Efficacy And Safety Of CDK4/6 Inhibitors In Hormone Receptor Positive And HER2-negative Advanced Breast Cancer: A Meta-analysis

Objective:This study is conducted to further evaluate the efficacy and safety of Cyclin-Dependent kinase 4 and 6(CDK4/6)inhibitors for hormone receptor-positive(HR+),HER2-negative(HER2-)advanced breast cancer,and explore the prefer population through subgroup analysis.Method:We searched the following databases from Jan 2008 up to April 2019:PUBMUD,MEDLINE,EMBASE,and The Cochrane Central Register of Controlled Trials.Searches were performed for all published and unpublished randomized controlled trials that compared CDK4/6 inhibitors plus endocrine therapy to endocrine therapy alone in HR+/HER2-advanced breast cancer.The primary outcome was progression-free survival(PFS),the secondary outcomes included clinical beneft rate(CBR),objective response rate(ORR),overall survival(OS),all grade adverse events(AEs)and grade 3 and 4 adverse events(G3-4 AEs).We calculated the hazard ratios(HRs)for PFS and OS,and risk ratios(RRs)for ORR,CBR,AEs and G3-4 AEs.Subgroup analyses were also performed to explore the prefer population of CDK4/6 inhibitors.The data analysis was calculated by Revman analysis software,and the results illustrated by forest plots.Statistical analysis was performed with the random-effects model.Statistical heterogeneity was assessed by calculating I~2 statistic.Reporting biases were evaluated by funnel plot and egger’s test.Result:Eight trials and 4,580 patients were included in this meta-analysis,2802 in the intervention group and 1778 in the control group.Compared to endocrine therapy alone,CDK4/6 inhibitors plus endocrine therapy not only produced a significantly longer PFS(HR 0.55,95%confidence interval[CI]:0.50-0.59,p<0.00001),but also manifested an extension of OS(HR 0.79,95%CI:0.67-0.93,p=0.004)for HR+/HER2-advanced breast cancer.Similarly,the benefit was also manifested in ORR(RR 1.47,95%CI:1.30-1.67,p<0.00001)and CBR(RR1.20,95%CI:1.12-1.30,p<0.00001).The improvements of PFS were observed in the combined treatment group as both the first-line(HR 0.56)and the second-line therapy(HR 0.53),and irrespective of previous treatment with chemotherapy(never received chemotherapy:HR 0.47;had received chemotherapy for(neo)adjuvant therapy:HR 0.57;had received chemotherapy for advanced disease:HR 0.47).The extension of PFS existed irrespective of menopausal status,the presence of visceral metastasis,their race or age.Nevertheless,more hematologic and gastrointestinal adverse events were observed with CDK4/6 inhibitors.The common Grade 3-4 AEs is neutropenia(RR 31.95),leukopenia(RR 22.08),anemia(RR 2.24)and diarrhea(RR 2.60).Conclusion:Significant advantages of PFS and OS was observed for CDK4/6inhibitors in HR+/HER2-advanced breast cancer.Furthermore,the benefit of PFS was across all subgroups.However,CDK4/6 inhibitors are also associated with more adverse events.