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Cabozantinib: Mechanism of Action, Adverse Effects, Contraindications, and Dosing

Mechanism of Action of Cabozantinib:

Cabozantinib is an oral multityrosine kinase inhibitor that potently inhibits MET, VEGFR-1/-2/-3, and AXL; it also inhibits RET, KIT, FLT3, and other kinases. This inhibition reduces tumor angiogenesis, invasion, and metastatic potential.

Urologic Indications for Cabozantinib:

In urology, cabozantinib is approved for metastatic renal cell carcinoma (RCC): as combination with nivolumab in the first line and as monotherapy (in selected first-line settings and after prior therapy).

• First-line therapy with nivolumab combined with cabozantinib: In the CheckMate-9ER trial, the combination improved progression-free survival (16 vs. 8 months), objective response rate, complete response rate, and overall survival (47 vs. 36 months) compared with sunitinib across IMDC risk groups (Motzer et al., 2025).
• First-line therapy with cabozantinib monotherapy: An option for patients with intermediate or poor prognosis who have contraindications to immune checkpoint inhibitors. In the CABOSUN trial, progression-free survival (9 vs. 5 months) was longer with cabozantinib than with sunitinib (Choueiri et al., 2018).
• Second-line and later therapy for metastatic RCC: In the METEOR trial, cabozantinib improved progression-free survival and overall survival (21 vs. 19 months) compared with everolimus after prior VEGF-targeted therapy (Choueiri et al., 2015).

Pharmacokinetics of Cabozantinib:

Cabozantinib is administered orally, exhibits high plasma protein binding, and undergoes hepatic metabolism predominantly via CYP3A4. Elimination occurs mainly in the feces. It has a long terminal half-life of approximately 110 hours.

Adverse Effects of Cabozantinib:

Common adverse effects include diarrhea, hypertension, fatigue, nausea, decreased appetite, and hand–foot skin reaction.

Gastrointestinal Tract:

Nausea, vomiting, diarrhea, and abdominal pain occur very frequently; mucositis or stomatitis occurs frequently. Rare but potentially serious gastrointestinal perforation has been reported (approximately 1%).

Skin:

Impaired wound healing may occur. Rash and hand–foot skin reaction (palmar-plantar erythrodysesthesia) are very common. Hypopigmentation, alopecia, and changes in hair color occur frequently.

Hematologic:

Anemia, thrombocytopenia, and neutropenia occur frequently.

Hepatic:

Elevations in liver enzymes occur frequently; hepatic dysfunction can occur.

Cardiovascular Adverse Effects:

Hypertension is very common. Arterial or venous thromboembolic events may occur. Heart failure and myocardial infarction have been reported but are uncommon to rare.

Other Adverse Effects:

Weakness/fatigue, headache, bleeding, dizziness, hypokalemia, hypomagnesemia, proteinuria, and weight loss may occur.

Contraindications to Cabozantinib:

• Severe hepatic impairment (Child–Pugh C).
• Pregnancy and lactation.
• Perioperative use until adequate wound healing is achieved.
• Discontinue cabozantinib if grade 3/4 toxicities persist despite dose reduction.

Drug–Drug Interactions:

Avoid coadministration of cabozantinib with strong CYP3A4 inhibitors, e.g., macrolides, azole antifungals such as ketoconazole, or grapefruit products, and with strong CYP3A4 inducers such as rifampin, because clinically relevant changes in cabozantinib exposure are expected.

Dosing of Cabozantinib:

• Monotherapy: 60 mg of cabozantinib orally once daily. Reduce stepwise to 40 mg and then 20 mg for toxicity management. For grade 3/4 toxicities, interrupt treatment and, after recovery to an acceptable grade, resume at a reduced dose.
• Combination with nivolumab: Cabozantinib 40 mg orally once daily (plus nivolumab according to the approved schedule).

Monitoring During Therapy:

Obtain regular complete blood counts; serum electrolytes (including phosphate); liver function tests; blood glucose; coagulation parameters; thyroid function tests; serum creatinine; urinalysis for proteinuria. Perform examinations of the skin and oral cavity and measure blood pressure.

Supportive Care:

For diarrhea, use loperamide; for mucositis, perform regular mouth rinses; for hand–foot skin reaction, prevent mechanical stress and consider keratolytic or topical glucocorticoid preparations; treat hypertension according to guidelines; institute thyroid hormone replacement in hypothyroidism. If adverse effects do not improve, reduce the dose or interrupt therapy.

References

T. K. Choueiri et al., “Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.,” vol. 373, no. 19, pp. 1814–1823, 2015.

T. K. Choueiri et al., “Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.,” Eur J Cancer, vol. 94, pp. 115–125, 2018.

Motzer RJ, Escudier B, Choueiri TK et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2025 Sep 23:S0923-7534(25)04714-3. doi: 10.1016/j.annonc.2025.09.006.

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