In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2− advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

e12543 Background: Previously, the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (aBC) has relied solely on endocrine therapy (ET). Unfortunately, almost all tumors developed resistance to ET. Although cyclin-dependent kinase inhibitors (CDKi)+ET clearly improve several clinical outcomes, many relevant questions remain unanswered: is there a benefit in (i) overall survival (OS) (ii) progression-free survival (PFS), and (iii) which CDKi is the best. Methods: A systematic review was performed to identify trials that compared CDKi+ET versus ET alone for HR+/HER2-aBC. Pooled meta-estimates were generated to assess CDKi+ET OS benefit and PFS benefit. Bayesian network meta-analysis was performed to compare each CDKi in terms of PFS, clinical benefit rate (CBR), response rate (RR) and toxicity. Results: 2,523 studies were screened and 8 studies satisfied the inclusion criteria. There was a trend for OS benefit with CDKi+ET compared to ET alone with 97% posterior probability that CDKi+ET is better than ET alone and HR 0.81 (95% CrI 0.66-1.00). CDKi+ET also showed > 99% probability of better than ET alone in both first and second-line settings in terms of PFS, RR, and CBR with PFS HR 0.56 (0.47-0.66) first line, 0.49 (0.39-0.60) second-line; RR OR 1.61 (1.29-1.97) first-line, 2.58 (1.71-3.80) second-line; CBR OR 1.75 (1.38-2.25) first-line, 2.38 (1.65-3.37) second-line. Ribociclib and abemaciclib showed weak-moderate evidence of better PFS and RR compared to palbociclib (64% to 81% posterior probability of superiority). There was no evidence of differences between ribociclib and abemaciclib. Palbociclib achieved better CBR compared to ribociclib and abemaciclib, although this difference may be related to the poor performance of placebo arm in studies that used palbociclib. In terms of safety, abemaciclib caused less neutropenia, but more diarrhea than ribociclib and palbociclib. Deep vein thrombosis was less frequent with ribociclib. Conclusions: CDKi+ET was 97% superior in terms of OS and > 99% superior in terms of PFS, RR, and CBR compared to ET alone. Further studies are necessary in order to find the best agent and the best sequencing of CDKi for HR+/HER2- aBC treatment.