Comparative efficacy of adjuvant CDK4/6 inhibitors in early breast cancer: A hazard ratio-based network meta-analysis using the NetMetaEasy platform

BACKGROUND: Adjuvant CDK4/6 inhibitors have shown variable results across phase III trials in hormone receptor-positive, HER2-negative early breast cancer, and no direct comparisons exist to clarify their relative efficacy. Network meta-analysis (NMA) enables the integration of direct and indirect evidence to compare multiple treatments simultaneously. In this study we applied a hazard ratio-based NMA to evaluate the comparative effectiveness of abemaciclib, ribociclib, and palbociclib using invasive disease-free survival (iDFS) as the primary endpoint. Endocrine therapy (ET) served as the standard-of-care reference across trials. METHODS: Data from four randomized phase III trials (case n=17,741) were analyzed. Treatment nodes included abemaciclib+endocrine therapy (ET), ribociclib+ET, palbociclib+ET, and ET alone. Analyses were performed using the NetMetaEasy platform (https://www.metaanalysisonline.com/netmetaeasy), an R/Shiny-based implementation supporting binary, continuous, and summary-effect inputs. A frequentist random-effects NMA was conducted using the inverse-variance method with the DerSimonian-Laird estimator for between-study variance (τ²). Standard NMA outputs were generated, including forest plots, network geometry, treatment ranking (P-scores), inconsistency assessments, and funnel plots. RESULTS: Ribociclib+ET showed the strongest effect versus ET (HR 0.72; 95% CI 0.62-0.83). Abemaciclib+ET also improved iDFS (HR 0.73; 95% CI 0.66-0.82). Palbociclib+ET did not differ significantly from ET (HR 0.89; 95% CI 0.79-1.00). Indirect comparisons yielded HR 0.82 (95% CI 0.70-0.97) for abemaciclib versus palbociclib, HR 1.25 (95% CI 1.03-1.50) for palbociclib versus ribociclib, and HR 1.03 (95% CI 0.85-1.23) for abemaciclib versus ribociclib. P-scores ranked ribociclib+ET highest (0.86), followed by abemaciclib+ET (0.80) and palbociclib+ET (0.33). Funnel-plot inspection did not indicate small-study effects. CONCLUSIONS: In this hazard ratio-based NMA, abemaciclib and ribociclib significantly improved iDFS compared with endocrine therapy, whereas palbociclib did not. Our findings illustrate the utility of NMA for comparative evaluation in the absence of head-to-head trials.