An overview of safety profile and clinical impact of CDK4/6 inhibitors in breast cancer – a systematic review of randomized phase II and III clinical trials.

Introduction. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have transformed the treatment of hormone receptorpositive (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 endocrine-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 in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events. 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. Aim and objectives. The greatest challenge in the research and development of CDK4/6 inhibitors might lie in dealing with the adverse effects and potential drug tolerance. Further, understanding the underlying mechanism and exploring the ideal combination therapy might help overcome the selectivity and drug tolerance of CDK inhibitors. Considering the similar efficacies and indications of palbociclib, ribociclib and abemaciclib, the evaluation of their toxicity profiles may facilitate treatment choice. This review explores the safety profiles of palbociclib, ribociclib and abemaciclib in all randomized phase II and III clinical trials. Materials and method. This systematic review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Extended systematic research was performed on ClinicalTrials.gov database clinical trials registries with results published or registered before July 2023. The keywords used were: palbociclib, ribociclib, abemaciclib, phase II and III, randomized, and available results. The last search was performed on the 8th of August 2023. The search returned 690 results. Literature articles were systematically assessed by searching in the PubMed Medline database from January 2016 until July 2023. The following keywords were used: CDK4/6 inhibitors, breast cancer, and toxicities. The inclusion criteria were: clinical studies on breast cancer patients, clinical phase II and III studies using currently approved doses for palbociclib (125 mg/day orally for three weeks, followed by one week off), ribociclib (200 mg X 3/day orally for three weeks, followed by one week off) or abemaciclib (150 mg X 2/day orally in combination with ET or 200 mg/day orally in monotherapy), and studies for which safety data or at least one adverse reaction were reported in the article in the form of the percentage or number of patients. Only free full-text articles were assessed. The exclusion criteria were: articles with unavailable abstracts, non-English written articles, conference presentations, metaanalyses and literature reviews, non-clinical studies, post-hoc or subgroup analyses, retrospective studies, and studies in which the adverse effects were not reported. In vivo and in vitro studies were also excluded. The search returned 130 results, all of which were already included in the first search on ClinicalTrials.gov. Conclusions. CDK4/6 inhibitors are generally well tolerated. The most common adverse reactions encountered on CDK4/6 inhibitors treatment include neutropenia, leukopenia, anemia, thrombocytopenia, fatigue, gastrointestinal side effects, hepatotoxicity and QTc prolongation. However, there are some distinctions between palbociclib, ribociclib and abemaciclib. The most prevalent adverse effect of palbociclib and ribociclib is neutropenia, while particular for ribociclib are the QTc prolongation and hepatobiliary toxicity, and for abemaciclib, the gastrointestinal toxicity. All these adverse reactions can be very well managed due to the possibility of multiple dosage decreases and adjustments. Therefore, in clinical practice, acknowledging a side effect is of paramount importance to best manage it. To the best of our knowledge, this is the latest and newest literature review compounding all phase II and III randomized clinical trials regarding the three CDK4/6 inhibitors’ toxicities. This review will hopefully be of real help to all clinicians in managing the adverse effects of CDK4/6 inhibitors, by providing an easier way to research the reported percentage of specific adverse reactions in consecrated clinical trials. [ABSTRACT FROM AUTHOR]