CDK4/6 inhibitors rechallenge post-progression in HR-positive HER2-negative advanced/metastatic breast cancer patients: a meta-analysis of Kaplan-Meier-reconstructed individual-level data.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard of care for hormone receptor (HR)-positive, HER2-negative advanced/metastatic breast cancer (BC). However, the optimal strategy after progression remains uncertain. PubMed, Cochrane, and Embase databases were searched in April 2025 for phase II/III clinical trials evaluating CDK4/6i rechallenge in advanced breast cancer. We evaluated progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards models, reporting hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were conducted on R (v.4.2.2). Eight trials including 1396 patients were included, of whom 839 received CDK4/6i rechallenge plus ET, and 557 received ET alone. Median PFS was 5.8 months vs 3.7 months, with a 29% reduction in risk of progression or death (HR 0.71; 95% CI 0.63-0.81; P < 0.001). No OS benefit was observed (HR 1.04; 95% CI 0.70-1.55). Switching to a different CDK4/6i appears to confer greater benefit (HR 0.61; 95% CI 0.52-0.72), yet most patients who switched CDK4/6i received abemaciclib, which was associated with the longest PFS (7.9 months) compared with palbociclib (4.6 months) or ribociclib (5.5 months). Patients harboring ESR1 or PIK3CA alterations demonstrated a median PFS of 5.3 (3.6-7.4) and 4.7 (3.6-6.7) months, respectively. This meta-analysis suggests that CDK4/6 inhibitor rechallenge post-progression offers additional benefit to ET alone.