2-aBC [30][31][32]. When the TT added to ET is a CDK4/6i, the DOT increased by 59% (601 days; HR = 0.41; 95% CI; 0.32, 0.54), compared to ET alone, demonstrating a statistically and clinically meaningful bene t in a non-curative setting (Table 2).…”

“…When the TT added to ET is a CDK4/6i, the DOT increased by 59% (601 days; HR = 0.41; 95% CI; 0.32, 0.54), compared to ET alone, demonstrating a statistically and clinically meaningful bene t in a non-curative setting (Table 2). Additionally, the well known and favorable safety pro le of CDK4/6i may have allowed longer treatment exposure, in comparison to other TTs [31,33]. These ndings are comparable to previous e cacy and safety data reported from pivotal RCTs, showing a consistent bene t in progression free intervals, which reassures the currently available evidence supporting CDK4/6i use [34][35][36].…”

Adverse Event Profiles of CDK4/6 inhibitors: A pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

“…Notably, very few skin and musculoskeletal AEs were reported for abemaciclib in our study. In previous studies, skin and musculoskeletal AEs due to CDK4/6 inhibitors were mainly in the form of rash (10%-25%), alopecia (5%-27%), and pruritus (7%-16%), mostly grade 1-2, with a very low incidence of grade 3 (approximately 1%) [42]. Patients are advised to avoid excessive sun exposure, maintain skin care, and use mild moisturizers.…”