Cabometyx EU

Cabometyx in Europe

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About CABOMETYX® (cabozantinib)

Learn more about CABOMETYX® for the treatment of renal cell carcinoma (RCC).

What are the CABOMETYX® indications?

CABOMETYX® is indicated for the treatment of advanced renal cell carcinoma (RCC):1

  • In treatment-naïve adults with intermediate or poor risk
  • In adults following prior vascular endothelial growth factor (VEGF)-targeted therapy

CABOMETYX® is also indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.1

Learn more about CABOMETYX® in HCC →

Indications

What is the mechanism of action of CABOMETYX®?

CABOMETYX® is a small molecule tyrosine kinase inhibitor that simultaneously inhibits multiple receptor tyrosine kinases implicated in RCC pathogenesis.These include:

Vascular endothelial growth factor receptor (VEGFR)1

  • RCC is a VEGF-driven disease and one of the most hypervascularised tumour types2-3
  • VEGFR promotes tumour angiogenesis and tumour growth2-3

Hepatocellular growth factor receptor protein (MET)1

  • Dysregulation of MET is implicated in tumour development, invasion, and angiogenesis4

Gas6 receptor (AXL)1

  • AXL promotes tumour progression5-6
  • Inactivation of AXL reverses the invasive and metastatic phenotype of clear cell RCC5

Mechanism of action

CABOMETYX® has a unique mechanism of action by inhibiting VEGFR as well as MET and AXL, the latter two of which are not inhibited by other tyrosine kinase inhibitors.1

CABOMETYX® mechanism of action in RCC

Adapted from SmPC1

For further information of the mechanism of action of CABOMETYX®, please refer to Section 5.1 of the Summary of Product Characteristics (SmPC).1

What are the dosing recommendations for CABOMETYX®?

The recommended dose for CABOMETYX® is 60 mg orally, once daily. Treatment should continue until it is no longer clinically beneficial or unacceptable toxicity occurs. Dosing can be adjusted to match patient therapy requirements as outlined below.1 

When taking CABOMETYX® patients should be given the following advice1:

 

A missed dose should not be taken if it is less than 12 hours before the next dose.1

As most adverse events occur early in the course of CABOMETYX® therapy, patients should be evaluated closely during the first 8 weeks of treatment to determine if dose modifications are necessary.1

Can I reduce the dose?

Dosing can be adjusted to match patient therapy requirements.1

It may be necessary to temporarily interrupt and/or reduce the dose of CABOMETYX® therapy if managing a suspected adverse drug reaction.1

If required, the following dose reductions can be used1:

  • Recommended dose – 60 mg once daily
  • First reduction – 40 mg once daily
  • Second reduction – 20 mg once daily

Recommended CABOMETYX® dose modifications for adverse reactions1

Treatment modification
Adverse reaction and severity Continue treatment Dose reduction Supportive care
Grade 1 & 2

Tolerable and easily managed

Yes

Usually not required

Consider adding as indicated

Grade 2

Intolerable and cannot be managed with a dose reduction or supportive care

Interrupt until resolution to Grade ≤1

Consider reinitiating at reduced dose

Add as indicated

Grade 3

Except clinically non-relevant laboratory abnormalities

Interrupt until resolution to Grade ≤1

Reinitiate at reduced dose

Add as indicated

Grade 4

Except clinically non-relevant laboratory abnormalities

Interrupt treatment

Institute appropriate medical care

If resolution to Grade ≤1, reinitiate at reduced dose

If no resolution, consider permanent discontinuation

Add as indicated

Adapted from SmPC1

For further information on dosing recommendations, including dose modifications, dose interruptions and use in special populations, please refer to Section 4.2 of the SmPC.1

Dosing

What are the adverse drug reactions of CABOMETYX®?

Adverse reactions reported in patients treated with CABOMETYX®

MedDRA system organ class*

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Infections and infestations
  • Abscess
Blood and lymphatic disorders
  • Anaemia
  • Thrombocytopaenia
  • Neutropenia
Endocrine disorders
  • Hypothyroidism
Metabolism and nutrition disorders
  • Decreased appetite
  • Hypomagnesaemia
  • Hypokalaemia
  • Dehydration
  • Hypoalbuminaemia
  • Hypophosphataemia
  • Hyponatraemia
  • Hypocalcaemia
  • Hyperkalaemia
  • Hyperbilirubinemia
  • Hyperglycaemia
  • Hypoglycaemia
Nervous system
disorders
  • Dysgeusia
  • Headache
  • Dizziness
  • Peripheral sensory neuropathy
Ear and labyrinth disorders
  • Tinnitus
Vascular disorders
  • Hypertension
  • Haemorrhage
  • Venous thrombosis
  • Arterial thrombosis
Respiratory, thoracic, and mediastinal disorders
  • Dysphonia
  • Dyspnoea
  • Cough
  • Pulmonary embolism
Gastrointestinal disorders
  • Diarrhoea
  • Nausea
  • Vomiting
  • Stomatitis
  • Constipation
  • Abdominal pain
  • Dyspepsia
  • Upper abdominal pain
  • Gastrointestinal perforation
  • Fistula
  • Gastro-oesophageal reflux disease
  • Haemorrhoids
  • Oral pain
  • Dry mouth
Skin and subcutaneous tissue disorders
  • PPES
  • Rash
  • Pruritus
  • Alopecia
  • Dry skin
  • Dermatitis acneiform
  • Hair colour change
Musculoskeletal and connective tissue disorders
  • Pain in extremity
  • Muscle spasms
  • Arthralgia
Renal and urinary disorders
  • Proteinuria
General disorders and administration site conditions
  • Fatigue
  • Mucosal inflammation
  • Asthenia
  • Peripheral oedema
Investigations
  • Weight decreased
  • Serum ALT, AST increased
  • Blood bilirubin increased
  • Creatinine increased
  • Triglycerides increased
  • White blood cell decreased
  • GGT increased
  • Amylase increase
  • Blood cholesterol increased
  • Lipase increased

*Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, Gamma-glutamyl transferase; PPES, palmar-plantar erythrodysaesthesia syndrome

Adapted from SmPC1

Adverse events

Management of adverse reactions

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction of CABOMETYX® therapy (see ‘What are the dosing recommendations for CABOMETYX®?’ above and Table 1 in Section 4.2 of the SmPC). When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily. Dose interruptions are recommended for management of common terminology criteria for adverse events (CTCAE) grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, could become serious or intolerable.1

 

Description of selected adverse reactions

Data for the following reactions are based on patients who received cabozantinib 60 mg once daily, orally in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC and in HCC following prior systemic therapy.1

Gastrointestinal (GI) perforation

In the METEOR study, conducted in patients with RCC who had reeceived prior VEGF-targeted therapy, GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.1

In the CABOSUN study, conducted in previously untreated RCC patients, GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.1

In the CELESTIAL study conducted in patients with HCC, GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks.1

Fatal perforations have occurred in the cabozantinib clinical programme.1

Hepatic encephalopathy

In the CELESTIAL study, hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks.1

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR and CABOSUN).1

Diarrhoea

In the METEOR study, diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.1

In the CABOSUN study, diarrhoea was reported in 73% of cabozantinib-treated patients (57/78);Grade 3-4 events in 10%.1

In the CELESTIAL study, diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3-4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.1

Fistulas

In the METEOR study, fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder was Grade 2. Median time to onset was 30.3 weeks.1

In the CABOSUN study, no cases of fistulas were reported.1

In the CELESTIAL study, fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.1

Fatal fistulas have occurred in the cabozantinib clinical programme.1

Haemorrhage

In the METEOR study, the incidence of severe haemorrhagic events (Grade ≥ 3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.1

In the CABOSUN study, the incidence of severe haemorrhagic events (Grade ≥ 3) was 5.1% (4/78) in cabozantinib-treated RCC patients.1

Fatal haemorrhages have occurred in the cabozantinib clinical programme.1

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

No case of RPLS was reported in the METEOR, CABOSUN or CELESTIAL studies, but RPLS has been reported rarely in other clinical studies (in 2/4,872 subjects; 0.04%).1

Reporting of suspected adverse reactions

To report an adverse event, please fill in our contact form contact form

For information on the adverse events associated with CABOMETYX®, please refer to Section 4.8 of the SmPC.1

© Ipsen Group 2019 Last updated on: October 2019. This site is published by Ipsen, which is solely responsible for the content. It is intended only for healthcare professionals from the EU – excluding France. Healthcare professionals from outside the EU, as well as any non-healthcare professionals, are excluded from the intended audience. CBZ-ALL-001685

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