Cyclin-Dependent Kinase 4/6 Inhibitors for Treatment of Hormone Receptor–Positive, ERBB2-Negative Breast Cancer

Importance: Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) and endocrine therapy (ET) has been a major advance for the treatment of hormone receptor-positive (HR+), ERBB2 (formerly HER2)-negative (ERBB2-) advanced or metastatic breast cancer. Observations: Randomized phase 3 studies demonstrated that the addition of CDK4/6i reduced the hazard risk of disease progression by approximately half compared with hormonal monotherapy (an aromatase inhibitor, tamoxifen, or fulvestrant) in the first-line (1L) and/or second-line (2L) setting. Hence, the US Food and Drug Administration and European Medicines Agency approved 3 CDK4/6i, in both 1L and 2L settings. However, differences among the CDK4/6i regarding mechanisms of action, adverse effect profiles, and overall survival (OS) are emerging. Both abemaciclib and ribociclib have demonstrated efficacy in high-risk HR+ early breast cancer. While ET with or without CDK4/6i is accepted as standard treatment for persons with advanced HR+ ERBB2- metastatic breast cancer, several key issues remain. First, why are there discordances in OS in the metastatic setting and efficacy differences in the adjuvant setting? Additionally, apart from HR status, there are few biomarkers predictive of response to CDK4/6i plus ET, and these are not used routinely. Despite the clear OS advantage noted in the 1L and 2L metastatic setting with some CDK4/6i, a subset of patients with highly endocrine-sensitive disease do well with ET alone. Therefore, an unanswered question is whether some patients can postpone CDK4/6i until the 2L setting, particularly if financial toxicity is a concern. Finally, given the lack of endocrine responsiveness following progression on some CDK4/6i, strategies to optimally sequence treatment are needed. Conclusions and Relevance: Future research should focus on defining the role of each CDK4/6i in HR+ breast cancer and developing a biomarker-directed integration of these agents.