Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer

Razelle Kurzrock, Steven I. Sherman, Douglas W. Ball, Arlene A. Forastiere, Roger B. Cohen, Ranee Mehra, David G. Pfister, Ezra E.W. Cohen, Linda Janisch, Forlisa Nauling, David S. Hong, Chaan S. Ng, Lei Ye, Robert F. Gagel, John Frye, Thomas Müller, Mark J. Ratain, Ravi Salgia

Research output: Contribution to journalArticle

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).

Original languageEnglish (US)
Pages (from-to)2660-2666
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number19
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kurzrock, R., Sherman, S. I., Ball, D. W., Forastiere, A. A., Cohen, R. B., Mehra, R., Pfister, D. G., Cohen, E. E. W., Janisch, L., Nauling, F., Hong, D. S., Ng, C. S., Ye, L., Gagel, R. F., Frye, J., Müller, T., Ratain, M. J., & Salgia, R. (2011). Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. Journal of Clinical Oncology, 29(19), 2660-2666. https://doi.org/10.1200/JCO.2010.32.4145