Cabometyx for advanced kidney, liver, thyroid, and neuroendocrine cancers

Cabometyx is an oral kinase inhibitor used to treat various advanced cancers, including renal cell carcinoma, hepatocellular carcinoma, differentiated thyroid cancer, and neuroendocrine tumors in adults and pediatric patients aged 12 and older. It is available as film-coated tablets in 20 mg, 40 mg, and 60 mg strengths and may be used alone or with nivolumab for certain kidney cancers.

Cabometyx is approved for the following conditions:

• Advanced renal cell carcinoma (RCC), including as first-line treatment combined with nivolumab.
• Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Locally advanced or metastatic differentiated thyroid cancer (DTC) in patients 12 years and older who have progressed after prior VEGFR-targeted therapy and are radioactive iodine-refractory or ineligible.
• Previously treated, unresectable, locally advanced or metastatic well-differentiated pancreatic neuroendocrine tumors (pNET) in patients 12 years and older.
• Previously treated, unresectable, locally advanced or metastatic well-differentiated extra-pancreatic neuroendocrine tumors (epNET) in patients 12 years and older.

cabozantinib s-malate

Cabometyx blocks multiple kinases involved in tumor growth, angiogenesis (formation of new blood vessels), and metastasis, including VEGFRs (vascular endothelial growth factor receptors). By inhibiting these pathways, it interferes with the cancer cells' ability to grow and spread.

General Administration

• Take on an empty stomach; at least 1 hour before or at least 2 hours after eating.
• Swallow tablets whole without crushing, chewing, or splitting.
• Do not substitute tablets with cabozantinib capsules.
• Stop at least 3 weeks before any scheduled surgery (including dental) and do not restart until adequate wound healing (at least 2 weeks after major surgery).
• Do not take a missed dose within 12 hours of the next scheduled dose.

Recommended Dosages by Indication

• Advanced Renal Cell Carcinoma (RCC):
  • Single agent: 60 mg orally once daily until disease progression or unacceptable toxicity.
  • Combination with nivolumab: 40 mg orally once daily plus nivolumab infusions (240 mg every 2 weeks, or 480 mg every 4 weeks IV; or nivolumab plus hyaluronidase subcutaneously at specified doses) until disease progression or unacceptable toxicity, for up to 2 years.
• Hepatocellular Carcinoma (HCC): 60 mg orally once daily until disease progression or unacceptable toxicity.
• Differentiated Thyroid Cancer (DTC) and Neuroendocrine Tumors (pNET and epNET):
  • Adults and pediatric patients 12 years and older weighing ≥40 kg: 60 mg orally once daily.
  • Pediatric patients 12 years and older weighing Treatment continues until disease progression or unacceptable toxicity.

Dosage Modifications

• Modify dose for adverse reactions, drug interactions, or moderate hepatic impairment.
• Adverse reaction management: Withhold for intolerable Grade 2 or any Grade 3-4 adverse reactions, osteonecrosis of the jaw, and specific serious events like hemorrhage or perforation; upon symptom improvement, resume at reduced dose as per specified schedules.
• Interactions with CYP3A4 inhibitors: Reduce daily dose by 20 mg during coadministration; resume previous dose 2-3 days after stopping inhibitor.
• Interactions with CYP3A4 inducers: Increase daily dose by 20 mg as tolerated; do not exceed 80 mg daily; return to prior dose 2-3 days after stopping inducer.
• For moderate hepatic impairment (Child-Pugh B), reduce starting dose from 60 mg to 40 mg, or from 40 mg to 20 mg in pediatric patients

None reported.

Important Warnings and Precautions

• Hemorrhage: Do not use if recent hemorrhage; discontinue permanently for Grade 3 or 4 bleeding.
• Perforations and Fistulas: Monitor symptoms; discontinue permanently for any Grade 4 fistula or gastrointestinal perforation.
• Thromboembolic Events: Discontinue permanently for myocardial infarction, severe cerebral infarction, or serious arterial/venous thromboembolism.
• Hypertension: Monitor blood pressure regularly; withhold for uncontrolled Grade 3 hypertension until ≤Grade 2 and resume at reduced dose; permanently discontinue for hypertensive crisis or uncontrolled hypertension.
• Cardiac Failure: Monitor for signs and symptoms throughout treatment.
• Diarrhea: May be severe; withhold until resolved to ≤Grade 1 and resume at reduced dose; manage with standard antidiarrheal treatment.
• Palmar-Plantar Erythrodysesthesia (PPE): Interrupt treatment until resolution or improvement to Grade 1; then resume at reduced dose.
• Hepatotoxicity: When combined with nivolumab, higher incidence of significant liver enzyme elevations; monitor liver function; consider corticosteroids and treatment discontinuation for severe cases.
• Adrenal Insufficiency: Possible with combination therapy; treat symptomatically, withhold therapy depending on severity.
• Proteinuria: Monitor urine protein; withhold until improvement, then resume at reduced dose; discontinue for nephrotic syndrome.
• Osteonecrosis of the jaw: Withhold at least 3 weeks prior to invasive dental procedures and for ONJ occurrence; resume only after resolution at reduced dose.
• Impaired Wound Healing: Withhold at least 3 weeks before surgery and until wound healing is adequate.
• Reversible Posterior Leukoencephalopathy Syndrome: Permanently discontinue if this occurs.

Common and Serious Side Effects

• Hemorrhage (bleeding)
• Gastrointestinal perforations and fistulas
• Blood clots including myocardial infarction and stroke
• Hypertension and hypertensive crises
• Cardiac failure symptoms
• Severe diarrhea
• Palmar-plantar erythrodysesthesia (skin redness, swelling, and pain on palms and soles)
• Elevated liver enzymes
• Adrenal insufficiency (fatigue, weakness)
• Proteinuria (excess protein in urine)
• Osteonecrosis of the jaw
• Impaired wound healing
• Reversible posterior leukoencephalopathy syndrome (neurological symptoms)

Drug Interactions

• CYP3A4 inhibitors (strong): Decrease cabozantinib dose by 20 mg to avoid increased drug exposure; resume prior dose 2-3 days after stopping inhibitor.
• CYP3A4 inducers (strong/moderate): Increase cabozantinib dose by 20 mg (up to a max of 80 mg daily) to compensate for reduced exposure; resume prior dose 2-3 days after stopping inducer.
• When given with nivolumab, monitor for increased incidence of hepatotoxicity and adrenal insufficiency; follow nivolumab prescribing information for combination use.