Comparative efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and network meta-analysis

Background: CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors are both emerging agents for hormonal receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. Evidence for the comparisons from head-to-head comparative trials is currently insufficient. This meta-analysis assessed the comparative efficacy and safety of these two groups of agents for HR+/HER2- metastatic breast cancer. Methods: Systematic searches of PubMed, Embase, CENTRAL, SciSearch between January 2010 to December 2019 were conducted. Randomized controlled trials (RCTs) which evaluated clinical benefits and toxicities of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy were adopted. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoint was treatment-related adverse event (TRAE). Pooled hazard ratio (HR) and risk rate (RR) were used to assess the differences between CDK4/6 and PI3K/AKT/mTOR inhibitors. Results: A total of twenty RCTs including 9771 participants were identified in this study. Pooled results showed that PFS was considerably prolonged by targeted therapy plus endocrine therapy. PFS was relatively better in CDK4/6 inhibitors than that of PI3K inhibitor group (HR, 1.43; 95%CrI, 1.12-1.61). Similar results were demonstrated in results after balancing lines of therapy or metastatic sites, both in viscera and bone-only. Coalesced outcomes revealed that CDK4/6 inhibitors plus endocrine therapy could significantly improve OS (HR, 0.78; 95%CrI, 0.65-0.94) than PI3K/mTOR inhibitors. Safety profiles of diarrhea and rash were consistent between CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors with no difference of estimated RR. Several TRAEs signified specificity, for instance, myelosuppression in CDK4/6 inhibitors or hyperglycemia in PI3K/mTOR inhibitors. Conclusions: Clinical efficacy is in favor of CDK4/6 inhibitors, and safety profiles are comparable between CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy.