Cabozantinib

L01X - Other antineoplastic agents ATC L01XE26 Small molecule approved 2012 Oral First-in-class Orphan Black-box warning

JFDA label: Cabometyx

⚠ Black-Box Warning

Perforations and fistulas (Cometriq):
Hemorrhage (Cometriq):

Mechanism of Action

Cabozantinib is a potent inhibitor of proinvasive receptor tyrosine kinases (RTKs), including AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3; induces apoptosis of cancer cells and suppresses tumor growth, metastasis, and angiogenesis (Yakes 2011).

Indications

Approved

Renal cell carcinoma, advanced (Cabometyx)
Thyroid cancer, medullary (Cometriq)

Contraindications

Source: Lexicomp

There are no contraindications listed in the manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Very Common Hypertension

Common arterial thromboembolism · hypotension · pulmonary embolism · Venous thromboembolism

Nervous system disorders (9)

Very Common dizziness · Fatigue · headache · mouth pain · voice disorder

Common Anxiety · paresthesia · peripheral neuropathy · peripheral sensory neuropathy

Hepatobiliary disorders (4)

Very Common hyperbilirubinemia · increased serum alkaline phosphatase · Increased serum ALT · increased serum AST

Renal and urinary disorders (2)

Very Common Increased serum creatinine · Proteinuria

Blood and lymphatic system disorders (5)

Very Common anemia · Lymphocytopenia · neutropenia · thrombocytopenia

Common Hemorrhage

Metabolism and nutrition disorders (12)

Very Common hyperglycemia · hypoalbuminemia · hypocalcemia · hypokalemia · hypomagnesemia · hyponatremia · hypophosphatemia · hypothyroidism · increased gamma-glutamyl transferase · Increased serum triglycerides · weight loss

Common Dehydration

Gastrointestinal disorders (14)

Very Common abdominal pain · constipation · decreased appetite · Diarrhea · dysgeusia · dyspepsia · dysphagia · mucosal inflammation · nausea · stomatitis · vomiting

Common gastrointestinal fistula · gastrointestinal perforation · Hemorrhoids

Skin and subcutaneous tissue disorders (7)

Very Common alopecia · erythema · hair discoloration · Palmar-plantar erythrodysesthesia · skin rash · xeroderma

Common Hyperkeratosis

Musculoskeletal and connective tissue disorders (6)

Very Common arthralgia · limb pain · muscle spasm · Weakness

Common Musculoskeletal chest pain · osteonecrosis of the jaw

General disorders and administration site conditions (2)

Common Fistula · wound healing impaired

Respiratory, thoracic and mediastinal disorders (2)

Very Common cough · Dyspnea

Dosing

Source: Lexicomp

Note: Do not substitute cabozantinib tablets and capsules. Cabozantinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea/vomiting (Hesketh 2017). Renal cell carcinoma, advanced: Cabometyx: Oral: 60 mg once daily, continue as long as benefiting clinically or until unacceptable toxicity occurs (Choueiri 2015; Choueiri 2017); do not exceed 80 mg daily Thyroid cancer, medullary, metastatic: Cometriq: Oral: 140 mg once daily until disease progression or unacceptable toxicity occurs (Schlumberger 2017); do not exceed 180 mg daily Missed doses: Do not take a missed dose within 12 hours of the next dose. Dosage adjustment for concomitant CYP3A4 inhibitors/inducers: Strong CYP3A4 inhibitors: Cabometyx: Reduce the daily dose of cabozantinib by 20 mg (from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). If the strong inhibitor is discontinued, allow ~2 to 3 days to elapse prior to adjusting the cabozantinib dose upwards to the dose used prior to the initiation of the strong inhibitor. Cometriq: Avoid concomitant use; if concomitant use is required, reduce the daily dose of cabozantinib by 40 mg (ie, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). If the strong inhibitor is discontinued, allow ~2 to 3 days to elapse prior to adjusting the cabozantinib dose upwards to the dose used prior to the initiation of the strong inhibitor. Strong CYP3A4 inducers: Cabometyx: Increase the daily dose of cabozantinib by 20 mg (from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated; do not exceed 80 mg daily. If the strong inducer is discontinued, allow ~2 to 3 days to elapse prior to reducing the cabozantinib dose to the dose used prior to the initiation of the strong inducer. Cometriq: Avoid concomitant use; if concomitant use is required, increase the daily dose of cabozantinib by 40 mg (ie, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily); do not exceed 180 mg. If the strong inducer is discontinued, allow ~2 to 3 days to elapse prior to reducing the cabozantinib dose to the dose used prior to the initiation of the strong inducer. Dosage adjustment for surgery: Withhold treatment for at least 28 days prior to scheduled surgery (including dental surgery). Resume therapy based on clinical judgment of adequate wound healing.

Note: The estimated glomerular filtration rate (eGFR) is estimated using MDRD (modification of diet in renal disease) equation. eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary. eGFR 2 or dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild or moderate impairment (Child-Pugh classes A and B): Cabometyx: Reduce the initial dose to 40 mg once daily. Cometriq: Reduce the initial dose to 80 mg once daily. Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Warnings & Precautions

Source: Lexicomp

Dermatologic toxicity

Palmar-plantar erythrodysesthesia syndrome (PPES) was commonly observed in clinical trials; severe PPES (≥ grade 3) also occurred frequently. May require dosage reduction and/or discontinuation.

GI toxicity

Diarrhea was commonly observed in cabozantinib-treated patients in clinical trials. May require therapy interruption and/or dosage reduction. Cabozantinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea/vomiting (Hesketh 2017). [US Boxed Warning]: Cometriq: Serious GI perforations and fistulas have been reported when used for medullary thyroid cancer; discontinue for GI perforation or fistula formation. May be fatal. Tracheal/esophageal fistulas were also noted; some cases were fatal. GI fistula/perforation (including fatal perforations) were also reported in patients with renal cell cancer. Monitor for signs/symptoms of perforations and fistulas, including abscess and sepsis. May require therapy discontinuation.

Hemorrhage

Cometriq: Serious and occasionally fatal hemorrhage (including hemoptysis and gastrointestinal) has occurred with cabozantinib when used for medullary thyroid cancer. Monitor for signs/symptoms of bleeding and do not administer to patients with severe hemorrhage or a recent history of hemorrhage or hemoptysis. Severe hemorrhage has also been reported in patients with renal cell cancer, including grade 3 or higher events. Do not administer to patients with or at risk for severe hemorrhage.

Hypertension

Treatment emergent hypertension was commonly seen in clinical trials (including grade 3 or higher toxicity and hypertensive crisis). Monitor blood pressure prior to therapy initiation and regularly thereafter; withhold for hypertension that is uncontrolled with appropriate medical management. May require cabozantinib dosage reduction and/or therapy discontinuation.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) occurred rarely; oral examinations should be performed prior to and periodically throughout therapy. Patients should maintain proper oral hygiene practices; if possible, withhold therapy for at least 28 days prior to scheduled invasive dental procedures. Discontinue cabozantinib if ONJ develops.

Proteinuria

Proteinuria occurred in a small number of patients receiving cabozantinib in clinical trials; nephrotic syndrome was also reported (rare). Monitor urine protein regularly and discontinue therapy if nephrotic syndrome develops.

Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), also referred to as posterior reversible leukoencephalopathy syndrome (PRES), occurred rarely in clinical studies. Monitor for signs/symptoms of RPLS (seizures, headache, visual disturbances, confusion or altered mental function); if diagnosis confirmed, discontinue therapy.

Thromboembolic events

An increased incidence of thrombotic events (venous thromboembolism, including pulmonary embolism and arterial thromboembolism) was seen in cabozantinib-treated patients in clinical trials; discontinue therapy in patients who develop an acute myocardial infarction, cerebral infarction, or other clinically significant arterial thromboembolic event.

Wound healing impairment

Cabozantinib inhibits vascular endothelial growth factor receptors 1, 2, and 3; wound complications have been reported with therapy. Hold treatment at least 28 days prior to scheduled surgery (including dental surgery); resume based on judgment of adequate wound healing post surgery. Withhold treatment in patients with dehiscence or other wound healing complications requiring intervention. Disease-related concerns:

Hepatic impairment

Cabozantinib exposure is increased in patients with hepatic impairment. Reduced initial doses are recommended for patients with mild or moderate impairment; use is not recommended in patients with severe impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Formulations

Cabozantinib is available in tablets (Cabometyx) and capsules (Cometriq) which are NOT interchangeable; do NOT substitute.

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in animal reproduction studies. Based on its mechanism of action, adverse effects on pregnancy would be expected. Patients (male and female) should use effective contraception during therapy and for 4 months after therapy completion. Cabozantinib may impair fertility in females and males.

Lactation

It is not known if cabozantinib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during treatment and for 4 months after the last dose.

Monitoring

Clinical pearl	Renal function, liver function, CBC with differential and platelets, serum electrolytes; blood pressure (prior to initiation and regularly during therapy); monitor for perforations, fistulas, signs/symptoms of bleeding, palmar-plantar erythrodysesthesia syndrome (PPES), reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria (regularly during therapy), osteonecrosis of the jaw (perform oral examination prior to initiation and periodically during therapy), wound healing complications, diarrhea, stomatitis. Monitor adherence.

Clinical pearl

Renal function, liver function, CBC with differential and platelets, serum electrolytes; blood pressure (prior to initiation and regularly during therapy); monitor for perforations, fistulas, signs/symptoms of bleeding, palmar-plantar erythrodysesthesia syndrome (PPES), reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria (regularly during therapy), osteonecrosis of the jaw (perform oral examination prior to initiation and periodically during therapy), wound healing complications, diarrhea, stomatitis. Monitor adherence.

Chemistry & Properties

Formula	C28H24FN3O5
Molecular weight	501.51 g/mol
IUPAC name	1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
CAS	849217-68-1
PubChem CID	25102847
InChIKey	`ONIQOQHATWINJY-UHFFFAOYSA-N`
logP	5.54 (XLogP 5.4)
Polar surface area	98.78 Å²
H-bond acceptors / donors	6 / 2
Drug-likeness (QED)	0.31
Lipinski violations	2

SMILES

COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	0.988 h
Volume of distribution	3.875 L/kg
Protein binding	93.7%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Inhibitor	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 3)

Target	Action	Affinity
kinase insert domain receptor (KDR)	Inhibitor	pIC50 10.5
MET proto-oncogene, receptor tyrosine kinase (MET)	Inhibitor	pIC50 8.9
ret proto-oncogene (RET)	Inhibitor	pIC50 8.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)MRP2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abarelix	major
Abciximab	major
Abiraterone	major
Acalabrutinib	major
Acetylsalicylic acid	major
Adenosine	major
Alfuzosin	major
Alimemazine	major
Alteplase	major
Amiodarone	major
Amisulpride	major
Amitriptyline	major
Amoxapine	major
Amprenavir	major
Anagrelide	major
Anisindione	major
Anistreplase	major
Antithrombin III human	major
Apalutamide	major
Apixaban	major
Apomorphine	major
Ardeparin	major
Argatroban	major
Arsenic trioxide	major
Asenapine	major
Astemizole	major
Atazanavir	major
Atomoxetine	major
Avapritinib	major
Azithromycin	major
Bedaquiline	major
Bepridil	major
Berotralstat	major
Betrixaban	major
Bicalutamide	major
Binimetinib	major
Bivalirudin	major
Boceprevir	major
Bosutinib	major
Bromfenac	major

Showing 40 of 100+.

Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cabometyx	Tablet 60 mg	30 tab	Petra Drug Store	—
Cabometyx	Tablet 40 mg	30 tab	Petra Drug Store	—
Cabometyx	Tablet 20 mg	30 tab	Petra Drug Store	—