Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis

Background: Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.

Methods: We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.

Results: 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3-4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.

Conclusions: Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.