Cabozantinib

Cabozantinib is a small molecule that inhibits several receptor tyrosine kinases involved in tumour growth and angiogenesis, pathological bone remodelling, drug resistance and metastatic spread. Its principal targets are MET, the receptor for hepatocyte growth factor, and the vascular endothelial growth factor (VEGF) receptors, so it acts both on tumour cells and on the blood vessels that supply them.

Mechanism of Action

• MET and VEGF receptors: MET signalling promotes tumour cell growth, invasion and metastasis; VEGF receptors 1, 2 and 3 drive the formation of new blood vessels.
• Other kinases: cabozantinib also inhibits AXL (the GAS6 receptor), RET, ROS1, TYRO3, MER, KIT (the stem cell factor receptor), TRKB, FLT3 and TIE-2.
• RET: its activity against RET is relevant to medullary thyroid carcinoma; when RET mutation status is negative or unknown, a possibly lower benefit should be taken into account.
• Cardiac electrophysiology: at 140 mg daily (the Cometriq dose), the QTcF interval rose by 10–15 ms on day 29, without new rhythms. No patient in that study, or in the RCC, HCC and NET studies at 60 mg, had a confirmed QTcF above 500 ms.

Pharmacokinetics

• Absorption: peak plasma levels 3 to 4 hours after a dose, with a second peak about 24 hours later that suggests enterohepatic recirculation. A high-fat meal raised peak concentration by 41% and AUC by 57%, so doses are taken fasting. Daily dosing (140 mg for 19 days) gave 4- to 5-fold accumulation, with steady state by about day 15. Tablets and capsules are not bioequivalent: peak concentration was 19% higher with the tablet, while AUC differed by less than 10%.
• Distribution: at least 99.7% bound to plasma proteins; central volume of distribution about 212 L.
• Metabolism: hepatic, mainly by CYP3A4, with a minimal CYP2C9 contribution. The main non-conjugated metabolites have less than 1% of the parent’s on-target potency.
• Elimination: slow; the plasma terminal half-life is about 110 hours and the mean clearance at steady state about 2.48 L/h. Of a radiolabelled dose, about 54% was recovered in faeces and 27% in urine over 48 days.
• Special populations: mild hepatic impairment did not change exposure; data in moderate hepatic impairment are limited and severe impairment was not studied. Exposure was up to 30% higher in mild or moderate renal impairment; severe renal impairment was not studied. Race has no clinically relevant effect.

Cabozantinib is used in adults. The two EU products have different indications and doses.

Cabometyx (film-coated tablets)

• Advanced renal cell carcinoma (RCC), monotherapy: first-line treatment in patients at intermediate or poor risk, or treatment after prior VEGF-targeted therapy.
• Advanced RCC, first line, in combination with nivolumab.
• Hepatocellular carcinoma (HCC), monotherapy: in patients previously treated with sorafenib.
• Differentiated thyroid carcinoma (DTC), monotherapy: locally advanced or metastatic DTC that is refractory or not eligible to radioactive iodine and has progressed during or after prior systemic therapy.
• Neuroendocrine tumours (NET): unresectable or metastatic, well-differentiated extra-pancreatic (epNET) and pancreatic (pNET) neuroendocrine tumours that have progressed after at least one prior systemic therapy other than somatostatin analogues.

Cometriq (hard capsules)

• Medullary thyroid carcinoma (MTC): progressive, unresectable locally advanced or metastatic MTC. In patients whose RET (rearranged during transfection) mutation status is unknown or negative, a possibly lower benefit should be weighed before the treatment decision.

• Hypersensitivity to cabozantinib or to any of the excipients.

In pooled monotherapy data for Cabometyx (1,355 patients with RCC, HCC, DTC or NET), the most frequent side effects of any grade (at least 25% of patients) were diarrhoea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysaesthesia syndrome (PPES, hand-foot syndrome) and hypertension.

Very common (≥1/10): anaemia, thrombocytopenia, hypothyroidism, decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia, hypocalcaemia, dysgeusia, headache, dizziness, hypertension, haemorrhage, dysphonia, dyspnoea, cough, diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, PPES, rash, pain in extremity, arthralgia, fatigue, mucosal inflammation, asthenia, peripheral oedema, weight decreased, increased ALT, AST and blood alkaline phosphatase.

Common (≥1/100 to <1/10): abscess, pneumonia, neutropenia, lymphopenia, dehydration, hypophosphataemia, hyponatraemia, hyperkalaemia, hyperbilirubinaemia, hyperglycaemia, hypoglycaemia, peripheral neuropathy, tinnitus, venous thrombosis, hypotension, embolism, pulmonary embolism, allergic rhinitis, gastrointestinal perforation, pancreatitis, fistula, gastro-oesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia, flatulence, hepatic encephalopathy, pruritus, alopecia, dry skin, hair colour change, hyperkeratosis, erythema, muscle spasms, proteinuria, increased GGT, creatinine, amylase, lipase, cholesterol and triglycerides, decreased white blood cell count.

Uncommon (≥1/1,000 to <1/100): convulsion, cerebrovascular accident, posterior reversible encephalopathy syndrome, acute myocardial infarction, cardiac failure, hypertensive crisis, arterial thrombosis, arterial embolism, pneumothorax, glossodynia, cholestatic hepatitis, osteonecrosis of the jaw, wound complications.

Not known: aneurysms and artery dissections, cutaneous vasculitis.

The most common serious reactions varied by tumour type and included pneumonia, pulmonary embolism, deep vein thrombosis and hyponatraemia (RCC), hepatic encephalopathy (HCC), pleural effusion, osteonecrosis of the jaw and renal impairment (DTC), and hypertension (NET). With nivolumab, severe (grade 3–4) rises in ALT and AST are more frequent than with cabozantinib alone. The Cometriq SmPC gives separate frequencies for its higher dose.

• Strong CYP3A4 inhibitors (such as ritonavir, itraconazole, erythromycin, clarithromycin and grapefruit juice): ketoconazole reduced cabozantinib clearance by 29% and raised single-dose exposure by 38%. Use with caution.
• Strong CYP3A4 inducers (such as phenytoin, carbamazepine, rifampicin, phenobarbital and St John’s wort): rifampicin increased clearance 4.3-fold and lowered exposure by 77%. Avoid chronic co-administration and prefer alternatives with little or no effect on CYP3A4.
• Acid-reducing medicines: esomeprazole had no clinically significant effect; no dose adjustment is needed with proton pump inhibitors, H2-receptor antagonists or antacids.
• MRP2 inhibitors (such as ciclosporin, efavirenz and emtricitabine): cabozantinib is an MRP2 substrate in vitro, so these may raise its plasma levels; use with caution.
• Bile acid sequestrants (colestyramine, colesevelam): may reduce absorption or reabsorption; the clinical significance is unknown.
• P-glycoprotein substrates: cabozantinib inhibits P-gp and may raise the levels of substrates such as dabigatran etexilate, digoxin, colchicine, fexofenadine, aliskiren, ambrisentan, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin and tolvaptan.
• Warfarin: an interaction is possible, so INR values should be monitored.
• Oral contraceptives: the effect on contraceptive steroids has not been studied, so an additional barrier method is recommended.
• Food: avoid grapefruit and grapefruit juice; food increases absorption, so doses are taken fasting (see below).

Treatment should be started by a physician experienced in the use of anticancer medicines. Cabometyx tablets and Cometriq capsules are not bioequivalent and must not be substituted for each other.

Cabometyx Monotherapy (RCC, HCC, DTC, NET)

• 60 mg once daily, for as long as the patient benefits clinically or until unacceptable toxicity.

Cabometyx with Nivolumab (First-Line Advanced RCC)

• 40 mg once daily, with nivolumab either intravenously (240 mg every 2 weeks or 480 mg every 4 weeks) or subcutaneously (600 mg every 2 weeks or 1,200 mg every 4 weeks).
• Cabozantinib continues until disease progression or unacceptable toxicity; nivolumab until progression, unacceptable toxicity or up to 24 months in patients without progression.

Cometriq (Medullary Thyroid Carcinoma)

• 140 mg once daily, taken as one 80 mg orange capsule and three 20 mg grey capsules, for as long as the patient benefits or until unacceptable toxicity.

Dose Adjustments

• Cabometyx monotherapy: reduce to 40 mg daily, then to 20 mg daily.
• Cabometyx with nivolumab: reduce to 20 mg once daily, then to 20 mg every other day (nivolumab is adjusted according to its own SmPC).
• Cometriq: reduce to 100 mg daily (one 80 mg and one 20 mg capsule), then to 60 mg daily (three 20 mg capsules).
• Tolerable grade 1–2 reactions usually need only supportive care. For intolerable grade 2 or for grade 3 reactions, treatment is interrupted until the reaction is grade 1 or lower and restarted at a reduced dose. Grade 4 reactions need interruption and medical care, with a restart at a reduced dose only if they resolve to grade 1 or lower; otherwise treatment is stopped permanently.
• Liver enzymes with nivolumab: if ALT or AST rises above 3 and up to 10 times the upper limit of normal without bilirubin at 2 times the upper limit or more, both medicines are interrupted until grade 1 or lower (corticosteroids may be considered). Above 10 times, or above 3 times with bilirubin at 2 times or more, both are stopped permanently.
• In the pivotal monotherapy trials, 46–67% of patients needed a dose reduction and 70–84% an interruption; with nivolumab, 54.1% and 73.4%. Most Cometriq patients need at least one dose adjustment.

Special Populations

• Elderly (65 years or older): no specific adjustment. With Cometriq, serious adverse events tended to be more frequent from 75 years.
• Renal impairment: use with caution in mild or moderate impairment; not recommended in severe impairment.
• Hepatic impairment (Cabometyx): no adjustment in mild impairment; data in moderate impairment (Child-Pugh B) are too limited for a dosing recommendation, so close monitoring is advised; not recommended in severe impairment (Child-Pugh C).
• Hepatic impairment (Cometriq): 60 mg once daily in mild or moderate impairment, with close monitoring; not recommended in severe impairment.
• Cardiac impairment: limited data; no specific recommendation.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed Dose and Method of Administration

• A missed dose should not be taken if the next dose is due in less than 12 hours.
• Swallow the tablets whole without crushing them, and the capsules whole without opening them, with a full glass of water. Nothing should be eaten for at least 2 hours before until 1 hour after each dose.

Close Monitoring in the First Weeks

Most adverse reactions occur early, so patients are evaluated closely during the first eight weeks. Reactions with early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, PPES, proteinuria and gastrointestinal events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting). Some serious reactions, such as gastrointestinal fistula, may depend on the cumulative dose and appear later. Diarrhoea, nausea, vomiting, decreased appetite and stomatitis are treated promptly (antiemetics, antidiarrhoeals or antacids) to prevent dehydration, electrolyte imbalance and weight loss.

Liver Function

Increases in ALT, AST and bilirubin are frequent. Liver function is tested before treatment and monitored closely during it, with dose changes for treatment-related worsening; with nivolumab, grade 3–4 rises are more frequent and the advice for both medicines applies. Rare cases of vanishing bile duct syndrome have occurred, all in patients who had received immune checkpoint inhibitors before or with cabozantinib.

Hepatic Encephalopathy

In the HCC study, hepatic encephalopathy was more frequent with cabozantinib than with placebo, and it was relatively more common in patients with moderate hepatic impairment (Child-Pugh B). In HCC patients with impaired liver function, the diarrhoea, vomiting, decreased appetite and electrolyte disturbances that cabozantinib can cause may precipitate it, so patients are monitored for its signs.

Perforations, Bleeding and Thromboembolism

• Gastrointestinal perforations and fistulas, sometimes fatal: patients with inflammatory bowel disease, tumour infiltration of the gut or complications of earlier bowel surgery are evaluated carefully before treatment and monitored closely. Treatment is stopped for a perforation or a fistula that cannot be managed.
• Haemorrhage, sometimes fatal: cabozantinib should not be given to patients who have or are at risk of severe bleeding. In HCC, fatal bleeding was more frequent than with placebo; risk factors include tumour invasion of major vessels and cirrhosis with oesophageal varices, portal hypertension or thrombocytopenia.
• Thromboembolism: venous events (including pulmonary embolism, and portal vein thrombosis in HCC) and arterial events, sometimes fatal. Use with caution in patients at risk, and stop for acute myocardial infarction or another clinically significant thromboembolic complication. Venous thromboembolism was more frequent in pancreatic (19%) than in extra-pancreatic NET (3.8%).
• Aneurysms and artery dissections: the risk is weighed before treatment in patients with hypertension or a history of aneurysm.

Blood Pressure, Heart and Kidneys

• Hypertension: blood pressure should be well controlled before starting and monitored early and regularly. Persistent hypertension despite treatment means interruption and a lower dose; hypertensive crisis means discontinuation.
• Cardiac failure: the risk is increased; patients are monitored, and treatment is stopped for severe cardiac failure.
• QT prolongation: use with caution in patients with a history of QT prolongation, on antiarrhythmics, or with heart disease, bradycardia or electrolyte disturbances; periodic ECGs and electrolyte checks should be considered.
• Proteinuria: urine protein is monitored regularly, and treatment is stopped for nephrotic syndrome.

Wound Healing and Osteonecrosis of the Jaw

Treatment should be stopped at least 28 days before planned surgery, including dental surgery or invasive dental procedures, where possible, and resumed only when the wound has healed adequately. An oral examination is done before and periodically during treatment, with advice on oral hygiene; caution is needed with other medicines linked to osteonecrosis of the jaw, such as bisphosphonates.

Other Monitoring

• Laboratory values: platelets, electrolytes (potassium, magnesium, calcium, sodium) and thyroid function are monitored; hypocalcaemia is more frequent and more severe in thyroid cancer.
• PPES: severe PPES may need an interruption, with a lower dose once it has resolved to grade 1.
• Posterior reversible encephalopathy syndrome: considered in patients with seizures, headache, visual disturbances or confusion; treatment is stopped if it occurs.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential, and the female partners of male patients, must avoid pregnancy. Patients and their partners use effective contraception during treatment and for at least 4 months afterwards; oral contraceptives should be combined with a barrier method.
• Pregnancy: animal studies showed embryo-foetal and teratogenic effects. Cabozantinib should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: stop during treatment and for at least 4 months afterwards.
• Fertility: non-clinical findings suggest that male and female fertility may be impaired; patients should seek advice and consider fertility preservation before treatment.

Lactose

Cabometyx tablets contain lactose (15.54 mg, 31.07 mg or 46.61 mg per tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially sodium-free.

Effect on Driving

Cabozantinib has a minor influence on the ability to drive and use machines. Fatigue and weakness can occur, so caution is advised.

Cabometyx tablets need no special storage conditions. They come in a plastic bottle of 30 tablets with a child-resistant closure and silica gel desiccant canisters. Cometriq capsules should not be stored above 25 °C and are kept in the original package to protect them from moisture. Keep out of the sight and reach of children.

Cabometyx: 4 years. Cometriq: 3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist experienced in anticancer treatment. Cabozantinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.