CDK4/6 inhibitor plus endocrine therapy after progression on CDK4/6 inhibition in HR+/HER2- advanced breast cancer: a systematic review and meta-analysis (ReIGNITE study)

Abstract

Objective: To systematically evaluate the efficacy and safety of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6) combined with endocrine therapy (ET) compared to ET alone in patients with hormone receptor-positive and human epidermal growth factor receptor-type 2-negative (HR+/HER2-) advanced breast cancer who progressed to prior CDK4/6 therapy.
Methods: This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic reviews and
Meta-Analyses (PRISMA) guidelines and was registered in the International Prospective Register of Systematic Reviews
(PROSPERO), under CRD420251007031). Randomized clinical trials were identified through comprehensive searches on
PubMed, Cochrane, Embase databases, and in ASCO, ESMO, and SABCS conference proceedings. The primary outcome
was progression-free survival, analyzed using hazard ratios (HR) with a random-effects model and 95% confidence intervals (CI). Adverse effects were evaluated through pooled odds ratios (OR). Results: Five randomized clinical trials encompassing 1,184 patients were included. Overall, CDK4/6 plus ET significantly improved progression-free survival versus
ET alone, yielding a HR of 0.72 (95%CI 0.56–0.92; p<0.05). Subgroup analyses highlighted superior efficacy when patients
switched to a different CDK4/6 following progression (HR 0.61; 95%CI 0.48–0.77; p<0.05), whereas continuation of the same
agent showed no significant benefit (HR 0.93; 95%CI 0.68–1.28; p=0.15). Genetic profiling demonstrated that patients harboring PIK3CA mutations experienced notable progression-free survival improvement (HR 0.71; 95%CI 0.52–0.98; p<0.05),
whereas no significant benefit was observed among patients with ESR1 mutations (HR 0.86; 95%CI 0.60–1.24; p=0.06).
CDK4/6 plus ET significantly increased odds of anemia (OR 2.67; 95%CI 1.45–4.93; p<0.05), neutropenia (OR 19.27; 95%CI
9.94–37.35; p<0.05), thrombocytopenia (OR 4.51; 95%CI 2.20–9.25; p<0.05), and diarrhea (OR 4.29; 95%CI 1.28–14.39; p<0.05)
compared to ET alone. Conclusion: Treatment with CDK4/6 combined with ET beyond CDK4/6 progression demonstrated significant clinical benefit in HR+/HER2- advanced breast cancer, particularly when switching between different
CDK4/6. Patients with PIK3CA mutations notably benefitted from this strategy. These findings provide critical insights
for the refinement of future clinical guidelines.