Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer

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 patien...

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Bibliographic Details
Published in:	Journal of clinical oncology Vol. 29; no. 19; pp. 2660 - 2666
Main Authors:	KURZROCK, Razelle, SHERMAN, Steven I, HONG, David S, NG, Chaan S, LEI YE, GAGEL, Robert F, FRYE, John, MÜLLER, Thomas, RATAIN, Mark J, SALGIA, Ravi, BALL, Douglas W, FORASTIERE, Arlene A, COHEN, Roger B, MEHRA, Ranee, PFISTER, David G, COHEN, Ezra E. W, JANISCH, Linda, NAULING, Forlisa
Format:	Journal Article
Language:	English
Published:	Alexandria, VA American Society of Clinical Oncology 01-07-2011
Subjects:	Administration, Oral Adult Aged Aged, 80 and over Anilides - therapeutic use Antineoplastic Agents - therapeutic use Biological and medical sciences Carcinoma, Neuroendocrine Endocrinopathies Faze Female Humans Male Malignant tumors Maximum Tolerated Dose Medical sciences Middle Aged Neoplasm Metastasis Original Reports Protein-Tyrosine Kinases - antagonists & inhibitors Proto-Oncogene Proteins c-ret - metabolism Pyridines - therapeutic use Thyroid Neoplasms - drug therapy Thyroid. Thyroid axis (diseases) Tumors Endocrinopathy Human Thyroid cancer Cancerology Tyrosine kinase inhibitor Thyroid diseases Malignant tumor Biological activity Cancer
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Summary:	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. 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. 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. 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).
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2010.32.4145