Cabozantinib – Uses, Dosage, Side Effects, Interaction

Mechanism of action

Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2, and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2. Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzymes produce an N-oxide metabolite.

Cabozantinib S-malate is the s-malate salt form of cabozantinib, an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually, lead to tumor regression.

Cabozantinib is an orally bioavailable, small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis and eventually lead to tumor regression.

Use in Cancer

Cabozantinib-s-malate is approved to treat:

• Differentiated thyroid cancer that has spread. It is used in adults and children aged 12 years and older who cannot receive radioactive iodine and whose cancer got worse after VEGF receptor–targeted therapy. This use is approved for the Cabometyx brand of cabozantinib-s-malate.
• Hepatocellular carcinoma (a type of liver cancer). It is used in patients who have already been treated with sorafenib. This use is approved for the Cabometyx brand of cabozantinib-s-malate.
• Medullary thyroid cancer has gotten worse and has metastasized (spread to other parts of the body). This use is approved for the Cometriq brand of cabozantinib-s-malate.
• Renal cell carcinoma (a type of kidney cancer) is advanced. It is either used with nivolumab as the first therapy or alone. This use is approved for the Cabometyx brand of cabozantinib-s-malate.

Cabozantinib-s-malate is also being studied in the treatment of other types of cancer.

Contraindications

• a condition with low thyroid? hormone levels
• low amount of calcium in the blood
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• high blood pressure
• significant uncontrolled high blood pressure
• a localized? weakening and ballooning in an artery wall called an arterial aneurysm
• obstruction of a blood vessel by a blood clot
• an occurrence of a blood clot in an artery
• blood clot formation in vein
• stomatitis is a condition with painful swelling? and sores inside the mouth
• an abnormal connection between the esophagus and windpipe
• a gastrointestinal tract fistula
• bleeding of the stomach or intestines
• nephrotic syndrome, a type of kidney disorder
• coughing up blood
• elevation of proteins in the urine
• abnormal liver function tests
• impaired wound healing
• pregnancy
• a patient who is producing milk and breastfeeding
• a rupture in the wall of the stomach or intestine
• problems with wound healing after a surgery
• invasive dental procedure
• a type of brain disorder called posterior reversible encephalopathy syndrome
• dissection of artery
• Child-Pugh class A liver impairment
• Child-Pugh class B liver impairment
• Child-Pugh class C liver impairment

Dosage?

Strengths: 140 mg daily-dose; 100 mg daily-dose; 60 mg daily-dose; 60 mg; 20 mg; 40 mg

Thyroid? Cancer

• Capsules: 140 mg orally once a day until the patient no longer experiences clinical benefit or unacceptable toxicity occurs
• Tablets: BSA greater than or equal to 1.2 m(2): 60 mg once a day until disease progression or unacceptable toxicity
• Do not substitute tablets with capsules.
• Stop a treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Renal? Cell Carcinoma

Tablets:

• As a single agent: 60 mg orally once a day until the patient no longer experiences clinical benefit or unacceptable toxicity occurs
• In combination with nivolumab: 40 mg once a day until disease progression or unacceptable toxicity
• When administering this drug in combination with nivolumab, refer to the nivolumab prescribing information.
• Do not substitute tablets with capsules.
• Stop a treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Hepatocellular Carcinoma

• Tablets: 60 mg orally once a day until the patient no longer experiences clinical benefit or unacceptable toxicity occurs
• Do not substitute tablets with capsules.
• Stop a treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Usual Pediatric Dose

Thyroid? Cancer

• Tablets: BSA greater than or equal to 1.2 m(2): 60 mg once a day until disease progression or unacceptable toxicity
• Tablets: BSA less than 1.2 m(2): 40 mg once a day until disease progression or unacceptable toxicity
• Do not substitute tablets with capsules.
• Stop a treatment at least 3 weeks prior to scheduled surgery, including dental surgery.

Renal? Dose Adjustments

Capsules/Tablets:

• Mild to moderate renal? dysfunction: No adjustment is recommended.
• Severe renal? dysfunction: Data not available

Liver Dose Adjustments

Capsule formulation (MTC):

• Mild to moderate hepatic dysfunction: 80 mg orally once a day
• Severe hepatic dysfunction: Use is not recommended.

Tablet formulation (MTC):

• Mild hepatic dysfunction: No adjustment is recommended.
• Moderate hepatic dysfunction: 40 mg daily OR 40 mg daily to 20 mg daily [for pediatric patients with BSA less than 1.2 m(2)].
• Severe hepatic dysfunction: Use is not recommended.

Tablet formulation (RCC):

• Mild to moderate hepatic dysfunction: 40 mg orally once a day
• Severe hepatic dysfunction: Use is not recommended.
• In combination with nivolumab
• If ALT or AST is greater than 3 times the upper limit of normal (ULN) but up to 10 times ULN with concurrent total jaundice?. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">bilirubin? less than 2 times ULN: Withhold this drug and nivolumab until adverse reactions recover to Grades 0 or 1 and consider corticosteroid therapy as appropriate. Might rechallenge with one or both drugs after recovery.
• If ALT or AST is greater than 10 times ULN or greater than 3 times ULN with a concurrent total jaundice?. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">bilirubin? of at least 2 times ULN: Permanently discontinue this drug and nivolumab. Corticosteroid therapy may be considered if an immune-mediated reaction is suspected.

Dose Adjustments

CAPSULE FORMULATION (MTC):

• Adverse Reactions (Grade 4, Grade 3, or intolerable Grade 2): Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If the previous dose was 140 mg/day: Reduce the dose to 100 mg/day
• If the previous dose was 100 mg/day: Reduce the dose to 60 mg/day
• If the previous dose is 60 mg/day: Do not dose reduce; resume at 60 mg/day if tolerated or discontinue therapy.
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 40 mg (e.g., from 140 mg/day to 100 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended. If concomitant use is necessary, increase the dose of this drug by 40 mg (e.g., from 140 mg/day to 180 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the CYP450 3A4 inducer. Do not exceed 180 mg/day.
• Permanently discontinue therapy for the development of perforation or fistula formation, severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, severe hypertension despite optimal medical management, osteonecrosis of the jaw, or reversible posterior leukoencephalopathy syndrome.

TABLET FORMULATION (RCC):

• Scheduled Surgery: Stop a treatment at least 28 days prior to scheduled surgery, including dental surgery.
• Adverse Reactions (Grade 4, Grade 3, or Intolerable Grade 2) or osteonecrosis of the jaw: Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If the previous dose 60 mg/day: Reduce the dose to 40 mg/day
• If the previous dose was 40 mg/day: Reduce the dose to 20 mg/day
• If the previous dose is 20 mg/day: Do not dose reduce; resume at 20 mg/day if tolerated or discontinue therapy
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 20 mg (e.g., from 60 mg/day to 40 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended if alternative therapy is available. If concomitant use is necessary, increase the dose of this drug by 20 mg (e.g., from 60 mg/day to 80 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the 3A4 inducer. Do not exceed 80 mg/day.
• Permanently discontinue therapy for the development of unmanageable fistula or GI perforation, severe hemorrhage, arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.

TABLET FORMULATION (RCC):

• Adverse Reactions (Grade 4, Grade 3, or intolerable Grade 2): Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If the previous dose is 60 mg daily in adult and pediatric patients with BSA greater than or equal to 1.2 m(2): Reduce the dose to 40 mg/day OR if the previous dose is 20 mg every other day; do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy
• If the previous dose is 40 mg daily in pediatric patients with BSA less than 1.2 m(2): Reduce the dose to 20 mg/day OR if the previous dose was 20 mg every other day, do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy

TABLET FORMULATION (RCC) IN COMBINATION WITH NIVOLUMAB:

• Scheduled Surgery: Stop a treatment at least 3 weeks prior to scheduled surgery, including dental surgery.
• Adverse Reactions (Grade 4, Grade 3, or Intolerable Grade 2) or osteonecrosis of the jaw: Withhold therapy until improvement to baseline or resolution to Grade 1; then adjust the dose as follows:
• If the previous dose 40 mg/day: Reduce the dose to 20 mg once a day
• If the previous dose is 20 mg/day: Reduce the dose to 20 mg every other day
• If the previous dose is 20 mg every other day: Do not dose reduce; resume at 20 mg every other day if tolerated or discontinue therapy
• Concomitant Use of Strong CYP450 3A4 Inhibitors: Use is not recommended. If concomitant use is necessary, reduce the dose of this drug by 20 mg (e.g., from 60 mg/day to 40 mg/day). Resume the dose used prior to initiation of the strong CYP450 3A4 inhibitor 2 to 3 days after discontinuation of the CYP450 3A4 inhibitor.
• Concomitant Use of Strong CYP450 3A4 Inducers: Use is not recommended if alternative therapy is available. If concomitant use is necessary, increase the dose of this drug by 20 mg (e.g., from 60 mg/day to 80 mg/day) as tolerated. Resume the dose used prior to initiation of the strong CYP450 3A4 inducer 2 to 3 days after discontinuation of the 3A4 inducer. Do not exceed 80 mg/day.
• Permanently discontinue therapy for the development of gastrointestinal perforation or Grade 4 fistula, severe hemorrhage, acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention, severe hypertension that cannot be controlled with anti-hypertensive therapy or hypertensive crisis, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.

Administration Advice:

• Tablets and capsules are not interchangeable.
• This drug should be taken on an empty stomach at least 2 hours before or 1 hour after a meal.
• Do not open/break/crush/chew tablets or capsules; swallow whole with a full glass of water.
• Do not take a missed dose if it is less than 12 hours before the next dose.
• Do not ingest foods (e.g., grapefruit) or nutritional supplements (e.g., St. John’s Wort) that are known to inhibit or induce CYP450 activity while taking this drug.

Side Effects

The Most Common

• constipation
• nausea
• vomiting
• difficulty swallowing
• change in the ability to taste food
• hemorrhoids
• redness, swelling, sores, or pain in your mouth or throat
• loss of appetite
• weight loss
• anxiety
• tiredness or weakness
• pale skin
• dry skin
• patchy thickening of the skin
• pain in joints, arms, or legs
• voice changes or hoarseness
• hair loss
• hair color turning lighter or gray
• slowed wound healing
• fluid build-up in the abdomen (e.g., rapid weight gain, abdominal pain, shortness of breath)
• jaw pain
• high blood pressure (e.g., headache, vision changes, nausea, vomiting)
• rash or skin redness
• shortness of breath
• signs of anemia (e.g., fatigue, pale skin, shortness of breath, loss of energy, weakness)
• signs of bleeding (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of a blood clot in the arm or leg (tenderness, pain, swelling, warmth, or redness in the arm or leg) or lungs (chest pain, coughing up blood, shortness of breath)
• signs of decreased thyroid function (e.g., constipation, dry skin, tiredness, weight gain, sensitivity to the cold)
• signs of fluid build-up around the lungs (e.g., chest pain, cough, hiccups, rapid breathing)
• signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
• signs of low electrolyte levels (e.g., muscle spasms or weakness, tingling or numbness, tiredness, twitching, or memory loss)
• sudden, severe pain in the back, chest, or abdomen

More Common

• chest pain, pressure, or tightness
• coughing up blood or blood clots
• vomiting material that is bloody or looks like coffee grounds
• menstrual bleeding that is heavier than usual
• red or black, tarry stool
• nose bleed
• diarrhea
• unusual or heavy bleeding or bruising
• tender or painful stomach area
• swelling around eyes, arms, hands, legs, feet, or ankles
• foamy urine
• shortness of breath or cough
• trouble breathing
• fast, pounding, or irregular heartbeat
• sudden severe headache
• lightheadedness or fainting
• seizures
• numbness or weakness of the face, arm, or leg on one side of your body
• sudden trouble walking
• sudden vision problems
• confusion
• sudden difficulty thinking or speaking clearly
• sudden difficulty with balance or coordination
• dizziness
• sweating more than usual
• jaw pain
• toothache
• loosening of the teeth
• swollen or painful gums
• rash
• redness, pain, swelling or blistering on the palms or the soles
• extreme tiredness, dizziness, fainting, weakness, nausea, or vomiting
• yellowing of skin or eyes, extreme tiredness, bleeding or bruising easily, nausea or vomiting, right-sided-stomach pain, dark-colored urine, decreased appetite
• muscle stiffness or spasms
• sudden weight gain
• numbness, burning or tingling in the hands, arms, feet, legs, or around the mouth

Rare

• decreased appetite
• diarrhea
• dizziness
• dry mouth
• dry skin
• fatigue
• hair loss
• hand-foot skin reaction (e.g., redness, blisters, and pain on the palms of hands or soles of feet)
• headache
• heartburn
• hoarseness
• mouth sores or mouth pain
• muscle spasms
• nausea
• pain in arms, legs, and joints
• signs of electrolyte imbalance (e.g., muscle pain or cramps, weakness, irregular heartbeat, lack of coordination, thirst, confusion)
• stomach pain
• trouble sleeping
• vomiting
• weakness
• weight loss
• dehydration (e.g., headache, thirst, loss of appetite, tiredness, weakness, dark or decreased urine)
• difficulty speaking
• fainting
• swelling in the hands, feet, or face
• symptoms of a fistula (e.g., anal bleeding, pain with bowel movements, fever, chills, foul-smelling discharge from the anus)
• symptoms of irregular heartbeat (e.g., chest pain; dizziness; rapid, pounding heartbeat; shortness of breath)
• wounds that do not heal
• aneurysm (weakened blood vessel; cough, coughing up blood, sharp unexpected pain, hoarseness, unusual sensation in chest or abdomen)
• decreased brain function due to liver problems (e.g., change in alertness, confusion, mood or personality changes, changes in sleep, loss of consciousness)
• seizures
• signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)
• signs of pancreatitis (e.g., abdominal pain on the upper left side, back pain, nausea, fever, chills, rapid heartbeat, swollen abdomen)
• signs of reversible posterior leukoencephalopathy syndrome (e.g., headache, seizures, weakness, confusion, high blood pressure, vision changes, difficulty thinking clearly)
• symptoms of severely increased blood pressure (e.g., chest pain, blurred vision, dizziness, excessive tiredness, headache, stronger or faster heartbeat)
• symptoms of a blood clot in the lungs (difficulty breathing, sharp chest pain that is worse when breathing in, coughing, coughing up blood, sweating, or passing out)

Drug Interaction

Drug-Food Interactions

Pregnancy and Lactation

FDA Pregnancy Category D

Pregnancy

The use of cabozantinib may cause harm to the developing baby if it is taken by the mother during pregnancy. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

No information is available on the clinical use of cabozantinib during breastfeeding. Because cabozantinib is more than 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life ranges from 55 to 99 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during cabozantinib therapy and for 4 months after the last dose.

References