title: Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma?
abstract: OBJECTIVE
  Pazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker.
  
  
  METHODS
  Data from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed.
  
  
  RESULTS
  Analyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN.
  
  
  CONCLUSIONS
  Neither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.
authors.affiliation: University of New South Wales and Prince of Wales Hospital, High St., Randwick, Sydney 2031, Australia. Electronic address: d.goldstein@unsw.edu.au.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Electronic address: rosenbj1@mskcc.org.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: robert.figlin@cshs.org.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA. Electronic address: futed@alum.mit.edu.
authors.forename: Lauren
authors.initials: L
authors.lastname: McCann
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC, USA. Electronic address: lini.pandite@adaptimmune.com.
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000503:physiopathology; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D007191:Indazoles; D007211:Indoles / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*; D012189:Retrospective Studies; D013449:Sulfonamides / Q000009:adverse effects*; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; D000077210:Sunitinib
keywords: Angiogenesis inhibitors; Hypertension; Overall survival; Predictive biomarker; Progression-free survival; Renal cell carcinoma