Continuation of CDK4/6 Inhibition and Switching of Hormonal Therapy After Progression on Prior CDK4/6 Inhibitors in HR+/HER2- Breast Cancer: A Systematic Review and Meta-Analysis.

Abstract

This study aims to determine the efficacy of maintaining cyclin-dependent kinase 4/6 (CDK4/6) inhibition and switching endocrine therapy (ET) versus ET alone after progression on prior CDK4/6 inhibitors (CDK4/6i) in patients with hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. We identified phase II and III comparative randomized clinical trials through a systematic search across relevant clinical databases. A random effects model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) according to the inverse-variance method. Heterogeneity was measured using tau² and I² statistics. The pooled odds ratio for the overall response rate was calculated through the Mantel-Haenszel method in a random effects model. A narrative review was done to describe treatment-related side effects. After the systematic search, we identified four trials (n=833) that accomplished the inclusion criteria. Switching ET and maintaining CDK4/6 inhibition was associated with longer PFS than switching the hormonal therapy alone (HR: 0.77; 95% CI: 0.60-0.99; p=0.04) with moderate heterogeneity among the included trials (tau²: 0.04; I²: 56%; p=0.08). Subgroup analysis identified a PFS benefit from this approach independently of the length of previous CDK4/6 inhibition. The PFS benefit was more pronounced in those individuals who received abemaciclib or ribociclib as second CDK4/6i. Continuation of CDK4/6 inhibition was associated with higher rates of grade 3 and 4 neutropenia (range: 25-40%) and anemia (range: 1.7-11%). In conclusion, switching CDK4/6i and ET conferred a statistically significant improvement of PFS in comparison to ET alone in patients with progression or recurrence on prior CDK4/6i-containing therapy.