Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. Academic Article uri icon

Overview

abstract

  • PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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).

publication date

  • May 23, 2011

Research

keywords

  • Anilides
  • Antineoplastic Agents
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-ret
  • Pyridines

Identity

PubMed Central ID

  • PMC3646303

Scopus Document Identifier

  • 79959936054

Digital Object Identifier (DOI)

  • 10.1200/JCO.2010.32.4145

PubMed ID

  • 21606412

Additional Document Info

volume

  • 29

issue

  • 19