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ABSTRACT
Introduction: Aberrant cellular proliferation due to dysregulation of the cyclin-dependent kinase (CDK) retinoblastoma (Rb)-pathway occurs in several cancers. Selective inhibition of CDK4/6 is an attractive target particularly in hormone-receptor positive (HR+) metastatic breast cancer (MBC), where it has transformed the treatment of these cancers in recent years. Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of HR+, HER2 negative (HER2-) MBC.
Areas covered: We reviewed and compared the pharmacology, clinical efficacy, and toxicity profiles of the three CDK4/6 inhibitors and discussed several challenges in the use of these drugs, particularly in identifying biomarkers, optimizing dosing strategies, and finding best combinations with other therapies.
Expert opinion: All three CDK4/6 inhibitors have shown remarkable efficacy when added to endocrine therapy in the treatment of HR+/HER2- MBC with consistent improvements in progression-free survival across all phase III trials. As efficacy appears similar between the drugs, differences in toxicities, dosing schedule, and monitoring requirements may influence the choice of CDK4/6 inhibitor. There is a paucity of predictive biomarkers that have been identified thus far, but a few promising biomarkers have been studied in the preclinical setting and results of ongoing clinical studies are awaited to validate their utility.
Article highlights
Three selective CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib have been approved for the treatment of HR+/HER2- metastatic breast cancer in combination with endocrine therapy in the first- and/or second-line setting.
Palbociclib and ribociclib have higher rates of G3-4 neutropenia (50–70%) than abemaciclib (20–25%), while abemaciclib has higher rates of diarrhea (all grade 80%, G3-4: 10%) compared to palbociclib and ribociclib (all grade 25–35%, G3-4: 1–2%).
Apart from loss of Rb function (accounting for 5% of resistance), proposed resistance mechanisms to CDK4/6 inhibitors include enhanced MAPK signaling, dysregulation of PI3K/mTOR signaling, and upregulation of cyclin E and CDK2.
Important questions that are currently being explored in ongoing clinical trials include: role of CDK4/6 inhibitors in the adjuvant setting, role of CDK4/6 inhibitors in other breast cancer subtypes (e.g. triple-negative breast cancer, HER2 + breast cancer), optimal timing of addition of CDK4/6 inhibitor to endocrine therapy in MBC (first- or second-line setting), role of continuing CDK4/6 inhibition beyond progression, efficacy of novel combinations (e.g. with PI3K/mTOR inhibitors, immunotherapy).
Identification of predictive biomarkers has been challenging; promising ones in the preclinical setting include D-cyclin activating features (DCAF) and Rb-positivity with low-molecular-weight isoform of cyclin E negativity (Rb+/LMWE-).
Declaration of interest
SC Lee has served on advisory boards for Pfizer (palbociclib) and Novartis (ribociclib) and is the site principal investigator of the ongoing adjuvant abemaciclib trial (monarchE; Eli Lilly). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.