Exelixis's Cabometyx (cabozantinib) Monograph

Published: August 22, 2025

Cabometyx (cabozantinib) is Exelixis's approved tyrosine kinase inhibitor indicated for advanced renal cell carcinoma, hepatocellular carcinoma, neuroendocrine tumors, and differentiated thyroid cancer. Cabometyx was first approved by the FDA in 2016, with additional approvals following through earlier this year.

Medication Overview:

Brand Name: Cabometyx
Generic Name: Cabozantinib
Treatment for: Advanced renal cell carcinoma, hepatocellular carcinoma, differentiated thyroid cancer, pancreatic neuroendocrine tumors, and extra-pancreatic neuroendocrine tumors
Manufacturer(s): Exelixis
Initial FDA Approval: April 2016

Cabometyx (cabozantinib) Indications Rundown

Indicated Condition	Indication	Age	Year Approved
Pancreatic Neuroendocrine Tumors (epNET)	Indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pNET.	12 years and older	2025
Extrapancreatic Neuroendocrine Tumors (epNET)	Indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated epNET.	12 years and older	2025
Advanced Renal Cell Carcinoma (RCC)	In combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.	Not specificed	2017
Advanced Renal Cell Carcinoma (RCC)	indicated for the treatment of patients with advanced RCC.	Not specificed	2016
Hepatocellular Carcinoma (HCC)	Indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.	Not specificed	2019
Differentiated Thyroid Cancer (DTC)	Indicated for the treatment of adult and pediatric patients 12 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 radioactive iodine-refractory or ineligible.	12 years and older	2021

Warnings and Precautions:

Hemorrhage: Cabometyx can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in Cabometyx patients in RCC, HCC, and DTC studies. Discontinue Cabometyx for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of Cabometyx patients. Monitor for signs and symptoms, and discontinue Cabometyx in patients with Grade 4 fistulas or GI perforation.
Thrombotic Events: Cabometyx can cause arterial or venous thromboembolic event. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of Cabometyx patients. Fatal thrombotic events have occurred. Discontinue Cabometyx in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.
Hypertension and Hypertensive Crisis: Cabometyx can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of Cabometyx patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of Cabometyx patients. Do not initiate Cabometyx in patients with uncontrolled hypertension. Monitor blood pressure regularly during Cabometyx treatment. Withhold Cabometyx for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue Cabometyx for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.
Diarrhea: Cabometyx can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold Cabometyx until improvement to ≤ Grade 1; resume at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): Cabometyx can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold Cabometyx until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: Cabometyx in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to Cabometyx alone. With the combination of Cabometyx and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding Cabometyx and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.
Adrenal Insufficiency: Cabometyx in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received Cabometyx with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Withhold Cabometyx and/or nivolumab and resume Cabometyx at a reduced dose depending on severity.
Proteinuria: Proteinuria was observed in 8% of Cabometyx patients. Monitor urine protein regularly during Cabometyx treatment. For Grade 2 or 3 proteinuria, withhold Cabometyx until improvement to ≤ Grade 1 proteinuria; resume Cabometyx at a reduced dose. Discontinue Cabometyx in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): Cabometyx can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to Cabometyx initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold Cabometyx for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold Cabometyx for development of ONJ until complete resolution; resume at a reduced dose.
Impaired Wound Healing: Cabometyx can cause impaired wound healing. Withhold Cabometyx for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of Cabometyx after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Cabometyx can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue Cabometyx in patients who develop RPLS.
Thyroid Dysfunction: Cabometyx can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of Cabometyx and monitor for signs and symptoms during treatment.
Hypocalcemia: Cabometyx can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of Cabometyx patients (2% Grade 3 and 1% Grade 4). Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume Cabometyx at a reduced dose upon recovery or permanently discontinue Cabometyx depending on severity.

Embryo-Fetal Toxicity: Cabometyx can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with Cabometyx and for 4 months after the last dose.

Dosage and Administration:

Do NOT substitute Cabometyx tablets with cabozantinib capsules.
Administer on an empty stomach at least 1 hour before or at least 2 hours after eating. (2.1, 2.9)
Stop treatment with Cabometyx at least 3 weeks prior to scheduled surgery, including dental surgery.

Recommended Dose:

60 mg orally, once daily.
40 mg orally, once daily, administered in combination with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.
40 mg orally, once daily, in pediatric patients 12 years of age and older with bodyweight less than 40 kg.

Dosage Forms and Strengths:

Tablets: 60 mg, 40 mg, 20 mg

Contraindications:

None.

Drug Interactions:

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the Cabometyx dosage. Avoid grapefruit or grapefruit juice.
Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the Cabometyx dosage. Avoid St. John’s wort.

Adverse Reactions:

The most common (≥20%) adverse reactions are:

Cabometyx as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.
Cabometyx in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Examples of Cabozantinib in Guidelines:

Renal Cell Carcinoma

European Association of Urology, June 2025
- Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal cell carcinoma.
- Offer cabozantinib after VEGF-targeted therapy in cc-mRCC.

Systemic Therapy for Advanced Hepatocellular Carcinoma

American Society of Clinical Oncology, March 2024
- Following first-line treatment with atezo +bev, second-line therapy with a tyrosine kinase inhibitor (TKI) (i.e., sorafenib, lenvatinib, or cabozantinib), or ramucirumab (alpha-fetoprotein [AFP] ≥400 ng/mL) are recommended.

Management of Metastatic Renal Clear Cell Cancer

American Society of Clinical Oncology, October 2023
- Recommendation 4.1: Nivolumab or cabozantinib should be offered to patients who progressed on a VEGFR TKI alone.

Please note: This article is current as of August 21, 2025. Sign up for alerts to keep up with the latest guidelines and FDA-related guideline updates.