title: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.
abstract: OBJECTIVE
  XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.
  
  
  METHODS
  A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.
  
  
  RESULTS
  Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.
  
  
  CONCLUSIONS
  Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).
authors: The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rkurzroc@mdanderson.org
authors: Razelle
authors: R
authors: Kurzrock
authors: Steven I
authors: SI
authors: Sherman
authors: Douglas W
authors: DW
authors: Ball
authors: Arlene A
authors: AA
authors: Forastiere
authors: Roger B
authors: RB
authors: Cohen
authors: Ranee
authors: R
authors: Mehra
authors: David G
authors: DG
authors: Pfister
authors: Ezra E W
authors: EE
authors: Cohen
authors: Linda
authors: L
authors: Janisch
authors: Forlisa
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authors: Nauling
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authors: Ye
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authors: J
authors: Frye
authors: Thomas
authors: T
authors: Müller
authors: Mark J
authors: MJ
authors: Ratain
authors: Ravi
authors: R
authors: Salgia
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