title: The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer.
abstract: BACKGROUND
  Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis in need of more effective treatment options. Published evidence indicates many ACCs express the vascular endothelial growth factor receptor (VEGFR), suggesting inhibiting vascular endothelial growth factor signaling could potentially impact tumor growth.
  
  
  OBJECTIVE
  The objective of the study was to determine the antitumor efficacy of axitinib (AG-013736), a potent, selective inhibitor of VEGFR1, -2, and -3.
  
  
  METHODS
  This was a phase II, open-label trial using a two-stage design.
  
  
  METHODS
  Thirteen patients with metastatic ACC previously treated with at least one chemotherapy regimen with or without mitotane participated in the study.
  
  
  METHODS
  Starting axitinib dose was 5 mg orally twice daily. Dose escalations were permitted if the administered dose was tolerable.
  
  
  RESULTS
  Thirteen patients were enrolled. Dose escalation was possible in seven patients, but the majority could not tolerate a dose higher than the starting 5 mg, twice-daily dose for prolonged periods of time. All patients experienced known grade 1/2 toxicities, and 10 of 13 patients had at least one grade 3/4 adverse event. No patient tumor could be scored as a Response Evaluation Criteria in Solid Tumors response, although the growth rate on therapy compared with that prior to starting axitinib was reduced in 4 of the 13 patients. The median progression-free survival was 5.48 months, and the median overall survival was longer than 13.7 months.
  
  
  CONCLUSIONS
  Axitinib has limited effectiveness in ACC. Together with 48 patients previously reported who received either sorafenib or sunitinib, a total of 61 ACC patients have now been treated with a VEGFR tyrosine kinase inhibitor without an objective Response Evaluation Criteria in Solid Tumors response. Future trials in ACC should look to other targets for possible active agents.
authors.affiliation: Medical Oncology Branch (C.O., M.E., M.V., J.W., S.B., T.F.), Center for Cancer Research, Laboratory of Pathology (S.P.), and National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis (S.X.Y., D.N.), National Cancer Institute, and Radiology and Imaging Sciences (A.M.V.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Ciara
authors.initials: C
authors.lastname: O'Sullivan
authors.forename: Maureen
authors.initials: M
authors.lastname: Edgerly
authors.forename: Margarita
authors.initials: M
authors.lastname: Velarde
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.forename: Aradhana M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Yang
authors.forename: Dat
authors.initials: D
authors.lastname: Nguyen
authors.forename: Sanjeeve
authors.initials: S
authors.lastname: Balasubramaniam
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000077784:Axitinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor