Cabometyx - summary of medicine characteristics

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 PARTICULARS4.1 Therapeutic indications

Renal cell carcinoma (RCC)

CABOMETYX is indicated as monotherapy for advanced renal cell carcinoma

• – as first-line treatment of adult patients with intermediate or poor risk (see section 5.1),

• – in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy (see section 5.1).

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 tablets and 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 reinitiating 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

No specific dose adjustment for the use of cabozantinib in elderly patients (> 65 years) is recommended.

Race

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

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.

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).

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 adverse reactions 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. Adverse reactions 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-naive 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 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 events (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 pM), 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

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

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.

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.

The effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated. An 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 p.M), 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 trials of cabozantinib as monotherapy or reported after postmarketing 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, thrombocytopenia
Common	neutropenia, lymphopenia
Endocrine disorders
Very common	hypothyroidism
Metabolism and nutrition disorders
Very common	decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia
Common	dehydration, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia, hyperglycaemia, hypoglycaemia
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	hypertension, haemorrhageb*
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 disord	ers
Very common	diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal pain, 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, erythema
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
Investigations3
Very Common	weight decreased, serum ALT increased, AST increased
Common	blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased, blood triglycerides increased
Injury, poisoning and procedural complications
Uncommon	wound complications0

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

a Based on reported adverse reactions

b Including epistaxis as the most commonly reported adverse reaction c 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 disorc	ers
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-Barre 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 disord	ers
Very common	diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia
Common	colitis, gastritis, oral pain, dry mouth, haemorrhoids
Uncommon	pancreatitis, small intestine perforation13, 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
Investigations6
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

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-naive 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-naive 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-naive 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-naive 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 trials (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-naive 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 national reporting system listed in Appendix V.

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 PROPERTIES5.1 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 trial 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, openlabel, 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)

CABOMETYX	187	152	92	68	20	6	2
Everolimus	188	99	46	29	10	2	0

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)

CABOMETYX330     318    296    264    239     178     105     41      6       3 0

Everolimus 328     307     262     229     202     141      82      32       8        1 0

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-naive renal cell carcinoma patients (CABOSUN)

The safety and efficacy of CABOMETYX for the treatment of treatment-naive 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

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CABOMETYX Sunitinib

Table 6: Efficacy results in treatment-naive 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 bc	0.74 (0/	17, 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)

Probability of progression-free survival

Progression-free Survival per BICR (months)

Number of subjects at risk

Nivolumab + cabozantinib

323   280   236   201    166   145   102     56    26    5     2 0

Sunitinib

328   230   160    122    87    61     37     17      7    2      1 0

Nivolumab + cabozantinib (events: 175/323), median and 95.0% CI: 16.95 (12.58, 19.38) - su – – Sunitinib (events: 206/328), median and 95.0% CI:8.31 (6.93, 9.69)

Figure 5 : Kaplan Meier curves of OS (CA2099ER)

0      3      6      9     12     15     18     21     24     27     30 33

Overall Survival (Months)

Number of subjects at risk

Nivolumab + cabozantinib

323   308	295	283	269	255	220	147	84	40	10	0
Sunitinib
328   295	272	254	236	217	189	118	62	22	4	0

Nivolumab + cabozantinib (events: 86/323), médian and 95% CI: NE – Sunitinib (events: 116/328), médian and 95% CI:29.47 (28.35, NE)

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.

The majority of patients (82%) were male: the median age was 64 years. The majority of patients (56%) were Caucasian and 34% of patients were Asian. Fifty three percent (53%) of patients had ECOG performance status (PS) 0 and 47% had ECOG PS 1. Almost all patients (99%) were Child Pugh A and 1% were Child Pugh B. Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV), 40% other (neither HBV nor HCV). Seventy-eight percent (78%) had macroscopic vascular invasion and/ or extra-hepatic tumour spread, 41% had alfa-fetoprotein (AFP) levels >400^ig/L, 44% had been treated by loco-regional transarterial embolisation or chemoinfusion procedures, 37% had radiotherapy prior to cabozantinib treatment. Median duration of sorafenib treatment was 5.32 months. Seventy-two percent (72%) of patients had received 1 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)’.	0.76 (0.63, 0.92)
p-value	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)	0.44 (0.36, 0.52)
p-value	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 (%)
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)

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

0

0

44

15

470

237

281

117

93

25

22

7

159

57

CABOMETYX

Placebo

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

2

0

0

0

39

5

470

237

10

2

3

1

131

21

CABOMETYX

Placebo

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 European Medicines Agency 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 compared to the capsule formulation was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet and capsule 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.

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 total 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. The geometric LS means for unbound plasma cabozantinib AUC0-inf was 0.2% higher for subjects with mild renal impairment (90% CI 55.9% to 180%) and 17% higher (90% CI 65.1% to 209.7%) 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 trials, 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 PARTICULARS6.1 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, three silica gel desiccant canisters and polyester coil. Each bottle contains 30 film-coated tablets.

6.6 Special precautions for disposal

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

EU/1/16/1136/002

Cabometyx 40 mg film-coated tablets

EU/1/16/1136/004

Cabometyx 60 mg film-coated tablets

EU/1/16/1136/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09 September 2016

Date of latest renewal: 21 April 2021