title: A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib.
abstract: BACKGROUND
  Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib.
  
  
  METHODS
  Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity.
  
  
  RESULTS
  Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR).
  
  
  CONCLUSIONS
  Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.
authors.affiliation: Stanford Cancer Institute, Stanford.
authors.forename: K N
authors.initials: KN
authors.lastname: Ganjoo
authors.forename: V M
authors.initials: VM
authors.lastname: Villalobos
authors.forename: A
authors.initials: A
authors.lastname: Kamaya
authors.forename: G A
authors.initials: GA
authors.lastname: Fisher
authors.forename: J E
authors.initials: JE
authors.lastname: Butrynski
authors.forename: J A
authors.initials: JA
authors.lastname: Morgan
authors.forename: A J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: D
authors.initials: D
authors.lastname: D'Adamo
authors.forename: A
authors.initials: A
authors.lastname: McMillan
authors.forename: G D
authors.initials: GD
authors.lastname: Demetri
authors.forename: S
authors.initials: S
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007191:Indazoles; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D017211:Treatment Failure; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D001549:Benzamides; D007191:Indazoles; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; D000068877:Imatinib Mesylate; D000077210:Sunitinib
keywords: GIST; KIT; pazopanib; tyrosine kinase inhibitors