title: Small molecule targeted therapies for the second-line treatment for metastatic renal cell carcinoma: a systematic review and indirect comparison of safety and efficacy.
abstract: BACKGROUND
  Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.
  
  
  METHODS
  A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).
  
  
  RESULTS
  Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.
  
  
  CONCLUSIONS
  Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.
authors.affiliation: University of Ioannina, Ioannina, Greece, george.dranitsaris@gmail.com.
authors.forename: George
authors.initials: G
authors.lastname: Dranitsaris
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmitz
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Broom
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077784:Axitinib; D001499:Bayes Theorem; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D011743:Pyrimidines; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000068338:Everolimus; D000077157:Sorafenib; D000077784:Axitinib; D020123:Sirolimus
references.citation: Lancet Oncol. 2013 May;14(6):552-62
references.pmid: 23598172
references.citation: J Clin Oncol. 2010 Feb 20;28(6):1061-8
references.pmid: 20100962
references.citation: J Med Econ. 2012;15(6):1139-48
references.pmid: 22808923
references.citation: N Engl J Med. 1996 Sep 19;335(12):865-75
references.pmid: 8778606
references.citation: Expert Opin Pharmacother. 2011 Jul;12(10):1491-7
references.pmid: 21599551
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1280-9
references.pmid: 19171708
references.citation: Biochem Biophys Res Commun. 2007 May 4;356(2):323-8
references.pmid: 17367763
references.citation: J Clin Oncol. 2004 Feb 1;22(3):454-63
references.pmid: 14752067
references.citation: Eur J Cancer. 2013 May;49(8):1898-904
references.pmid: 23490648
references.citation: J Natl Cancer Inst. 2009 Dec 2;101(23):1642-9
references.pmid: 19903805
references.citation: Eur J Cancer. 2010 Sep;46(13):2432-40
references.pmid: 20656473
references.citation: Cancer Treat Rev. 2007 May;33(3):299-313
references.pmid: 17329029
references.citation: Stat Med. 2010 Sep 10;29(20):2078-89
references.pmid: 20623822
references.citation: BMC Cancer. 2009 Jan 27;9:34
references.pmid: 19173737
references.citation: Eur J Cancer. 2012 Feb;48(3):333-9
references.pmid: 22209391
references.citation: Expert Opin Investig Drugs. 2008 May;17(5):741-8
references.pmid: 18447599
references.citation: Nat Rev Clin Oncol. 2012 Apr 10;9(6):327-37
references.pmid: 22473096
references.citation: Stat Med. 2004 Oct 30;23(20):3105-24
references.pmid: 15449338
references.citation: N Engl J Med. 2007 Jan 11;356(2):115-24
references.pmid: 17215529
references.citation: Ann Oncol. 2012 Oct;23 Suppl 7:vii65-71
references.pmid: 22997456
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Lancet. 2008 Aug 9;372(9637):449-56
references.pmid: 18653228
references.citation: Lancet. 2011 Dec 3;378(9807):1931-9
references.pmid: 22056247
references.citation: Nat Med. 2006 Jan;12(1):122-7
references.pmid: 16341243
references.citation: Cancer. 1997 Oct 1;80(7):1198-220
references.pmid: 9317170
references.citation: N Engl J Med. 2007 Jan 11;356(2):125-34
references.pmid: 17215530
references.citation: J Clin Oncol. 2002 Jan 1;20(1):289-96
references.pmid: 11773181
references.citation: World J Urol. 2010 Jun;28(3):343-51
references.pmid: 20458483
references.citation: J Clin Oncol. 2009 Jul 10;27(20):3312-8
references.pmid: 19451442
references.citation: Expert Opin Pharmacother. 2013 Jan;14(1):27-39
references.pmid: 23256638