Cabozantinib

Cabozantinib is an orally administered targeted anticancer medicine belonging to the tyrosine kinase inhibitor class. It inhibits multiple receptor tyrosine kinases involved in tumor growth, blood-vessel formation and cancer-cell signaling, including MET, VEGF receptors, AXL and RET, with additional activity against other kinases. By interfering with these signaling pathways, cabozantinib can reduce processes that support cancer-cell proliferation, survival, invasion and development of tumor-associated blood vessels. Cabozantinib is used in several advanced malignancies, including renal cell carcinoma, hepatocellular carcinoma, differentiated thyroid carcinoma and selected pancreatic and extra-pancreatic neuroendocrine tumors, depending on the regulatory jurisdiction and treatment setting. It may be administered alone or, in advanced renal cell carcinoma, in combination with the immune checkpoint inhibitor nivolumab. Cabozantinib is supplied as oral tablets and is generally taken once daily on an empty stomach because food can increase drug exposure. The dose and treatment duration depend on the cancer type, combination regimen, previous therapy, body weight in certain pediatric indications and individual tolerability. Because cabozantinib affects multiple biological pathways, treatment requires careful monitoring for gastrointestinal, cardiovascular, hepatic, bleeding, wound-healing and other toxicities. Dose interruptions and reductions are commonly used to manage clinically significant adverse effects while maintaining treatment when appropriate.

Cabozantinib was developed as a multi-targeted tyrosine kinase inhibitor with activity against signaling pathways involved in cancer growth and angiogenesis. The U.S. Food and Drug Administration initially approved cabozantinib in 2012 under the name Cometriq for progressive metastatic medullary thyroid cancer. The tablet formulation marketed as Cabometyx received FDA approval in 2016 for advanced renal cell carcinoma following prior VEGF-targeted therapy, followed by additional approvals for hepatocellular carcinoma in 2019, first-line advanced renal cell carcinoma in combination with nivolumab in 2021, and differentiated thyroid cancer in 2021. In March 2025, FDA expanded Cabometyx to previously treated, unresectable, locally advanced or metastatic well-differentiated pancreatic and extra-pancreatic neuroendocrine tumors in adults and pediatric patients 12 years of age and older. In the European Union, Cabometyx received marketing authorisation on 9 September 2016 for advanced renal cell carcinoma following prior VEGF-targeted therapy, with subsequent variations expanding its indications. Current European product information includes advanced renal cell carcinoma as monotherapy and in combination with nivolumab, hepatocellular carcinoma after prior sorafenib, differentiated thyroid carcinoma after prior systemic therapy and selected pancreatic and extra-pancreatic neuroendocrine tumors. Key clinical development programmes include METEOR, CELESTIAL, EXAM, CheckMate 9ER, COSMIC-311 and CABINET.

Cabozantinib is used for several advanced cancers, with the approved indication depending on the regulatory jurisdiction, disease stage and previous treatment. In renal cell carcinoma, it is used as monotherapy in advanced disease and as first-line combination treatment with nivolumab in appropriate adults. In hepatocellular carcinoma, cabozantinib is used after previous treatment with sorafenib in the applicable adult population. In differentiated thyroid carcinoma, it is used for locally advanced or metastatic disease that has progressed following prior VEGFR-targeted systemic therapy and is refractory to radioactive iodine or unsuitable for radioactive iodine treatment. Cabozantinib is also approved for previously treated, unresectable, locally advanced or metastatic well-differentiated pancreatic and extra-pancreatic neuroendocrine tumors in specified adult and pediatric populations. The exact treatment setting and eligibility requirements vary between the United States, European Union and other countries. Cabozantinib may be used alone or, for first-line advanced renal cell carcinoma, together with nivolumab according to the approved regimen.

Cabozantinib is administered orally once daily and should generally be taken without food, with administration separated from meals according to prescribing information. For adults with advanced renal cell carcinoma, hepatocellular carcinoma or differentiated thyroid carcinoma treated with Cabometyx as monotherapy, the usual recommended dose is 60 mg once daily. For first-line advanced renal cell carcinoma when combined with nivolumab, the recommended cabozantinib dose is 40 mg once daily, while nivolumab is administered according to its separate approved schedule. In adults and pediatric patients 12 years of age and older with body weight of at least 40 kg being treated for selected pancreatic or extra-pancreatic neuroendocrine tumors, the recommended dose is 60 mg once daily, while a lower dose is used for pediatric patients weighing less than 40 kg. Treatment is generally continued until disease progression or unacceptable toxicity, although the duration and maximum treatment period of combination therapy may be specified by the applicable regimen. Dose interruption and reduction are commonly required for clinically significant adverse reactions. Cabozantinib should not be substituted between different formulations or indications without considering the relevant prescribing information because formulations and dosing recommendations can differ.

Common side effects of cabozantinib include diarrhea, fatigue, decreased appetite, nausea, vomiting, weight loss, mouth or throat discomfort, abdominal pain, hypertension and palmar-plantar erythrodysesthesia, also known as hand-foot syndrome. Changes in taste, constipation, weakness and abnormalities in laboratory tests can also occur. In combination with nivolumab, some adverse effects may reflect either medicine or overlapping effects of the two treatments. The frequency and severity of adverse reactions vary according to the cancer type, dose and combination regimen. Many adverse effects can be managed through supportive treatment, monitoring, dose interruption or dose reduction under medical supervision.

Important serious risks associated with cabozantinib include severe or persistent diarrhea, gastrointestinal perforation or fistula, significant bleeding, thromboembolic events, severe hypertension, impaired wound healing, proteinuria, hepatotoxicity, severe skin reactions and reversible posterior leukoencephalopathy syndrome. Cabozantinib can also cause osteonecrosis of the jaw, particularly in patients with relevant dental or bone risk factors. Rare but serious complications involving blood vessels, the gastrointestinal tract or other organs may require permanent treatment discontinuation. Liver toxicity requires particular attention when cabozantinib is combined with nivolumab because immune-mediated and drug-related hepatic injury can overlap. Cabozantinib should generally be withheld before planned major surgery and restarted only after adequate wound healing according to clinical judgment and prescribing information. Treatment should be interrupted or discontinued when clinically significant toxicity occurs, depending on the severity and type of adverse reaction.

Patients should be assessed for baseline cardiovascular risk, blood pressure, liver and kidney function, urine protein, bleeding risk, gastrointestinal abnormalities, dental problems and planned surgical procedures before and during treatment. Cabozantinib is primarily metabolized by CYP3A4, so strong CYP3A4 inhibitors can increase cabozantinib exposure and strong CYP3A4 inducers can decrease exposure. Concomitant use with such medicines should generally be avoided when suitable alternatives are available, or dose adjustment should be considered according to prescribing information. Patients should also inform healthcare professionals about anticoagulants, medicines affecting blood pressure and other anticancer treatments. Cabozantinib may increase the risk of bleeding and impaired wound healing, making surgical planning important. Pregnancy should be avoided during treatment because cabozantinib can cause fetal harm. Effective contraception is recommended for appropriate patients during treatment and for the specified period after the final dose. Patients receiving cabozantinib with nivolumab require monitoring for both cabozantinib-related toxicities and immune-mediated adverse reactions associated with nivolumab.

Prescribers should confirm the exact cancer indication, previous therapies, treatment combination and applicable regulatory dosing before initiating cabozantinib. Baseline blood pressure, liver function, kidney function and urine protein should be assessed, with additional evaluation based on the patient's cardiovascular, gastrointestinal, dental and bleeding history. Blood pressure should be monitored regularly because hypertension can develop or worsen during treatment. Patients should receive practical counselling regarding diarrhea, hand-foot syndrome, oral symptoms, nutritional intake and early reporting of bleeding or severe abdominal pain. A complete medication review is important because CYP3A4 inhibitors and inducers can substantially alter cabozantinib exposure. Before invasive dental procedures or major surgery, the potential effect of cabozantinib on wound healing should be considered. When cabozantinib is combined with nivolumab, monitoring should also include immune-mediated toxicities affecting the liver, bowel, lungs, endocrine organs and other tissues. Pharmacists should verify the once-daily schedule, fasting administration requirements, formulation, interaction profile and any dose modifications before dispensing.