title: Comparative Effectiveness of Second-Line Targeted Therapies for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World Observational Studies.
abstract: The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC.
  
  
  
  A search was conducted in Medline and Embase (2009-2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011-2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS).
  
  
  
  Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I2 = 68%; P = 0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I2 = 0%; P = 0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR = 0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study.
  
  
  
  Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.
authors.affiliation: Department of Medical Oncology, Tom Baker Cancer Center, Alberta Health Services Cancer Care, University of Calgary, Calgary, Canada.
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Heng
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Signorovitch
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: Elyse
authors.initials: E
authors.lastname: Swallow
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: Paige
authors.initials: P
authors.lastname: Qin
authors.affiliation: Analysis Group, Inc., Boston, Massacusetts, United States of America.
authors.forename: Daisy Y
authors.initials: DY
authors.lastname: Zhuo
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Xufang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Park
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Stergiopoulos
authors.affiliation: Department of Oncology, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
mesh_terms: D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D009362:Neoplasm Metastasis; D016019:Survival Analysis