MedKoo product information:

Cabozantinib

Description of Cabozantinib: Cabozantinib (XL 184) is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several tyrosine receptor kinases. Specifically, cabozantinib appears to have a strong affinity for the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in inhibition of tumor growth and angiogenesis, and tumor regression. This agent has also been shown to inhibit mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (Flt3) and tyrosine-protein kinase receptor (Tie-2). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Exelixis, Inc.

Cabozantinib (XL184) is being developed by Exelixis Inc. XL184 was recently granted orphan-drug status by the FDA and given the generic name, cabozantinib.  It is currently in a number of clinical trials for prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular, kidney, and medullary thyroid cancer. Phase II results for prostate cancer have been released. One US trial reported in May 2011 : The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease. Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial. [source: http://en.wikipedia.org/wiki/Cabozantinib].

Highlight on recent research using cabozantinib

Review article: clinical development: focus on XL-184 (cabozantinib) (data published in 2011): XL-184 (cabozantinib) showed particular activity against hepatocyte growth factor receptor (tyrosine-protein kinase Met), vascular endothelial growth factor receptor 2 (VEGFR-2) and proto-oncogene tyrosine-protein kinase receptor Ret. There is ample evidence of Met, VEGFR-2 and Ret signaling in several tumor types. Preclinical data suggest that XL-184 has activity in tumors derived from both epithelial and mesenchymal origins. Phase I and II clinical studies support significant antitumor activity, particularly in medullary thyroid cancer and cancers metastatic to the bone. This review will evaluate XL-184's preclinical pharmacology, pharmacokinetics, drug interactions and clinical activity in phase I through phase III studies. (source: Drugs Today (Barc). 2011 Nov;47(11):857-8.)

Cabozantinib suppresses Metastasis, Angiogenesis, and Tumor Growth.(data published in 2011):   Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. (source: Mol Cancer Ther; 10(12); 2298-308.)

1: You WK, Sennino B, Williamson CW, Falcon B, Hashizume H, Yao LC, Aftab DT, McDonald DM. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011 Jun 1. [Epub ahead of print] PubMed PMID: 21613405.

2: Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Mller T, Ratain MJ, Salgia R. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer. J Clin Oncol. 2011 May 23. [Epub ahead of print] PubMed PMID: 21606412.

3: Torres K, Zhu QS, Bill K, Lopez G, Ghadimi M, Xie X, Young E, Liu J, Nguyen T, Bolshakov S, Belousov R, Wang S, Lahat G, Liu J, Hernandez B, Lazar A, Lev DC. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011 May 3. [Epub ahead of print] PubMed PMID: 21540237.

4: Verbeek HH, Alves MM, de Groot JW, Osinga J, Plukker JT, Links TP, Hofstra RM. The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab. 2011 Jun;96(6):E991-5. Epub 2011 Apr 6. PubMed PMID: 21470995.

5: Ball DW. Management of medullary thyroid cancer. Minerva Endocrinol. 2011 Mar;36(1):87-98. PubMed PMID: 21460789.

6: Durante C, Russo D, Verrienti A, Filetti S. XL184 (cabozantinib) for medullary thyroid carcinoma. Expert Opin Investig Drugs. 2011 Mar;20(3):407-413. PubMed PMID: 21314233.

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