title: An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.
abstract: BACKGROUND
  There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity.
  
  
  OBJECTIVE
  The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings.
  
  
  METHODS
  Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m-2body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points.
  
  
  RESULTS
  Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17).
  
  
  CONCLUSIONS
  In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Thurneysen
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: P F
authors.initials: PF
authors.lastname: Cheng
authors.affiliation: Department of Nuclear Medicine, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: H W
authors.initials: HW
authors.lastname: Nagel
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Jaberg-Bentele
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Nägeli
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ziegler
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Guenova
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: S M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Mangana
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastraße 31, 8091, Zurich, Switzerland. reinhard.dummer@usz.ch.
authors.forename: R
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007191:Indazoles; D007262:Infusions, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D017239:Paclitaxel