title: Pazopanib as third line therapy for metastatic renal cell carcinoma: clinical efficacy and temporal analysis of cytokine profile.
abstract: OBJECTIVE
  Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood.
  
  
  METHODS
  Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™).
  
  
  RESULTS
  A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic.
  
  
  CONCLUSIONS
  Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. Electronic address: spal@coh.org.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Dewan Md Sakib
authors.initials: DM
authors.lastname: Hossain
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Paul Henry
authors.initials: PH
authors.lastname: Frankel
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Courtney
authors.initials: C
authors.lastname: Carmichael
authors.affiliation: Department of Biostatistics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.affiliation: Department of Urology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Clayton
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D005260:Female; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: biological markers; cytokines; kidney neoplasms; mortality; pazopanib