title: Retrospective comparison of triple-sequence therapies in metastatic renal cell carcinoma.
abstract: BACKGROUND
  The optimal sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been defined.
  
  
  OBJECTIVE
  To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy.
  
  
  METHODS
  Retrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n=62) or VEGFi-mTORi-rTKI (n=41) at two German academic centers.
  
  
  METHODS
  Sequence of systemic targeted treatment.
  
  
  METHODS
  Response was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression.
  
  
  CONCLUSIONS
  Sequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8-5.4), 4.1 mo (95% CI, 3.4-4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7-8.1) for mTORi treatment (p=0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p=0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4-37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4-52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases.
  
  
  CONCLUSIONS
  The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.
authors.affiliation: Department of Urology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Busch
authors.forename: Christoph
authors.initials: C
authors.lastname: Seidel
authors.forename: Barbara
authors.initials: B
authors.lastname: Erber
authors.forename: Ahi Sema
authors.initials: AS
authors.lastname: Issever
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.forename: Carsten
authors.initials: C
authors.lastname: Kempkensteffen
authors.forename: Ahmed
authors.initials: A
authors.lastname: Magheli
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.forename: Steffen
authors.initials: S
authors.lastname: Weikert
mesh_terms: D000046:Academic Medical Centers; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases