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.

It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer.^[rx] In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in 2019 for the treatment of hepatocellular carcinoma in previously treated patients.^[rx,rx]

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 that 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.

Contraindication

• 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, 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 of 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.
• For progressive metastatic medullary thyroid cancer (MTC)
• For the treatment of adults 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

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.
• For patients with advanced renal cell carcinoma (RCC)
• In combination with nivolumab, indicated for the first-line treatment of patients with advanced RCC

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.
• For patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Pediatric Dose for Thyroid Cancer

• Tablets: BSA greater than or equal to 1.2 m(2): 60 mg once a day until disease progression or unacceptable toxicityTablets: 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 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 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 is 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 was 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 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 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 previous dose 40 mg/day: Reduce the -dose to 20 mg once a day
• If previous dose 20 mg/day: Reduce the dose to 20 mg every other day
• If the previous dose 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.

Side Effects

The Most Common

• tiredness
• decreased appetite
• nausea
• vomiting
• weight loss
• constipation
• difficulty speaking
• tiredness
• mouth sores
• rash
• low thyroid hormone levels (hypothyroidism)
• pain in muscles, bones, and joints
• decreased appetite
• nausea
• changes in the way things taste
• stomach-area (abdominal) pain
• cough
• upper respiratory tract infection
• severe headache, blurred vision, pounding in your neck or ears;
• vomiting, diarrhea, or constipation that are severe and ongoing;
• swelling in your hands, arms, legs, or feet;
• easy bruising or bleeding (nosebleeds, bleeding gums, heavy menstrual bleeding, or any bleeding that will not stop);
• bloody or tarry stools, cough with bloody mucus or vomit that looks like coffee grounds;
  jaundice (yellowing of the skin or eyes);
• pain, blisters, bleeding, or severe rash in the palms of your hands or the soles of your feet;
• confusion, thinking problems, weakness, vision changes, seizure;
• a light-headed feeling, like you might pass out;
• jaw pain or numbness, red or swollen gums, loose teeth, or slow healing after dental work;
• low blood calcium –muscle spasms or contractions, numbness or tingly feeling (around your mouth, or in your fingers and toes;
• low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing;
• adrenal gland problems–nausea, vomiting, extreme tiredness, dizziness, weakness, fainting; or
• signs of a stroke or blood clot–sudden numbness or weakness on one side of your body, problems with vision or balance, trouble speaking or understanding what is said to you, chest pain, trouble breathing, swelling or pain in an arm or leg.

More Common

• constipation
• nausea
• vomiting
• difficulty swallowing
• change in 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

Rare

• 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

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category D

Pregnancy

Based on findings from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. There are no available data on pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at

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