CDK4/6 inhibition versus mTOR blockade as second-line strategy in postmenopausal patients with hormone receptor-positive advanced breast cancer

Abstract

Background:Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib and abemaciclib) and mammalian target of rapamycin (mTOR) inhibitors (everolimus) are effective agents for restoring endocrine sensitivity in patients with advanced breast cancer progression on prior aromatase inhibitors. We conducted a network meta-analysis to compare these treatments in terms of progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR).Methods:The PubMed and Embase databases were searched for relevant publications between January 2000 and June 2018. Treatments were ranked based on a network meta-analysis. Ranking was determined by P-score. A random-effect model was used when heterogeneity was detected; otherwise, a fixed-effect model was used.Results:Six trials comprising 4063 patients formed the comparison network. Compared with everolimus plus exemestane, the combinations of palbociclib or abemaciclib with fulvestrant showed similar efficacies in PFS and no differences in ORR. For the CBR, palbociclib demonstrated improvement, while abemaciclib did not. Incidences of severe adverse events did not significantly differ. A total of 29%, 15.9%, and 4% of patients discontinued everolimus, abemaciclib, and palbociclib, respectively, due to toxicity.Conclusion:These results suggest similar efficacies between CDK4/6 inhibition and mTOR blockade; however, CDK4/6 inhibitors were associated with favorable toxicity profiles.

CDK4/6 inhibitors, PI3K/mTOR inhibitors, and HDAC inhibitors as second-line treatments for hormone receptor-positive, HER2-negative advanced breast cancer: a network meta-analysis

“…One previous network meta-analysis involving six trials with 4,063 patients indirectly compared the efficacy of palbociclib, abemaciclib and everolimus for restoring endocrine sensitivity and demonstrated that the combinations of palbociclib or abemaciclib with fulvestrant showed similar efficacies to everolimus plus exemestane in terms of PFS and ORR [ 43 ]. This finding indicates that the efficacies of CDK4/6 inhibition and mTOR blockade are similar.…”

Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

“…The most frequent AEs are hyperglycemia, stomatitis, anemia, dyspnea, and fatigue and this led to dose reduction in two-thirds of patients and a therapy discontinuation in more than 12% in several studies [ 74 ]. However, a network analysis showed a similar significant improvement of PFS in studies with CDK4/6 inhibitor- based combinations compared with studies with everolimus plus exemestane; no randomized trial of both these combinations has been performed [ 75 ]. An improvement of OS was observed in randomized phase III studies with everolimus, but without statistical relevance [ 76 ].…”

CDK4/6 inhibitors in advanced breast cancer, what is beyond?

“…There is some data suggested that the CDK4/6I may show some benefit of HR+/HER2+ABC. 50 Many ongoing phase II and III trials to justify the role of CDK4/6I with anti-HER2 therapy in HR+/HER2+ABC; NCT02448420, palbociclib, and trastuzumab±letrozole; NCT02947685, anti-HER-2 therapy/ET±palbociclib; NCT02657343, ribociclib in combination with trastuzumab or T-DM1.…”