Overall survival of CDK4/6-inhibitors-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors þ endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HRþ)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups. Methods: We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors þ ET reporting OS data in first- or second-line therapy of HRþ/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP). Results: Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] 1⁄4 0.68, 95% confidence interval [CI] 1⁄4 0.54 to 0.85, I2 1⁄4 0.0%) and with visceral involvement (HR 1⁄4 0.76, 95% CI 1⁄4 0.65 to 0.89, I2 1⁄4 0.0%), with at least 3 metastatic sites (HR 1⁄4 0.75, 95% CI 1⁄4 0.60 to 0.94, I2 1⁄4 11.6%), in an endocrine-resistant (HR 1⁄4 0.79, 95% CI 1⁄4 0.67 to 0.93, I2 1⁄4 0.0%) and sensitive subset (HR 1⁄4 0.73, 95% CI 1⁄4 0.61 to 0.88, I2 1⁄4 0.0%), for younger than 65 years (HR 1⁄4 0.80, 95% CI 1⁄4 0.67 to 0.95, I2 1⁄4 0.0%) and 65 years or older (HR 1⁄4 0.71, 95% CI 1⁄4 0.53 to 0.95, I2 1⁄4 44.4%), in postmenopausal (HR 1⁄4 0.76, 95% CI 1⁄4 0.67 to 0.86, I2 1⁄4 0.0%) and pre- or perimenopausal setting (HR 1⁄4 0.76, 95% CI 1⁄4 0.60 to 0.96, I2 1⁄4 0.0%) as well as in chemotherapy-naive patients (HR 1⁄4 0.72, 95% CI 1⁄4 0.55 to 0.93, I2 1⁄4 0.0%). Conclusions: CDK4/6-inhibitors þ ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.