title: Efficacy of fourth-line targeted therapy in patients with metastatic renal cell carcinoma: a retrospective analysis.
abstract: BACKGROUND
  Evidence for sequencing targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) beyond third line is limited. Treatment decisions for these sequence options are largely based on individual preferences and experience. The aim of this study was to describe the efficacy and toxicity of fourth-line TT.
  
  
  METHODS
  We retrospectively reviewed patients treated with fourth-line TT for mRCC after failure of previous treatment lines at a German academic high-volume center. Out of 406 patients treated in first line, 56 patients (14.8 %) were identified with more than three lines of TT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were applied to explore predictors of PFS and OS in uni- and multivariable analysis.
  
  
  RESULTS
  For the fourth-line treatment, disease control rate was 35.7 %. Median OS from beginning of first-line therapy was 47.4 months (IQR 31.0-76.5). Primary resistance at first-line TT, metastatic disease at initial diagnosis and an intermediate MSKCC score were independent predictors of shorter OS from start of first-line TT. Median OS from the time of initiation of fourth-line therapy was 10.5 months (IQR 5.6-22.6). The corresponding median PFS for fourth-line TT was 3.2 months (IQR 1.6-8.0) and was not correlated with treatment response in first-line TT. The rate of toxicity-induced treatment termination was 16.1 %. Limitations are the retrospective and unicentric design with a limited number of patients.
  
  
  CONCLUSIONS
  Patients might benefit from subsequent treatment lines independently from treatment response in first line.
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany. Bernhard.Ralla@charite.de.
authors.forename: Bernhard
authors.identifier: http://orcid.org/0000-0001-7226-3852
authors.initials: B
authors.lastname: Ralla
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Erber
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Irena
authors.initials: I
authors.lastname: Goranova
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: von der Aue
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Floercken
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kempkensteffen
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Magheli
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Urology, Charité Universitaetsmedizin Berlin, Charité Platz 1, 10117, Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Busch
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
keywords: Fourth-line; Metastasis; Renal cell carcinoma; TKI; Targeted therapy; Tyrosine kinase inhibitor; VEGF; Vascular endothelial growth factor receptor