Cabozantinib

Names
Pronunciation	ka" boe zan' ti nib[1]
Trade names	Cometriq, Cabometyx, others
Other names	XL184, BMS907351
IUPAC name N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Clinical data
Drug class	Tyrosine kinase inhibitor[2]
Main uses	Medullary thyroid cancer,renal cell carcinoma,hepatocellular carcinoma[3][2]
Side effects	Diarrhea, tiredness, high blood pressure, nausea, weight loss[2]
Pregnancy category	AU: D[4]
Routes of use	By mouth
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a613015
Legal
License data	EU EMA: by INN US DailyMed: Cabozantinib US FDA: Cabozantinib
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) [6][7] US: ℞-only [8][9] EU: Rx-only [3][5]
Pharmacokinetics
Protein binding	≥99.7%
Metabolism	Liver (CYP3A4-mediated)
Eliminationhalf-life	110 hours
Excretion	Feces (54%), urine (27%)
Chemical and physical data
Formula	C28H24FN3O5
Molar mass	501.514 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(C1(CC1)C(NC2=CC=C(F)C=C2)=O)NC(C=C3)=CC=C3OC4=C(C=C(OC)C(OC)=C5)C5=NC=C4
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) Key:ONIQOQHATWINJY-UHFFFAOYSA-N

Cabozantinib, sold under the brand namesCometriq andCabometyx among others, is a medication used to treatmedullary thyroid cancer,renal cell carcinoma, andhepatocellular carcinoma.^[3][2] It is used in advanced disease or cases which have failed other treatments.^[2] It is taken by mouth.^[2]

Common side effects include diarrhea, tiredness, high blood pressure, nausea, and weight loss.^[2] Other side effects may include bleeding,fistula, blood clots, liver problems, andreversible posterior leukoencephalopathy syndrome.^[2] Use in pregnancy may harm the baby.^[2] It is atyrosine kinase inhibitor ofMET,VEGFR, andAXL.^[2]

Cabozantinib was approved for medical use in the United States in 2012 and Europe in 2014.^[2][3] In the United Kingdom a dose of 60 mg a day for a month costs about £5,150 as of 2021.^[10] This amount in the United States costs about 22,600 USD.^[11]

Medical uses

Cabozantinib is used in two forms. A capsule form is used since 2012, to treatmedullary thyroid cancer^[9][7] and a tablet form is used since 2016, as a second line treatment forrenal cell carcinoma.^[8][6]

In the United States, cabozantinib (Cabometyx) is also indicated for the treatment of people aged twelve years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are ineligible or refractory to radioactive iodine.^[12]

Dosage

It is generally taken at a dose of 60 mg per day.^[2] Doses of of 140 mg per day may be used for thyroid cancer.^[10]

The brands Cometriq and Cabometyx have different formulations and are not interchangeable.^[13]

Contraindications

Cabozantinib has not been tested in pregnant women; it causes harm to fetuses in rodents. Pregnant women should not take this drug, and women should not become pregnant while taking it. It is not known if cabozantinib is excreted in breast milk.^[7][6]

The drug should be used with caution in people with a history of heart rhythm problems, including long QT interval.^[6]

Side effects

In the US, the capsule formulation (Cometriq) carries ablack box warning of the risk ofholes forming in the stomach or intestines as well as formation offistulas (tunnels between the GI tract and the skin).^[9] The black box also warns against the risk of uncontrolled bleeding.^[9] The tablet formulation (Cabometyx) warns of these effects as well.^[8][6]

The labels also warn of the risk of clots forming and causing heart attacks or strokes, high blood pressure includinghypertensive crisis, osteonecrosis of the jaw, severe diarrhea,skin sloughing off the palms and soles,a syndrome with headaches, confusion, loss of vision, and seizures, and protein appearing in urine.^[9][8][7][6]

Very common adverse effects (greater than 10% of people) include decreased appetite; low calcium, potassium, phosphate, and magnesium levels; highbilirubin levels; distorted sense of taste, headache, and dizziness; high blood pressure; distorted sense of hearing, earaches and sore throat; diarrhea, nausea, constipation, vomiting, stomach pain and upset stomach, and inflammation of the mouth and lips and a burning sensation in the mouth; skin sloughing off the palms and soles, hair color changes and hair loss, rash, dry skin, and red skin; joint pain and muscle spasms; fatigue and weakness; weight loss,elevated transaminases, higher cholesterol levels, and loss of red and white blood cells.^[6]

Common adverse effects (between 1% and 10% of people) include abscesses (inside the body, on the skin, and in teeth skin), pneumonia, inflamed hair follicles, fungal infections, low thyroid levels, dehydration, loss ofalbumin, anxiety, depression, and confusion, peripheral neuropathy, tingling, and tremor, tinnitus, atrial fibrillation, low blood pressure, blocked veins, paleness, chills, fistulas forming in the trachea and esophagus, blood clots in the lungs, and bleeding in the respiratory tract, GI perforation, bleeding in the stomach and intestines, pancreatitis, hemorrhoids, anal fissure, anal inflammation, gallstones, hard skin growths, acne, blisters, abnormal hair growth, loss of skin color and skin flaking, chest pain, blood or protein in urine, wounds that don't heal well, and facial swelling.^[6]

Interactions

Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.^[6]

Cabozantinib is a substrate ofCYP3A4 andmultidrug resistance-associated protein 2; drugs that inhibit these enzymes will increase thehalf-life of cabozantinib and potentially increase its adverse effects; drugs that activate them may cause cabozantinib to be less effective.^[6]

It inhibitsP-glycoprotein, so will change the availability of other drugs that depend on this transporter.^[6]

Pharmacology

It inhibits the followingreceptor tyrosine kinases: MET (hepatocyte growth factor receptor protein) and VEGFR, RET, GAS6 receptor (AXL), KIT), and Fms-like tyrosine kinase-3 (FLT3).^[6]

History

Cabozantinib was grantedorphan drug status by the U.S.Food and Drug Administration (FDA) in November 2010,^[14] and in February 2017.^[15]

Exelixis filed anew drug application with the FDA in the first half of 2012,^[16] and on November 29, 2012 cabozantinib in its capsule formulation was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients withmedullary thyroid cancer.^[17][18] The capsule form was approved in the European Union for the same purpose in 2014.^[3]

In March 2016 Exelixis licensed toIpsen worldwide rights (outside the US, Canada, and Japan) to market cabozantinib.^[19]

Exelixis' Phase III trial results of testing the drug in renal cancer published in the NEJM in 2015.^[20] In April 2016 the FDA granted approval for marketing the tablet formulation as a second line treatment forkidney cancer^[21][22] and the same was approved in the European Union in September of that year.^[5]

In December 2017, the FDA granted approval to cabozantinib (Cabometyx, Exelixis, Inc.) for treatment of people with advanced renal cell carcinoma (RCC).^[13] The approval was based on data from CABOSUN (NCT01835158), a randomized, open-label phase II multicenter study in 157 participants with intermediate and poor-risk previously untreated RCC.^[13]

In January 2019, the FDA approved cabozantinib (Cabometyx, Exelixis, Inc.) for people with hepatocellular carcinoma (HCC) who have been previously treated withsorafenib.^[23] The approval was based on CELESTIAL (NCT01908426), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in participants with HCC who had previously received sorafenib and hadChild Pugh Class A liver impairment.

Research

Cabozantinib is being researched^[24] for efficacy as a treatment forrenal cell carcinoma (RCC),hepatocellular carcinoma (HCC),cervical cancer,colorectal cancer (CRC),urothelial cancer,prostate cancer,gastric andgastroesophageal cancer,bladder cancer,melanoma,merkel cell carcinoma,brain cancers (includingglioblastoma multiforme andanaplastic astrocytoma),non-small cell lung cancer (NSCLC),adrenocortical carcinoma, varioussarcomas,head and neck squamous cell carcinomas (HNSCC),breast cancer,endometrial cancer,neuroendocrine cancers, andneurofibromatosis type 1.^[25]

References

External links

• "Cabozantinib s-malate".Drug Information Portal. U.S. National Library of Medicine.Archived from the original on 2021-02-08. Retrieved2021-10-05.
• "Cabozantinib s-malate".NCI Drug Dictionary. National Cancer Institute.Archived from the original on 2020-10-20. Retrieved2021-10-05.
• "Cabozantinib (liver and kidney cancer)".MedlinePlus.Archived from the original on 2021-08-16. Retrieved2021-10-05.
• Clinical trial numberNCT01835158 for "Cabozantinib-s-malate or Sunitinib Malate in Treating Patients With Previously Untreated Locally Advanced or Metastatic Kidney Cancer" atClinicalTrials.gov
• Clinical trial numberNCT01908426 for "Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL)" atClinicalTrials.gov
• Clinical trial numberNCT03690388 for "A Study of Cabozantinib Compared With Placebo in Subjects With Radioiodine-refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy" atClinicalTrials.gov

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