Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis

J Natl Cancer Inst. 2020 Nov 1;112(11):1089-1097. doi: 10.1093/jnci/djaa071.

Abstract

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/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 + ET reporting OS data in first- or second-line therapy of HR+/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] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).

Conclusions: CDK4/6-inhibitors + 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.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Female
  • Humans
  • Letrozole / administration & dosage
  • Neoplasm Metastasis
  • Piperazines / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage
  • Pyridines / administration & dosage
  • Randomized Controlled Trials as Topic

Substances

  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Letrozole
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib