A Systematic Literature Review of the Effectiveness of CDK 4/6 Inhibitors for First-Line Treatment of HR+/HER2− Advanced/Metastatic Breast Cancer: A Comparison of Real-World Evidence

Background/Objective: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for HR+/HER2− advanced/metastatic breast cancer (a/mBC), yet no head-to-head randomized trials have compared palbociclib, ribociclib, and abemaciclib. This systematic literature review (SLR) aimed to synthesize available real-world evidence (RWE) on the comparative effectiveness of these three CDK4/6i in the first-line setting. Methods: An SLR was conducted following PRISMA guidelines. Searches of MEDLINE, Embase, Cochrane, and gray literature (January 2015–September 2025) identified RWE studies reporting real-world progression-free survival (rwPFS) and/or overall survival (OS) for first-line CDK4/6i regimens. Eligible studies included adults with HR+/HER2− a/mBC receiving palbociclib, ribociclib, or abemaciclib, combined with endocrine-based therapy. Comparative outcomes were summarized qualitatively; study quality was assessed using the Newcastle–Ottawa Scale, ISPOR-AMCP-NPC questionnaire, and ESMO-GROW checklist. Results: From 13,345 records, 39 publications (32 unique studies) were identified, of which 21 were full-text studies meeting inclusion criteria. Most included studies used retrospective cohort designs, and approximately 50% evaluated all three CDK4/6is. Given the comparative nature of the included studies, quality issues were found to be related to study design and analytical approaches. Several analyses were unadjusted, and reporting of follow-up duration varied across studies, with some analyses providing incomplete follow-up information. Study sample sizes differed substantially across agents, with smaller populations generally reported for ribociclib and abemaciclib. Among the studies reporting rwPFS hazard ratios (HRs), 8/11 studies showed comparable rwPFS and 5/6 studies reported comparable OS outcomes between CDK4/6i regimens. Three full-text studies reported HRs favoring ribociclib or abemaciclib relative to palbociclib; these analyses primarily included populations receiving palbociclib, with smaller comparator cohorts for ribociclib and abemaciclib, as well as varied follow-up times. Conclusions: Most real-world studies included in the SLR suggested similar effectiveness of the three CDK4/6is in first-line HR+/HER2− a/mBC. Heterogeneity in patient characteristics, definitions of outcomes, follow-up time, sample size, and statistical approach may have important implications on study interpretability.