cabozantinib   

GtoPdb Ligand ID: 5887

Synonyms: BMS907351 | Cabometyx® | Cometriq® | XL-184 | XL184
cabozantinib is an approved drug (FDA (2012), EMA (2014))
Compound class: Synthetic organic
Comment: Cabozantinib is a Type-1, oral, small-molecule tyrosine kinase inhibitor.
Marketed formulations contain cabozantinib S-malate (PubChem CID 25102846).
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2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 10
Topological polar surface area 98.78
Molecular weight 501.17
XLogP 4.58
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES COc1cc2c(ccnc2cc1OC)Oc1ccc(cc1)NC(=O)C1(CC1)C(=O)Nc1ccc(cc1)F
Isomeric SMILES COc1cc2c(ccnc2cc1OC)Oc1ccc(cc1)NC(=O)C1(CC1)C(=O)Nc1ccc(cc1)F
InChI InChI=1S/C28H24FN3O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
InChI Key ONIQOQHATWINJY-UHFFFAOYSA-N
No information available.
Summary of Clinical Use
In 2009 cabozantinib was granted orphan designation by the European Commission for the treatment of medullary thyroid carcinoma. US FDA full approval was granted in 2012, for the treatment of medullary thyroid cancer that cannot be removed by surgery or that has metastasized. EU approval for this indication followed in 2014.
Preliminary results from a Phase 3 trial in metastatic renal cell carcinoma that had progressed after VEGFR-targeted therapy (NCT01865747) reported a 50% improvement in progression-free survival over everolimus [2]. These clinical trial results translated to full FDA marketing authorisation for Cabometyx® branded cabozantinib in April 2016. Cabometyx® is approved for use in patients with advanced renal cell carcinoma who have already been treated with anti-angiogenic therapy, and as first-line therapy (FDA approval in December 2017 [4]) .
Earlier stage clinical trials are evaluating cabozantinib against many other cancer types, and in combination or comparision with other anti-cancer therapeutics- click here to link to ClinicalTrials.gov's list of current cabozantinib trials.
NCT01639508 (Phase II) is evaluating the effectiveness of cabozantinib in advanced non-small cell lung cancers with various gene alterations, such as RET, ROS1, or NTRK fusion, or increased MET or AXL activity.
In May 2018, the FDA accepted a supplemental New Drug Application (sNDA) from Exelixis for the use of cabozantinib as a treatment for patients with previously treated advanced hepatocellular carcinoma (HCC). Encouraging preliminary results from the Phase 3 CELESTIAL trial (NCT01908426) of cabozantinib in advanced HCC were published in July 2018 [1]. This sNDA led to full FDA approval in January 2019 that covers the use of cabozantinib for HCC patients who have been previously treated with sorafenib [3].
Mechanism Of Action and Pharmacodynamic Effects
Cabozantinib is effective against progressive, metastatic medullary thyroid cancer (MTC), particularly against cancer cells with a mutated RET gene. In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT01639508 Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity Phase 2 Interventional Memorial Sloan Kettering Cancer Center
NCT01865747 A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma Phase 3 Interventional Exelixis
NCT01908426 Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib Phase 3 Interventional Exelixis
Pharmacokinetics
Absorption/Distribution
Peak plasma concentration is achieved 2-5 hours after oral administration. The majority of circulating cabozantinib (> 99.7%) is bound to plasma proteins .
Biotransformation/Metabolism
Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9, therefore avoid administration of cabozantinib with agents that are strong CYP3A4 inducers or inhibitors.
Elimination
Cabozantinib is eliminated mostly in the feces (54%) and also in the urine (27%).
Population pharmacokinetics
There are no clinically relevant differences in clearance of cabozantinib associated with age, gender or race.
Organ function impairment
Cabozantinib is not recommended for use in patients with moderate and severe hepatic impairment as safety and efficacy have not been established. No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with cabozantinib in patients with severe renal impairment.
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