The Efficacy And Safety Of Combination CDK4/6 Inhibitors And Endocrine Therapy For Advanced Breast Cancer:A Meta-analysis

[Objectives] Hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)constitutes 60%-65% of all the disease.Except for de novo disease is metastatic from primary diagnosis,a proportion of patients with early breast cancer will progress to advanced disease during the long-term treatment courses.This meta-analysis aimed to assess the efficacy and safety of cyclin-dependent kinase(CDK)4/6 inhibitors plus endocrine therapy(ET)in hormonal receptor-positive(HR+),human epidermal growth factor receptor 2-negative(HER2-)advanced breast cancer(ABC).[Methods]PubMed,Embase,Cochrane,Clinical Trials.gov.,ASCO,ESMO and AACR databases from inception to February 10,2021 for randomized controlled trials(RCTs)were searched for compared CDK 4/6 inhibitors plus ET to single-agent ET.The inclusion criteria were:(1)phase II or III randomized clinical trials;(2)eligible adults with HR+,HER2-advanced breast cancer,compared combination treatment of CDK 4/6 inhibitors and endocrine therapy to single-agent endocrine therapy;(3)The trials reported with enough data for the pooled analysis.The main outcomes analyzed were progression-free survival(PFS),overall survival(OS)and grade 3/4 hematology adverse events(AEs).[Results]9 RCTs with 5043 women were eligible and included among 938 identified studies.Compared with ET alone,CDK 4/6 inhibitors and ET combination improved in PFS(hazard ratio(HR)0.54,95% confidence interval(CI)0.50–0.58,p< 0.00001)and OS(HR 0.76,95%CI 0.67-0.84,p< 0.00001),regardless of ET strategies(HR 0.55,95% CI0.51–0.59 in PFS;HR 0.77,95% CI 0.69–0.85 in OS),treatment line of advanced disease(HR 0.53,95% CI 0.48– 0.57 in PFS;HR 0.75,95% CI 0.66–0.84 in OS)and menopausal status(HR 0.54,95% CI 0.50–0.58 in PFS;HR 0.76,95% CI 0.68–0.84 in OS).We found that CDK 4/6 inhibitors plus ET significantly increased the incidence of neutropenia(RR 19.32,p < 0.00001),leukopenia(RR 28.3,p< 0.00001)anemia(RR2.98,p < 0.0001)and Thrombocytopenia(RR 2.95,p< 0.00001)compared to single-agent ET,but those AEs last shortly and recover soon.[Conclusion]Combination therapy with CDK 4/6 inhibitors and ET prolongs survival in HR+/HER2-ABC.This combination is a better therapeutic strategy than endocrine monotherapy in HR +/HER2-ABC,regardless of treatment line,menopausal status and other individual characteristics.The adverse events can be tolerated.