title: Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors.
abstract: BACKGROUND
  The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.
  
  
  OBJECTIVE
  To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.
  
  
  METHODS
  Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.
  
  
  METHODS
  Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11).
  
  
  METHODS
  We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).
  
  
  CONCLUSIONS
  Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.
  
  
  CONCLUSIONS
  The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.
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: Carsten
authors.initials: C
authors.lastname: Kempkensteffen
authors.forename: Manfred
authors.initials: M
authors.lastname: Johannsen
authors.forename: Ingmar
authors.initials: I
authors.lastname: Wolff
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
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; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D005858:Germany; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; 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; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D000077210:Sunitinib; D015996:Survival Rate; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; D020123:Sirolimus