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

Shanghai Jiao Tong University, Shanghai, Shanghai Shi, China
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2011; 29(19):2660-6. DOI: 10.1200/JCO.2010.32.4145
Source: PubMed


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 ( number NCT00215605).

Download full-text


Available from: David S Hong, Nov 24, 2015
  • Source
    • "Small trials studying dacarbazine, 5-fluorouracil, and doxorubicin [15–20], used alone or in combination, have demonstrated partial biochemical and tumor responses in 10-20% of patients. More recently, inhibitors of the RET kinase, such as vandetanib [21] and cabozantinib [22], have shown evidence of significant progression- free survival benefit, and hence are FDA-approved for the treatment of patients with advanced MTC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with advanced endocrine cancers, such as adrenocortical carcinoma and medullary thyroid carcinoma, have few well-validated therapeutic options. Pre-clinical studies have suggested potential activity of imatinib in these tumors. We therefore sought to establish a safe, novel treatment regimen combining imatinib with cytotoxic chemotherapy for future study in endocrine cancers. A standard 3 + 3 dose-escalation design was used with a 21-day cycle, including imatinib on days 1–21, dacarbazine on days 1–3, and capecitabine on days 1–14. Twenty patients were treated. The most frequent toxicities were edema and fatigue, with dose-limiting fatigue and dyspnea. The recommended phase II regimen is dacarbazine 250 mg/m2 daily on day 1–3, capecitabine 500 mg/m2 twice daily on days 1–14, and imatinib 300 mg daily on days 1–21 of a 21-day cycle. Interestingly, responses were seen in patients with adrenocortical carcinoma, with 1 of 6 patients experiencing a partial response and a second experiencing a minor response, with progression-free survival of 8.8 and 6.4 months, respectively. The regimen of imatinib, dacarbazine, and capecitabine is well-tolerated. It may have some activity in adrenocortical carcinoma, and further study of this combination or its components may be beneficial for this disease with limited treatment options. Trial registration identifier NCT00354523, registered July 18, 2006.
    Full-text · Article · Aug 2014 · BMC Cancer
  • Source
    • "Ten of 35 evaluable patients with MTC had a partial response; an additional 15 patients with MTC had stable disease for at least 6 months. Activating RET mutations were seen in 81% of patients with MTC and the presence of these mutations appeared to correlate with response to cabozantinib.58 In a Phase III EXAM study, 330 patients with locally advanced or metastatic MTC were assigned in a 2:1 ratio to receive cabozantinib 160 mg daily or placebo, respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF) receptor, a member of the receptor tyrosine kinase (RTK) family. HGF, also known as scatter factor (SF), is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis), mobility (motogenesis), and differentiation (morphogenesis); it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.
    Full-text · Article · Jun 2014 · OncoTargets and Therapy
  • Source
    • "Analysis of biomarkers showed reductions in serum calcitonin of 3% to 99% from baseline in 28 of 30 patients. A CEA reduction of 13%–94% was seen in 24 patients.22 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantinib, a tyrosine kinase inhibitor, after promising results were shown in a large Phase III clinical trial. This review summarizes the clinical pharmacology, clinical trials, and safety data for cabozantinib and concludes with a discussion of possible future directions for the treatment of medullary thyroid cancer.
    Full-text · Article · May 2014 · Therapeutics and Clinical Risk Management
Show more