This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

CABOMETYX 20 mg film-coated tablets

CABOMETYX 40 mg film-coated tablets

CABOMETYX 60 mg film-coated tablets

2. Qualitative and quantitative composition

CABOMETYX 20 mg film-coated tablets

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 20 mg cabozantinib.

Excipients with known effect

Each film-coated tablet contains 15.54 mg lactose.

CABOMETYX 40 mg film-coated tablets

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 40 mg cabozantinib.

Excipients with known effect

Each film-coated tablet contains 31.07 mg lactose.

CABOMETYX 60 mg film-coated tablets

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 60 mg cabozantinib.

Excipients with known effect

Each film-coated tablet contains 46.61 mg lactose

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

CABOMETYX 20 mg film-coated tablets

The tablets are yellow round with no score, and debossed with “XL” on one side and “20” on the other side of the tablet.

CABOMETYX 40 mg film-coated tablets

The tablets are yellow triangle shaped with no score, and debossed with “XL” on one side and “40” on the other side of the tablet.

CABOMETYX 60 mg film-coated tablets

The tablets are yellow oval shaped with no score, and debossed with “XL” on one side and “60” on the other side of the tablet.

4. Clinical particulars
4.1 Therapeutic indications

Renal Cell Carcinoma (RCC)

CABOMETYX is indicated as monotherapy for the treatment of advanced renal cell carcinoma (RCC):

- in treatment-naïve adults with intermediate or poor risk (see section 5.1),

- in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).

Hepatocellular Carcinoma (HCC)

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

4.2 Posology and method of administration

Therapy with CABOMETYX should be initiated by a physician experienced in the administration of anticancer medicinal products.

Posology

CABOMETYX (cabozantinib) tablets and COMETRIQ (cabozantinib) capsules are not bioequivalent and should not be used interchangeably (see section 5.2).

CABOMETYX as monotherapy

For RCC and HCC, the recommended dose of CABOMETYX is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

CABOMETYX in combination with nivolumab in first-line advanced RCC

The recommended dose of CABOMETYX is 40 mg once daily in combination with nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks. CABOMETYX treatment should continue until disease progression or unacceptable toxicity. Nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression (see the Summary of Product Characteristics (SmPC) for posology of nivolumab).

Treatment modification

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction of CABOMETYX therapy (see Table 1). When dose reduction is necessary in monotherapy, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.

When CABOMETYX is administered in combination with nivolumab, it is recommended to reduce the dose to 20 mg of CABOMETYX once daily, and then to 20 mg every other day (refer to the nivolumab SmPC for recommended treatment modification for nivolumab).

Dose interruptions are recommended for management of 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.

If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.

Table 1: Recommended CABOMETYX dose modifications for adverse reactions

Adverse reaction and severity

Treatment Modification

Grade 1 and Grade 2 adverse reactions which are tolerable and easily managed

Dose adjustment is usually not required.

Add supportive care as indicated.

Grade 2 adverse reactions which are intolerable and cannot be managed with a dose reduction or supportive care

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Consider re-initiating at a reduced dose.

Grade 3 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Re-initiate at a reduced dose.

Grade 4 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment.

Institute appropriate medical care.

If adverse reaction resolves to Grade ≤1, re-initiate at a reduced dose.

If adverse reaction does not resolve, permanently discontinue CABOMETYX.

Liver enzymes elevations for RCC patients treated with CABOMETYX in combination with nivolumab

ALT or AST > 3 times ULN but ≤10 times ULN without concurrent total bilirubin ≥ 2 times ULN

Interrupt CABOMETYX and nivolumab until these adverse reactions resolves to Grade≤1

Corticosteroid therapy may be considered if immune-mediated reaction is suspected (refer to nivolumab SmPC).

Re-initiate with a single medicine or sequential re-initiating with both medicines after recovery may be considered. If re-initiating with nivolumab, refer to nivolumab SmPC.

ALT or AST > 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN

Permanently discontinue CABOMETYX and nivolumab.

Corticosteroid therapy may be considered if immune-mediated reaction is suspected (refer to nivolumab SmPC).

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4)

Concomitant medicinal products

Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided (see sections 4.4 and 4.5).

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.

Special populations

Elderly patients

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended.

Race

No dose adjustment is necessary based on ethnicity (see section 5.2)

Patients with renal impairment

Cabozantinib should be used with caution in patients with mild or moderate renal impairment.

Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.

Patients with hepatic impairment

In patients with mild hepatic impairment no dose adjustment is required. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2). There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients (see section 5.2).

Patients with cardiac impairment

There are limited data in patients with cardiac impairment. No specific dosing recommendations can be made.

Paediatric population

The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet been established. No data are available.

Method of administration

CABOMETYX is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking CABOMETYX.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

As most events occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting).

Management of suspected adverse reactions may require temporary interruption or dose reduction of cabozantinib therapy (see section 4.2):

In renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy, dose reductions and dose interruptions due to an adverse event (AE) occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial (METEOR). Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.

In treatment-naïve renal cell carcinoma, dose reductions and dose interruptions occurred in 46% and 73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN).

When cabozantinib is given in combination with nivolumab in first-line advanced renal cell carcinoma, dose reduction and dose interruption of cabozantinib due to an AE occurred in 54.1% and 73.4% of patients in the clinical trial (CA2099ER). Two dose reductions were required in 9.4% of patients. The median time to first dose reduction was 106 days, and to first dose interruption was 68 days.

In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptions occurred in 62% and 84%, respectively, of cabozantinib-treated patients in the clinical trial (CELESTIAL). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised in patients with mild or moderate hepatic impairment.

Hepatotoxicity

Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinib treatment (i.e. where no alternative cause is evident), the dose modification advice in Table 1 should be followed (see section 4.2).

When cabozantinib is given in combination with nivolumab, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported relative to cabozantinib monotherapy in patients with advanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for nivolumab).

Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. CABOMETYX is not recommended for use in patients with severe hepatic impairment (Child-Pugh C, see section 4.2).

Hepatic encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting, decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, these non-hepatic effects may be precipitating factors for the development of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.

Perforations and fistulas

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses and sepsis. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.

Gastrointestinal (GI) disorders

Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI adverse reactions (see section 4.8). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1).

Thromboembolic events

Events of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events.

In the HCC study (CELESTIAL), portal vein thrombosis was observed with cabozantinib, including one fatal event. Patients with a history of portal vein invasion appeared to be at higher risk of developing portal vein thrombosis. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant thromboembolic complication.

Haemorrhage

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.

In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence with cabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCC population may include tumour invasion of major blood vessels and the presence of underlying liver cirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplatelet agents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk for bleeding were also excluded from this study.

The study of cabozantinib in combination with nivolumab in first-line advanced RCC (CA2099ER) excluded patients with anticoagulants at therapeutic doses.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Thrombocytopenia

In the HCC study (CELESTIAL), thrombocytopenia and decreased platelets were reported. Platelet levels should be monitored during cabozantinib treatment and the dose modified according to the severity of the thrombocytopenia (see Table 1).

Wound complications

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery or invasive dental procedures, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.

Hypertension

Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Osteonecrosis

Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. Cabozantinib treatment should be held at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.

Palmar-plantar erythrodysaesthesia syndrome

Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.

Proteinuria

Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.

Prolongation of QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.

Thyroid dysfunction

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of cabozantinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during cabozantinib treatment. Thyroid function should be monitored periodically throughout treatment with cabozantinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice.

Biochemical laboratory test abnormalities

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1).

CYP3A4 inducers and inhibitors

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see sections 4.2 and 4.5).

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib (see section 4.5).

MRP2 inhibitors

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution (see section 4.5).

Excipient related warnings

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on cabozantinib

CYP3A4 inhibitors and inducers

Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore, co-administration of strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.

Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John's Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.

Gastric pH modifying agents

Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.

MRP2 inhibitors

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.

Bile salt-sequestering agents

Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section 5.2). The clinical significance of these potential interactions is unknown.

Effect of cabozantinib on other medicinal products

The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.

Because of high plasma protein binding levels of cabozantinib (section 5.2) a plasma protein displacement interaction with warfarin may be possible. In case of such combination, INR values should be monitored.

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception”, they should be used together with another method, such as a barrier method (see section 4.5).

Pregnancy

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.

Breast-feeding

It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). Both men and women should be advised to seek advice and consider fertility preservation before treatment.

4.7 Effects on ability to drive and use machines

Cabozantinib has minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

4.8 Undesirable effects

Cabozantinib as monotherapy

Summary of safety profile

The most common serious adverse drug reactions in the RCC population (≥1% incidence) are abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and palmar-plantar erythrodysaesthesia syndrome (PPES).

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, fatigue, nausea, decreased appetite, PPES, hypertension, weight decreased, vomiting, dysgeusia, constipation, and AST increased. Hypertension was observed more frequently in the treatment naïve RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).

The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, decreased appetite, PPES, fatigue, nausea, hypertension and vomiting.

Tabulated list of adverse reactions

Adverse reactions identified in clinical studies of cabozantinib as monotherapy or reported after post-marketing use of cabozantinib are listed in Table 2, according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse drug reactions (ADRs) reported in clinical trials or after post-marketing use in patients treated with cabozantinib in monotherapy

Infections and infestations

Common

abscess

Blood and lymphatic disorders

Very Common

anaemia, thrombocytopeniaa

Common

neutropeniaa, lymphopeniaa

Endocrine disorders

Very Common

hypothyroidismc

Metabolism and nutrition disorders

Very Common

decreased appetite, hypomagnesaemiab, hypokalaemiab, hypoalbuminaemiab

Common

dehydration, hypophosphataemiab, hyponatraemiab, hypocalcaemiab, hyperkalaemiac, hyperbilirubinemiac, hyperglycaemiac, hypoglycaemiab

Nervous system disorders

Very Common

dysgeusia, headache, dizziness

Common

peripheral neuropathy (including sensory)

Uncommon

convulsion

Not Known

cerebro-vascular accident

Ear and labyrinth disorders

Common

tinnitus

Cardiac disorders

Not Known

myocardial infarction

Vascular disorders

Very Common

hypertensione, haemorrhage*

Common

deep vein thrombosis, venous thrombosis, arterial thrombosis

Not Known

aneurysms and artery dissections

Respiratory, thoracic, and mediastinal disorders

Very Common

dysphonia, dyspnoea, cough

Common

pulmonary embolism

Gastrointestinal disorders

Very Common

diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal paind, dyspepsia, upper abdominal pain

Common

gastrointestinal perforation*, fistula*, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia, glossodynia

Uncommon

pancreatitis

Hepatobiliary disorders

Common

hepatic encephalopathy*

Uncommon

hepatitis cholestatic

Skin and subcutaneous tissue disorders

Very Common

palmar-plantar erythrodysaesthesia syndrome, rash

Common

pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change, hyperkeratosis

Musculoskeletal and connective tissue disorders

Very Common

pain in extremity

Common

muscle spasms, arthralgia

Uncommon

osteonecrosis of the jaw

Renal and urinary disorders

Common

proteinuria

General disorders and administration site conditions

Very Common

fatigue, mucosal inflammation, asthenia, peripheral oedema

Investigations

Very Common

weight decreased, serum ALT increased, AST increased

Common

blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increasedc, blood triglycerides increasedc

Injury, poisoning and procedural complications

Uncommon

wound complicationsf

*See section 4.8 Description of selected adverse reactions for further characterisation.

The following terms have been combined to derive appropriate frequency categorisation:

a Lowered haematology parameters: Lymphopenia and lymphocyte count decreased; Neutropenia and neutrophil count decreased; Thrombocytopenia and platelet count decreased.

b Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood calcium decreased; Hypoglycaemia and blood glucose decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; Hyponatraemia and blood sodium decreased; Hypohosphataemia and blood phosphorus decreased.

c Elevated biochemistry parameters: Blood cholesterol increased and hypercholesterolaemia; Hyperbilirubinaemia and blood bilirubin increased; Hyperglycaemia and blood glucose increased; Hypothyroidism and blood thyroid stimulating hormone increased; Hyperkalaemia and blood potassium increased; Triglycerides increased and hypertriglyceridaemia.

d Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower.

e Hypertension and blood pressure increased.

f Impaired healing and incision site complication.

Cabozantinib in combination with nivolumab in first-line advanced RCC

Summary of safety profile

When cabozantinib is administered in combination with nivolumab, refer to the SmPC for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, please refer to the nivolumab SmPC.

In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n =320), with a minimum follow‑up of 16 months, the most common serious adverse drug reactions (≥1% incidence) are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting, dehydration.

The most frequent adverse reactions (≥25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decrease appetite, nausea, abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Tabulated list of adverse reactions

Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 3, according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions with cabozantinib in combination with nivolumab

Infections and infestations

Very Common

upper respiratory tract infection

Common

pneumonia

Blood and lymphatic system disorders

Common

eosinophilia

Immune system disorders

Common

hypersensitivity (including anaphylactic reaction)

Uncommon

infusion related hypersensitivity reaction

Endocrine disorders

Very common

hypothyroidism, hyperthyroidism

Common

adrenal insufficiency

Uncommon

hypophysitis, thyroiditis

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration

Nervous system disorders

Very common

dysgeusia, dizziness, headache

Common

peripheral neuropathy

Uncommon

encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome

Ear and labyrinth disorders

Common

tinnitus

Eye disorders

Common

dry eye, blurred vision

Uncommon

uveitis

Cardiac disorders

Common

atrial fibrillation, tachycardia

Uncommon

myocarditis

Vascular disorders

Very common

hypertension

Common

thrombosisa

Respiratory, thoracic and mediastinal disorders

Very common

dysphonia, dyspnoea, cough

Common

pneumonitis, pulmonary embolism, epistaxis, pleural effusion

Gastrointestinal disorders

Very common

diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia

Common

colitis, gastritis, oral pain, dry mouth, haemorrhoids

Uncommon

pancreatitis, small intestine perforationb, glossodynia

Hepatobiliary disorders

Common

hepatitis

Skin and subcutaneous tissue disorders

Very common

palmar-plantar erythrodysaesthesia syndrome, rashc, pruritus

Common

alopecia, dry skin, erythema, hair colour change

Uncommon

psoriasis, urticaria

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal paind, arthralgia, muscle spasm,

Common

arthritis

Uncommon

myopathy, osteonecrosis of the jaw, fistula

Renal and urinary disorders

Very common

proteinuria

Common

renal failure, acute kidney injury

Uncommon

nephritis

General disorders and administration site conditions

Very common

fatigue, pyrexia, oedema

Common

pain, chest pain

Investigationse

Very common

increased ALT, increased AST, hypophosphataemia, hypocalcaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopaenia, increased alkaline phosphatase, increased lipase, increased amylase, thrombocytopaenia, increased creatinine, anaemia, leucopoenia, hyperkalaemia, neutropaenia, hypercalcaemia, hypoglycaemia, hypokalaemia, increased total bilirubin, hypermagnesaemia, hypernatraemia, weight decreased

Common

blood cholesterol increased, hypertriglyceridaemia

Adverse reaction frequencies presented in Table 3 may not be fully attributable to cabozantinib alone but may contain contributions from the underlying disease or from nivolumab used in a combination.

a Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb

b Fatal cases have been reported

c Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption

d Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain

e Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements with the exception of weight decreased, blood cholesterol increased and hypertriglyceridaemia

Description of selected adverse reactions

Data for the following reactions are based on patients who received CABOMETYX 60 mg orally once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC and in HCC following prior systemic therapy or in patients who received CABOMETYX 40 mg orally once daily in combination with nivolumab in first-line advanced RCC (section 5.1).

Gastrointestinal (GI) perforation (see section 4.4)

In the study in RCC following prior VEGF-targeted therapy (METEOR), 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.

In the treatment-naïve RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.

In the HCC study (CELESTIAL), 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.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of GI perforations was 1.3% (4/320) treated patients. One event was grade 3, two events were grade 4 and one event was grade 5 (fatal).

Fatal perforations have occurred in the cabozantinib clinical program.

Hepatic encephalopathy (see section 4.4)

In the HCC study (CELESTIAL), 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.

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR, CABOSUN and CA2099ER).

Diarrhoea (see section 4.4)

In the study in RCC following prior VEGF-targeted therapy (METEOR), 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.

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

In the HCC study (CELESTIAL), 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.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidence of diarrhoea was reported in 64.7% (207/320) of treated patients; Grade 3-4 events in 8.4% (27/320). Median time to onset of all events was 12.9 weeks. Dose delay or reduction occurred in 26.3% (84/320) and discontinuation in 2.2% (7/320) of patients with diarrhoea, respectively.

Fistulas (see section 4.4)

In the study in RCC following prior VEGF-targeted therapy (METEOR), 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 were Grade 2. Median time to onset was 30.3 weeks.

In the treatment-naïve RCC study (CABOSUN), no cases of fistulas were reported.

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

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.

Fatal fistulas have occurred in the cabozantinib clinical program

Haemorrhage (see section 4.4)

In the study in RCC following prior VEGF-targeted therapy (METEOR), 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.

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

In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥ 3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥ Grade 3 haemorrhage was in 1.9% (6/320) of treated patients.

Fatal haemorrhages have occurred in the cabozantinib clinical program.

Posterior reversible encephalopathy syndrome (PRES) (see section 4.4)

No case of PRES was reported in the METEOR or CABOSUN or CA2099ER or CELESTIAL studies, but PRES has been reported rarely in other clinical studies (in 2/4872 subjects; 0.04%).

Elevated liver enzymes when cabozantinib is combined with nivolumab in RCC

In a clinical study of previously untreated patients with RCC receiving cabozantinib in combination with nivolumab, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%) were observed relative to cabozantinib monotherapy in patients with advanced RCC (ALT increased of 3.6% and AST increased of 3.3% in METEOR study). The median time to onset of grade > 2 increased ALT or AST was 10.1 weeks (range: 2 to 106.6 weeks; n=85). In patients with grade ≥ 2 increased ALT or AST, the elevations resolved to Grades 0-1in 91% with median time to resolution of 2.29 weeks (range: 0.4 to 108.1 weeks).

Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either cabozantinib (n=10) or nivolumab (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥2 increased ALT or AST was observed in 4 patients receiving cabozantinib, in 3 patients receiving nivolumab and 8 patients receiving both cabozantinib and nivolumab.

Hypothyroidism

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).

In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.

In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not been established.

In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to be treated symptomatically.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE26.

Mechanism of action

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac electrophysiology

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 – 15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg once daily) was observed in a controlled clinical study in medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

Clinical efficacy and safety

Renal cell carcinoma

Randomized study in RCC patients who have received prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

The safety and efficacy of CABOMETYX for the treatment of renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy were evaluated in a randomized, open-label, multicenter Phase 3 study (METEOR). Patients (N=658) with advanced RCC with a clear cell component who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) were randomized (1:1) to receive CABOMETYX (N=330) or everolimus (N=328). Patients could have received other prior therapies, including cytokines, and antibodies targeting VEGF, the programmed death 1 (PD-1) receptor, or its ligands. Patients with treated brain metastases were allowed. Progression-free survival (PFS) was assessed by a blinded independent radiology review committee, and the primary analysis was conducted among the first 375 subjects randomized. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter.

The baseline demographic and disease characteristics were similar between the CABOMETYX and everolimus arms. The majority of the patients were male (75%), with a median age of 62 years. Seventy-one percent (71%) received only one prior VEGFR TKI; 41% of patients received sunitinib as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center criteria for prognostic risk category, 46% were favourable (0 risk factors), 42% were intermediate (1 risk factor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%). The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus.

A statistically significant improvement in PFS was demonstrated for CABOMETYX compared to everolimus (Figure 1 and Table 4). A planned interim analysis of OS was conducted at the time of the PFS analysis and did not reach the interim boundary for statistical significance (202 events, HR=0.68 [0.51, 0.90], p=0.006). In a subsequent unplanned interim analysis of OS, a statistically significant improvement was demonstrated for patients randomized to CABOMETYX as compared with everolimus (320 events, median of 21.4 months vs. 16.5 months; HR=0.66 [0.53, 0.83], p=0.0003; Figure 2). Comparable results for OS were observed with a follow-up analysis (descriptive) at 430 events.

Exploratory analyses of PFS and OS in the ITT population have also shown consistent results in favour of CABOMETYX compared to everolimus across different subgroups according to age (<65 vs. ≥65, sex, MSKCC risk group (favourable, intermediate, poor), ECOG status (0 vs. 1), time from diagnosis to randomisation (<1 year vs. ≥1 year), tumour MET status (high vs. low vs. unknown), bone metastases (absence vs. presence), visceral metastases (absence vs. presence), visceral and bone metastases (absence vs. presence), number of prior VEGFR-TKIs (1 vs. ≥2), duration of first VEGFR-TKI (≤6 months vs. >6 months).

Objective response rate findings are summarized in Table 5.

Figure 1: Kaplan Meier curve for progression-free survival by independent radiology review committee, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (first 375 subjects randomized) (METEOR)

Table 4: Summary of PFS findings by independent radiology review committee in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

Primary PFS analysis Population

Intent-To-Treat Population

Endpoint

CABOMETYX

Everolimus

CABOMETYX

Everolimus

N = 187

N = 188

N = 330

N = 328

Median PFS (95% CI), months

7.4 (5.6, 9.1)

3.8 (3.7, 5.4)

7.4 (6.6, 9.1)

3.9 (3.7, 5.1)

HR (95% CI), p-value1

0.58 (0.45, 0.74), p<0.0001

0.51 (0.41, 0.62), p<0.0001

1 stratified log-rank test

Figure 2: Kaplan-Meier curve of overall survival in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

Table 5: Summary of ORR findings per independent radiology committee review (IRC) and investigator review, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy

Primary Analysis ORR Intent-To-Treat Population (IRC)

ORR per Investigator Review Intent-To-Treat Population

Endpoint

CABOMETYX

Everolimus

CABOMETYX

Everolimus

N = 330

N = 328

N = 330

N = 328

ORR (partial responses only) (95% CI)

17% (13%, 22%)

3% (2%, 6%)

24% (19%, 29%)

4% (2%, 7%)

p-value1

p<0.0001

p< 0.0001

Partial Response

17%

3%

24%

4%

Median time to First Response, months (95% CI)

1.91 (1.6, 11.0)

2.14 (1.9, 9.2)

1.91 (1.3, 9.8)

3.50 (1.8, 5.6)

Stable Disease as Best Response

65%

62%

63%

63%

Progressive Disease as Best Response

12%

27%

9%

27%

1 chi-squared test

Randomized study in treatment-naïve renal cell carcinoma patients (CABOSUN)

The safety and efficacy of CABOMETYX for the treatment of treatment-naïve renal cell carcinoma were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N=157) with previously untreated, locally advanced or metastatic RCC with a clear cell component were randomized (1:1) to receive CABOMETYX (N=79) or sunitinib (N=78). Patients had to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). Approximately 75% of patients had a nephrectomy prior to onset of treatment.

For intermediate risk disease, one or two of the following risk factors were met, while for poor risk, three or more factors were met: time from diagnosis of RCC to systemic treatment < 1 year, Hgb < LLN, Corrected calcium > ULN, KPS < 80%, Neutrophil count > ULN and Platelet count > ULN.

The primary endpoint was PFS. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 12 weeks.

The baseline demographic and disease characteristics were similar between the CABOMETYX and sunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 risk factors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOG performance status of 2. Thirty-six percent (36%) of patients had bone metastases.

A statistically significant improvement in PFS as retrospectively assessed by a blinded Independent Radiology Committee (IRC) was demonstrated for CABOMETYX compared to sunitinib (Figure 3 and Table 6). The results from the Investigator determined analysis and IRC-determined analysis of PFS were consistent.

Patients with both positive and negative MET status showed a favourable effect with CABOMETYX compared to sunitinib, with greater activity in patients with a positive MET status compared to patients with a negative MET status (HR=0.32 (0.16, 0.63) vs 0.67 (0.37, 1.23)) respectively.

CABOMETYX treatment was associated with a trend for longer survival compared to sunitinib (Table 6). The study was not powered for the OS analysis and the data are immature.

Objective response rate (ORR) findings are summarized in Table 6.

Figure 3: Kaplan Meier curve for progression-free survival by IRC in treatment-naïve RCC subjects

Table 6: Efficacy results in treatment-naïve RCC subjects (ITT population, CABOSUN)

CABOMETYX

(N=79)

Sunitinib

(N=78)

Progression-free survival (PFS) by IRC a

Median PFS in months (95% CI)

8.6 (6.2, 14.0)

5.3 (3.0, 8.2)

HR (95% CI); stratified b,c

0.48 (0.32, 0.73)

Two-sided log-rank p-value: stratified b

p=0.0005

Progression-free survival (PFS) by Investigator

Median PFS in months (95% CI)

8.3 (6.5, 12.4)

5.4 (3.4, 8.2)

HR (95% CI); stratified b,c

0.56 (0.37, 0.83)

Two-sided log-rank p-value: stratified b

p=0.0042

Overall Survival

Median OS in months (95% CI)

30.3 (14.6, NE)

21.0 (16.3, 27.0)

HR (95% CI); stratified b,c

0.74 (0.47, 1.14)

Objective Response Rate n (%) by IRC

Complete responses

0

0

Partial responses

16 (20)

7 (9)

ORR (partial responses only)

16 (20)

7 (9)

Stable disease

43 (54)

30 (38)

Progressive Disease

14 (18)

23 (29)

Objective Response Rate n (%) by Investigator

Complete responses

1 (1)

0

Partial responses

25 (32)

9 (12)

ORR (partial responses only)

26 (33)

9 (12)

Stable disease

34 (43)

29 (37)

Progressive Disease

14 (18)

19 (24)

a in accord with EU censoring

b Stratification factors per IxRS comprise IMDC risk categories (intermediate risk, poor risk and bone metastasis (yes, no)

c Estimated using the Cox proportional hazard model adjusted for stratification factors per IxRS. Hazard ratio < 1 indicates progression-free survival in favour of cabozantinib

Randomised phase 3 study of cabozantinib in combination with nivolumab vs. sunitinib (CA2099ER)

The safety and efficacy of cabozantinib 40 mg orally daily in combination with nivolumab 240 mg intravenously every 2 weeks for the first-line treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open label study (CA2099ER). The study included patients (18 years or older) with advanced or metastatic RCC with a clear cell component, Karnofsky Performance Status (KPS) > 70%, and measurable disease as per RECIST v1.1 were included regardless of their PD-L1 status or IMDC risk group. The study excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression, patients who had prior treatment with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, poorly controlled hypertension despite antihypertensive therapy, active brain metastases and uncontrolled adrenal insufficiency. Patients were stratified by IMDC prognostic score, PD-L1 tumour expression, and region.

A total of 651 patients were randomised to receive either cabozantinib 40 mg once daily orally in combination with nivolumab 240 mg (n=323) administered intravenously every 2 weeks or sunitinib (n = 328) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off. Treatment continued until disease progression or unacceptable toxicity with nivolumab administration up to 24 months. Treatment beyond initial Investigator-assessed RECIST version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug, as determined by investigator. First tumour assessment post-baseline was performed at 12 weeks (± 7 days) following randomisation. Subsequent tumour assessments occurred at every 6 weeks (± 7 days) until Week 60, then every 12 weeks (± 14 days) until radiographic progression, confirmed by the Blinded Independent Central review (BICR). The primary efficacy outcome measure was PFS as determined by a BICR. Additional efficacy measures included OS and ORR as key secondary endpoints.

Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 28-90) with 38.4% ≥ 65 years of age and 9.5% ≥ 75 years of age. The majority of patients were male (73.9%) and white (81.9%). Eight percent of patients were Asian, 23.2% and 76.5% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. Patient distribution by IMDC risk categories was 22.6% favourable, 57.6% intermediate, and 19.7% poor. For tumour PD-L1 expression, 72.5% of patients had PD-L1 expression < 1% or indeterminate and 24.9% of patients had PD-L1 expression ≥ 1%. 11.5% of patients had tumours with sarcomatoid features. The median duration of treatment was 14.26 months (range: 0.2-27.3 months) in cabozantinib with nivolumab-treated patients and was 9.23 months (range: 0.8-27.6 months) in sunitinib-treated patients.

The study demonstrated a statistically significant benefit in PFS, OS, and ORR for patients randomised to cabozantinib in combination with nivolumab as compared to sunitinib.

Efficacy results from the primary analysis (minimum follow-up 10.6 months; median follow-up 18.1 months) are shown in Table 7.

Table 7: Efficacy results (CA2099ER)

nivolumab + cabozantinib

(n = 323)

sunitinib

(n = 328)

PFS per BICR

Events

144 (44.6%)

191 (58.2%)

Hazard ratioa

0.51

95% CI

(0.41, 0.64)

p-valueb, c

< 0.0001

Median (95% CI)d

16.59 (12.45, 24.94)

8.31 (6.97, 9.69)

OS

Events

67 (20.7%)

99 (30.2%)

Hazard ratioa

0.60

98.89% CI

(0.40, 0.89)

p-valueb,c,e

0.0010

Median (95% CI)

N.E.

N.E. (22.6, N.E.)

Rate (95% CI)

At 6 months

93.1 (89.7, 95.4)

86.2 (81.9,89.5)

ORR per BICR (CR + PR)

180 (55.7%)

89 (27.1%)

(95% CI)f

(50.1, 61.2)

(22.4, 32.3)

Difference in ORR (95% CI)g

28.6 (21.7, 35.6)

p-valueh

< 0.0001

Complete response (CR)

26 (8.0%)

15 (4.6%)

Partial response (PR)

154 (47.7%)

74 (22.6%)

Stable disease (SD)

104 (32.2%)

138 (42.1%)

Median duration of responsed

Months (range)

20.17 (17.31, N.E.)

11.47 (8.31, 18.43)

Median time to response

Months (range)

2.83 (1.0-19.4)

4.17 (1.7-12.3)

a Stratified Cox proportional hazards model. Hazard ratio is nivolumab and cabozantinib over sunitinib.

b 2-sided p-values from stratified regular log-rank test.

c Log-rank test stratified by IMDC prognostic risk score (0, 1-2, 3-6), PD-L1 tumour expression (≥1% versus <1% or indeterminate) and region (US/Canada/W Europe/N Europe, ROW) as entered in the IRT.

d Based on Kaplan-Meier estimates.

e Boundary for statistical significance p-value <0.0111.

f CI based on the Clopper and Pearson method.

g Strata adjusted difference in objective response rate (nivolumab+cabozantinib - Sunitinib) based on DerSimonian and Laird

h 2-sided p-value from CMH test.

NE = non-estimable

The primary analysis of PFS included censoring for new anti-cancer treatment (Table 7). Results for PFS with and without censoring for new anti-cancer treatment were consistent.

PFS benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of tumour PD L1 expression. Median PFS for tumour PD L1 expression ≥ 1% was 13.08 for cabozantinib in combination with nivolumab, and was 4.67 months in the sunitinib arm (HR = 0.45; 95% CI: 0.29, 0.68). For tumour PD L1 expression < 1%, the median PFS was 19.84 months for the cabozantinib in combination with nivolumab, and 9.26 months in the sunitinib arm (HR = 0.50; 95% CI: 0.38, 0.65).

PFS benefit was observed in the cabozantinib in combination with nivolumab arm vs. sunitinib regardless of the (IMDC) risk category. Median PFS for the favourable risk group was not reached for cabozantinib in combination with nivolumab, and was 12.81 months in the sunitinib arm (HR = 0.60; 95% CI: 0.37, 0.98). Median PFS for the intermediate risk group was 17.71 months for cabozantinib in combination with nivolumab and was 8.38 months in the sunitinib arm (HR = 0.54; 95% CI: 0.41, 0.73). Median PFS for the poor risk group was 12.29 months for cabozantinib in combination with nivolumab and was 4.21 months in the sunitinib arm (HR = 0.36; 95% CI: 0.23, 0.58).

An updated PFS and OS analysis were performed when all patients had a minimum follow-up of 16 months and a median follow-up of 23.5 months (see figures 4 and 5). The PFS hazard ratio was 0.52 (95% CI: 0.43; 0.64). The OS hazard ratio was 0.66 (95% CI: 0.50; 0.87). Updated efficacy data (PFS and OS) in subgroups for the IMDC risk categories and PD-L1 expression levels confirmed the original results. With the updated analysis, median PFS is reached for the favourable risk group.

Figure 4: Kaplan-Meier curves of PFS (CA2099ER)

Figure 5 : Kaplan Meier curves of OS (CA2099ER)

Hepatocellular Carcinoma

Controlled study in patients who have received sorafenib (CELESTIAL)

The safety and efficacy of CABOMETYX were evaluated in a randomized, double-blind, placebo-controlled Phase 3 study (CELESTIAL). Patients (N=707) with HCC not amenable to curative treatment and who had previously received sorafenib for advanced disease were randomized (2:1) to receive CABOMETYX (N=470) or placebo (N=237). Patients could have received one other prior systemic therapy for advanced disease in addition to sorafenib. Randomization was stratified by aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region (Asia, other regions) and by presence of extrahepatic spread of disease and/or macrovascular invasions (Yes, No).

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints were progression-free survival (PFS) and objective response rate (ORR), as assessed by the Investigator using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments were conducted every 8 weeks. Subjects continued blinded study treatment after radiological disease progression whilst they experienced clinical benefit or until the need for subsequent systemic or liver-directed local anticancer therapy. Crossover from placebo to cabozantinib was not allowed during the blinded treatment phase.

The baseline demographic and disease characteristics were similar between the CABOMETYX and placebo arms and are shown below for all 707 randomised patients:

Male: 82%

Median age: 64 years.

Caucasian: 56%, Asian: 34%

ECOG performance status (PS) 0: 53% or ECOG PS 1: 47%.

Child Pugh A: 99%, Child Pugh B: 1 %

Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV), 40% other (neither HBV nor HCV).

Presence of macroscopic vascular invasion and/ or extra-hepatic tumour spread:78%,

Alfa-fetoprotein (AFP) levels ≥400 μg/L: 41%.

Loco-regional transarterial embolisation or chemoinfusion procedures: 44%

Radiotherapy prior to cabozantinib treatment: 37%

Median duration of sorafenib treatment: 5.32 months

Seventy-two percent (72%) of patients had received one and 28% had received 2 prior systemic therapy regimens for advanced disease.

A statistically significant improvement in OS was demonstrated for CABOMETYX compared to placebo (Table 8 and Figure 6).

PFS and ORR findings are summarized in Table 8.

Table 8: Efficacy results in HCC (ITT population, CELESTIAL)

CABOMETYX

(N=470)

Placebo

(N=237)

Overall Survival

Median OS (95% CI), months

10.2 (9.1, 12.0)

8.0 (6.8, 9.4)

HR (95% CI) 1,2

0.76 (0.63, 0.92)

p-value1

p=0.0049

Progression-free survival (PFS) 3

Median PFS in months (95% CI)

5.2 (4.0, 5.5)

1.9 (1.9, 1.9)

HR (95% CI)1

0.44 (0.36, 0.52)

p-value1

p<0.0001

Kaplan-Meier landmark estimates of percent of subjects event-free at 3 months

% (95% CI)

67.0% (62.2%, 71.3%)

33.3% (27.1%, 39.7%)

Objective Response Rate n (%)3

Complete responses (CR)

0

0

Partial responses (PR)

18 (4)

1 (0.4)

ORR (CR+PR))

18 (4)

1 (0.4)

p-value1,4

p=0.0086

Stable disease

282 (60)

78 (33)

Progressive Disease

98 (21)

131 (55)

1 2-sided stratified log-rank test with aetiology of disease (HBV [with or without HCV], HCV [without HBV], or Other), geographic region (Asia, Other Regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data)

2 estimated using the Cox proportional-hazard model

3 as assessed by investigator per RECIST 1.1

4 stratified Cochran-Mantel-Haenszel (CMH) test

Figure 6: Kaplan-Meier curve of overall survival (CELESTIAL)

Figure 7: Kaplan Meier curve for progression-free survival (CELESTIAL)

The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancer therapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receiving these therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use of NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was 0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan- Meier estimates for median duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placebo arm, an estimated 4.2-month difference in the medians.

Non-disease specific quality of life (QoL) was assessed using the EuroQoL EQ-5D-5L. A negative effect of CABOMETYX versus placebo on the EQ-5D utility index score was observed during the first weeks of treatment. Only limited QoL data are available after this period.

Paediatric population

The Licensing Authority has deferred the obligation to submit the results of studies with CABOMETYX in one or more subsets of the paediatric population in treatment of solid malignant tumours (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212 L. Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function.

Biotransformation

Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.

Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalysed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction).

Elimination

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy volunteers following oral administration of a range of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr . Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

Renal impairment

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Hepatic impairment

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic impairment (n=558). There is limited data in patients with moderate hepatic impairment (n=15) as per NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

Race

A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race.

5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or in combination with malignant pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinical relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low.

Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the intended human therapeutic exposure.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observed in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.

Juvenile rats (comparable to a >2 year- old paediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Juvenile rats (correlating to a <2- year paediatric population) showed similar treatment-related findings but appeared to be more sensitive to cabozantinib-related toxicity at comparable dose levels.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet content

Microcrystalline cellulose

Anhydrous lactose

Hydroxypropyl cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Film-coating

Hypromellose 2910

Titanium dioxide (E171)

Triacetin

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

HDPE bottle with a polypropylene child-resistant closure and three silica gel desiccant canisters. Each bottle contains 30 film-coated tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Ipsen Pharma

65 quai Georges Gorse

92100 Boulogne-Billancourt

France

8. Marketing authorisation number(s)

Cabometyx 20 mg film-coated tablets

PLGB 28247/0001

Cabometyx 40 mg film-coated tablets

PLGB 28247/0002

Cabometyx 60 mg film-coated tablets

PLGB 28247/0003

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 01 January 2021

10. Date of revision of the text

13 May 2021