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 2) 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.

External links

For extended ADME data see the following: Electronic Medicines Compendium (eMC) Drugs.com European Medicines Agency (EMA)