CABOMETYX 60mg tablets medication leaflet

CABOMETYX 20 mg film-coated tablets

CABOMETYX 40 mg film-coated tablets

CABOMETYX 60 mg film-coated tablets

CABOMETYX 20 mg film-coated tablets

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

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.

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.

Each film-coated tablet contains 46.61 mg lactose

For the full list of excipients, see section 6.1.

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 otherside 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” onthe 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 theother side of the tablet.

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 (seesection 5.1).

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

Hepatocellular carcinoma (HCC)

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

Differentiated thyroid carcinoma (DTC)

CABOMETYX is indicated as monotherapy for the treatment of adult patients with locally advancedor metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine(RAI) who have progressed during or after prior systemic therapy.

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

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

CABOMETYX as monotherapy

For RCC, HCC and DTC, the recommended dose of CABOMETYX is 60 mg once daily.

Treatment should continue until the patient is no longer clinically benefiting from therapy or untilunacceptable 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 nivolumabadministered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks. The treatmentshould continue until disease progression or unacceptable toxicity. Nivolumab should be continueduntil disease progression, unacceptable toxicity, or up to 24 months in patients without diseaseprogression (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/ordose reduction (see Table 1). When dose reduction is necessary in monotherapy, it is recommended toreduce to 40 mg daily, and then to 20 mg daily.

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

Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities orintolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, couldbecome serious or intolerable.

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

Table 1: Recommended CABOMETYX dose modifications for adverse reactions

Adverse reaction and severity Treatment modification

Grade 1 and grade 2 adverse reactions Dose adjustment is usually not required.which are tolerable and easilymanaged Add supportive care as indicated.

Grade 2 adverse reactions which are Interrupt treatment until the adverse reaction resolves tointolerable and cannot be managed grade ≤1.with a dose reduction or supportivecare Add supportive care as indicated.

Consider re-initiating at a reduced dose.

Grade 3 adverse reactions (except Interrupt treatment until the adverse reaction resolves toclinically nonrelevant laboratory grade ≤1.abnormalities) Add supportive care as indicated.

Re-initiate at a reduced dose.

Grade 4 adverse reactions (except Interrupt treatment.clinically nonrelevant laboratoryabnormalities) Institute appropriate medical care.

If adverse reaction resolves to grade ≤1, re-initiate at areduced dose.

If adverse reaction does not resolve, permanentlydiscontinue the treatment.

Liver enzymes elevations for RCCpatients treated with CABOMETYXin combination with nivolumab

ALT or AST > 3 times ULN but ≤10 Interrupt CABOMETYX and nivolumab until thesetimes ULN without concurrent total adverse reactions resolves to Grade≤1bilirubin ≥ 2 times ULN 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 beconsidered. If re-initiating with nivolumab, refer tonivolumab SmPC.

ALT or AST > 10 times ULN or > 3 Permanently discontinue CABOMETYX and nivolumab.times ULN with concurrent totalbilirubin ≥ 2 times ULN 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 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 beavoided (see sections 4.4 and 4.5).

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

No specific dose adjustment for the use of cabozantinib in elderly patients (≥ 65 years) isrecommended.

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

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 andefficacy have not been established in this population.

In patients with mild hepatic impairment no dose adjustment is required. Since only limited data areavailable for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendationcan be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4and 5.2). There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), socabozantinib 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 canbe made.

The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

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

CABOMETYX.

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

As most adverse reactions occur early in the course of treatment, the physician should evaluate thepatient closely during the first eight weeks of treatment to determine if dose modifications arewarranted. 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 ofcabozantinib 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 dosereductions 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% and73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN).

When cabozantinib is given in combination with nivolumab in first-line advanced renal cellcarcinoma, dose reduction and dose interruption of cabozantinib due to an AE occurred in 54.1% and73.4% of patients in the clinical trial (CA2099ER). Two dose reductions were required in 9.4% ofpatients. The median time to first dose reduction was 106 days, and to first dose interruption was 68days.

In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptionsoccurred 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 dosereduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised inpatients with mild or moderate hepatic impairment.

In differentiated thyroid carcinoma, dose reductions and dose interruptions occurred in 67% and 71%respectively of cabozantinib treated patients in the clinical trial (COSMIC-311). Two dose reductionswere required in 33% of patients. The median time to first dose reduction was 57 days and to firstdose interruption was 38.5 days.

Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartateaminotransferase [AST] and bilirubin) have been frequently observed in patients treated withcabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) beforeinitiation of cabozantinib treatment and to monitor closely during treatment. For patients withworsening of liver function tests considered related to cabozantinib treatment (i.e. where noalternative cause is evident), the dose modification advice in Table 1 should be followed (see section4.2).

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 withadvanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of andperiodically throughout treatment. Medical management guidelines for both medicines should befollowed (see section 4.2 and refer to the SmPC for nivolumab).

Rare instances of vanishing bile duct syndrome have been reported. All cases have occurred inpatients who have received immune checkpoint inhibitors, either before or concurrently withcabozantinib treatment.

Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety isrecommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). Ahigher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developedhepatic encephalopathy with cabozantinib treatment. Cabozantinib is not recommended for use inpatients 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 thecabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting,decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, thesenon-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. Patientswho 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 fromprior GI surgery (particularly when associated with delayed or incomplete healing) should becarefully evaluated before initiating cabozantinib therapy and subsequently they should be monitoredclosely for symptoms of perforations and fistulas including abscesses and sepsis. Persistent orrecurring 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 thatcannot be adequately managed.

Gastrointestinal (GI) disorders

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

Events of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism,sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution inpatients 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, includingone fatal event. Patients with a history of portal vein invasion appeared to be at higher risk ofdeveloping portal vein thrombosis. Cabozantinib should be discontinued in patients who develop anacute myocardial infarction or any other clinically significant thromboembolic complication.

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

In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence withcabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCCpopulation may include tumour invasion of major blood vessels and the presence of underlying livercirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The

CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplateletagents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk forbleeding 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.

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

In the HCC study (CELESTIAL) and in the DTC study (COSMIC-311), thrombocytopenia anddecreased platelets were reported. Platelet levels should be monitored during cabozantinib treatmentand the dose modified according to the severity of the thrombocytopenia (see Table 1).

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

Hypertension, including hypertensive crisis has been observed with cabozantinib. Blood pressureshould be well-controlled prior to initiating cabozantinib.After cabozantinib initiation, blood pressureshould be monitored early and regularly and treated as needed with appropriate antihypertensivetherapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinibtreatment should be interrupted until blood pressure is controlled, after which cabozantinib can beresumed at a reduced dose. Cabozantinib should be discontinued if hypertension is severe andpersistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case ofhypertensive crisis, cabozantinib should be discontinued.

Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examinationshould 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 atleast 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Cautionshould 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 (PPES) has been observed with cabozantinib. When

PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinibshould 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 duringcabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephroticsyndrome.

Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. Thissyndrome should be considered in any patient presenting with multiple symptoms, including seizures,headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should bediscontinued 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 withon-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should beconsidered.

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

Biochemical laboratory test abnormalities

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (includinghypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). Hypocalcaemia hasbeen observed with cabozantinib at a higher frequency and/or increased severity (including Grade 3and 4) in patients with thyroid cancer compared to patients with other cancers. It is recommended tomonitor biochemical parameters during cabozantinib treatment and to institute appropriatereplacement therapy according to standard clinical practice if required. Cases of hepaticencephalopathy in HCC patients can be attributed to the development of electrolyte disturbances.

Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered incase 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 isrequired when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrentadministration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease incabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4inducers 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) transportactivities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib mayhave the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjectsshould 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 beapproached with caution (see section 4.5).

Excipient

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

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

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 healthyvolunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinibexposure (AUC) by 38%. Therefore, co-administration of strong CYP3A4 inhibitors (e.g., ritonavir,itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approachedwith caution.

Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthyvolunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinibexposure (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 singledose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect onplasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifyingagents (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 cabozantiniband may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section5.2). 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 beeninvestigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptivemethod, such as a barrier method, is recommended.

The effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated. Aninteraction with warfarin may be possible. In case of such combination, INR values should bemonitored.

P-glycoprotein substrates

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

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

There are no studies in pregnant women using cabozantinib. Studies in animals have shownembryo-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 requirestreatment with cabozantinib.

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

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

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

Cabozantinib as monotherapy

The most common serious adverse drug reactions in the RCC population (≥1% incidence) arepneumonia, abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonaryembolism, 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, weightdecreased, vomiting, dysgeusia, constipation, and AST increased. Hypertension was observed morefrequently 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 hepaticencephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain andthrombocytopenia.

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 andvomiting.

The most common serious adverse drug reactions in the DTC population (≥1% incidence) arediarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep veinthrombosis, hypocalcemia, osteonecrosis of jaw, pain, palmar-plantar erythrodysaesthesia syndrome,vomiting and renal impairment.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the

DTC population included diarrhoea, PPES, hypertension, fatigue, decreased appetite, nausea, alanineaminotransferase increased, aspartate aminotransferase increased and hypocalcaemia.

Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in

RCC, HCC and DTC (n=1128) or reported after post-marketing use of cabozantinib are listed in Table2. The adverse reactions are listed by 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 usein patients treated with cabozantinib in monotherapy

Common abscess, pneumonia

Blood and lymphatic disorders

Very common anaemia, thrombocytopenia

Common neutropenia, lymphopenia

Very common hypothyroidism*

Very common decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia

Common dehydration, hypophosphataemia, hyponatraemia, hypocalcaemia,hyperkalaemia, hyperbilirubinemia, hyperglycaemia, hypoglycaemia

Very common dysgeusia, headache, dizziness

Common peripheral neuropathya

Uncommon convulsion, cerebrovascular accident, posterior reversible encephalopathysyndrome

Ear and labyrinth disorders

Common tinnitus

Uncommon acute myocardial infarction

Very common hypertension, haemorrhageb*

Common venous thrombosisc

Uncommon hypertensive crisis, arterial thrombosis, embolism arterial

Not known aneurysms and artery dissections

Respiratory, thoracic, and mediastinal disorders

Very common dysphonia, dyspnoea, cough

Common pulmonary embolism

Uncommon pneumothorax

Very common diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal pain,dyspepsia

Common gastrointestinal perforation*, pancreatitis, fistula*, gastroesophageal refluxdisease, haemorrhoids, oral pain, dry mouth, dysphagia

Uncommon glossodynia

Common hepatic encephalopathy*

Uncommon hepatitis cholestatic

Very common palmar-plantar erythrodysaesthesia syndrome, rash

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

Not known cutaneous vasculitis

Very common pain in extremity

Common muscle spasms, arthralgia

Uncommon osteonecrosis of the jaw

Common Proteinuria

Very common fatigue, mucosal inflammation, asthenia, peripheral oedema

Investigationsd

Very Common weight decreased, serum ALT increased, AST increasedblood ALP increased, GGT increased, blood creatinine increased,

Common amylase increased, lipase increased, blood cholesterol increased, bloodtriglycerides increased

Uncommon wound complicationse

*See section 4.8 Description of selected adverse reactions for further characterisation.a including polyneuropathy; peripheral neuropathy is mainly sensoryb Including epistaxis as the most commonly reported adverse reactioncAll venous thrombosis including deep vein thrombosisd Based on reported adverse reactionse Impaired healing, incision site complication and wound dehiscence

Cabozantinib in combination with nivolumab in first-line advanced RCC

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

In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every twoweeks in RCC (n =320), with a minimum follow‑up of 16 months, the most common serious adversedrug 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-plantarerythrodysaesthesia 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).

Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab arelisted in Table 3, according to MedDRA System Organ Class and frequency categories. Frequenciesare 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 eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions with cabozantinib in combination with nivolumab

Very Common upper respiratory tract infection

Common pneumonia

Common eosinophilia

Common hypersensitivity (including anaphylactic reaction)

Uncommon infusion related hypersensitivity reaction

Very common hypothyroidism, hyperthyroidism

Common adrenal insufficiency

Uncommon hypophysitis, thyroiditis

Very common decreased appetite

Common dehydration

Very common dysgeusia, dizziness, headache

Common peripheral neuropathy

Uncommon encephalitis autoimmune, Guillain-Barré syndrome, myasthenicsyndrome

Ear and labyrinth disorders

Common tinnitus

Common dry eye, blurred vision

Uncommon uveitis

Common atrial fibrillation, tachycardia

Uncommon myocarditis

Very common hypertension

Common thrombosisa

Uncommon embolism arterial

Very common dysphonia, dyspnoea, cough

Common pneumonitis, pulmonary embolism, epistaxis, pleural effusion

Uncommon pneumothorax

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

Common colitis, gastritis, oral pain, dry mouth, haemorrhoids

Uncommon pancreatitis, small intestine perforationb, glossodynia

Common hepatitis

Not known vanishing bile duct syndromec

Very common palmar-plantar erythrodysaesthesia syndrome, rashd, pruritus

Common alopecia, dry skin, erythema, hair colour change

Uncommon psoriasis, urticaria

Not known cutaneous vasculitis

Very common musculoskeletal paine, arthralgia, muscle spasm,

Common arthritis

Uncommon myopathy, osteonecrosis of the jaw, fistula

Very common proteinuria

Common renal failure, acute kidney injury

Uncommon nephritis

Very common fatigue, pyrexia, oedema

Common pain, chest pain

Investigationsfincreased ALT, increased AST, hypophosphataemia, hypocalcaemia,hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopenia,increased alkaline phosphatase, increased lipase, increased amylase,

Very common thrombocytopaenia, increased creatinine, anaemia, leucopenia,hyperkalaemia, neutropenia, 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 maycontain 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 veinthrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limbb Fatal cases have been reportedc With prior or concomitant immune checkpoint inhibitor exposured Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliativerash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruriticand drug eruptione Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chestpain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal painf Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening frombaseline in laboratory measurements with the exception of weight decreased, blood cholesterol increasedand hypertriglyceridaemia

Data for the following reactions are based on patients who received CABOMETYX 60 mg orallyonce daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy andin treatment-naïve RCC, in HCC following prior systemic therapy and in DTC in patient refractory ornot eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy orin patients who received CABOMETYX 40 mg orally once daily in combination with nivolumab infirst-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 werereported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Mediantime to onset was 10.0 weeks.

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

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

In the DTC study (COSMIC-311), GI perforation grade 4 was reported in one patient (0.6%) ofcabozantinib-treated patients and occurred after 14 weeks of treatment.

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 4and 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) and in the DTC study (COSMIC-311).

Diarrhoea (see section 4.4)

In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onsetwas 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. Diarrhoealed to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and5/467 (1%) of subjects, respectively.

In the DTC study (COSMIC-311), diarrhoea was reported in 62% of cabozantinib treated patients(105/170); Grade 3-4 events in 7.6%. Diarrhoea led to dose reduction and interruption in 24/170(14%) and 36/170 (21%) of subjects respectively.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidenceof 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 in1.2% (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 30.3weeks.

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. Mediantime to onset was 14 weeks.

In the DTC study (COSMIC-311), fistulas (two anal and one pharyngeal fistula) were reported in 1.8% (3/170) of the cabozantinib treated patients.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence offistula 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 severehaemorrhagic events (Grade ≥ 3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Mediantime 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.

In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (grade ≥ 3) was 2.4%in cabozantinib-treated patients (4/170). Median time to onset was 80.5 days.

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, CABOSUN, CA2099ER or CELESTIAL studies,but PRES has been reported in one patient in the DTC study (COSMIC-311) and rarely in otherclinical 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 combinationwith 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 (ALTincreased 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 resolutionof 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 eithercabozantinib (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.

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

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

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

In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (4/170), all grade 1-2,none requiring modification of treatment.

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

Paediatric population (see section 5.1)

In study ADVL1211, a limited dose-escalation study of cabozantinib in paediatric and adolescentpatients with recurrent or refractory solid tumors including CNS tumors, the following events:aspartate aminotransferase (AST) increased (very common, 76.9%), alanine aminotransferase (ALT)increased (very common, 71.8%), lymphocyte count decreased (very common, 48.7%), neutrophilcount decreased (very common, 35.9%), and lipase increased (very common, 33.3%) were observedat a higher frequency in all subjects across all dose groups included in the safety population (N=39),compared to adults. The increased rates for these Preferred Terms (PTs) concern any grade as well asgrade 3/4 of these ADRs. The adverse events reported are in line qualitatively with the recognisedsafety profile for cabozantinib in adult populations. However, the small numbers of subjects precludea conclusive assessment of trends and frequencies and further comparison with the recognised safetyprofile of cabozantinib.

In study ADVL1622 of cabozantinib in children and young adults with the following solid tumorstrata: Ewing sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS),osteosarcoma, Wilms tumor and other rare solid tumors (nonstatistical cohort), the safety profile ofcabozantinib treated children and young adults in all strata was comparable with that observed inadults treated with cabozantinib.

Physeal widening has been observed in children with open growth plates when treated withcabozantinib.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have notbeen 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 clinicallyappropriate to assess any possible changing trends. Adverse reactions associated with overdose are tobe treated symptomatically.

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01EX07.

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated intumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastaticprogression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety ofkinases 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 tyrosinekinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factorreceptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

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

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) wasobserved in a controlled clinical trial in medullary thyroid cancer patients. This effect was notassociated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treatedsubjects 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).

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 priorvascular 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 cellcomponent who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor(VEGFR TKI) were randomized (1:1) to receive cabozantinib (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 metastaseswere allowed. Progression-free survival (PFS) was assessed by a blinded independent radiologyreview 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). Tumourassessments 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 cabozantinib andeverolimus 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 sunitinibas their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center criteriafor prognostic risk category, 46% were favourable (0 risk factors), 42% were intermediate (1 riskfactor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or moreorgans 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 receivingcabozantinib and 4.4 months (range 0.21 - 18.9) for patients receiving everolimus.

A statistically significant improvement in PFS was demonstrated for cabozantinib compared toeverolimus (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 significantimprovement was demonstrated for patients randomized to cabozantinib 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 infavour of cabozantinib 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 fromdiagnosis 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 bonemetastases (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 reviewcommittee, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (first 375 subjects randomized) (METEOR)1 .00 .90 .80 .70 .60 .50 .40 .30 .2 CABOMETYX

Everolimus0 .10 .00 3 6 9 1 2 1 5 1 8

M o ntth s

NNuom. abte Rr iastk r isk:

CABOMETYX 187 152 92 68 20 6 2

Everrolliimus 188 99 46 29 10 2 0

Probability of Progression-free Survival

P ro b a b ility o f P ro g re s s io n -fre e S u rv iv a l

Table 4: Summary of PFS findings by independent radiology review committee in RCC subjectsfollowing 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% 7.4 (5.6, 9.1) 3.8 (3.7, 5.4) 7.4 (6.6, 9.1) 3.9 (3.7, 5.1)

CI), months

HR (95% CI), 0.58 (0.45, 0.74), p<0.0001 0.51 (0.41, 0.62), p<0.0001p-value11 stratified log-rank test

Figure 2: Kaplan-Meier curve of overall survival in RCC subjects following prior vascularendothelial growth factor (VEGF)-targeted therapy (METEOR)1 .00 .90 .80 .70 .60 .50 .40 .3

CCAAB O M E TYYXX0 .2

EEvve rro lliimuuss0 .10 .00 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0

Number at risk: M Mo notnhtshs

CABOMETYX 330 318 296 264 239 178 105 41 6 3 0

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

P ro b a b ility o f O v e ra ll S u rv iv a l

Probability of Overall Survival

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

Primary analysis ORR intent-to- ORR per investigator reviewtreat population (IRC) intent-to-treat population

Endpoint CABOMETYX Everolimus CABOMETYX Everolimus

N = 330 N = 328 N = 330 N = 328

ORR (partial 17% (13%, 22%) 3% (2%, 6%) 24% (19%, 29%) 4% (2%, 7%)responses only)(95% CI)p-value1 p<0.0001 p< 0.0001

Partial response 17% 3% 24% 4%

Median time to first 1.91 (1.6, 11.0) 2.14 (1.9, 9.2) 1.91 (1.3, 9.8) 3.50 (1.8, 5.6)response, months(95% CI)

Stable disease as 65% 62% 63% 63%best response

Progressive disease 12% 27% 9% 27%as best response1 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 carcinomawere evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N=157) withpreviously untreated, locally advanced or metastatic RCC with a clear cell component were randomized(1:1) to receive cabozantinib (N=79) or sunitinib (N=78). Patients had to have intermediate or poor riskdisease as defined by the International Metastatic RCC Database Consortium (IMDC) risk groupcategories. 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) andoverall survival (OS). Tumour assessments were conducted every 12 weeks.

The baseline demographic and disease characteristics were similar between the cabozantinib andsunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patientdistribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 riskfactors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOGperformance 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 cabozantinib compared to sunitinib (Figure 3 and

Table 6). The results from the investigator determined analysis and IRC-determined analysis of PFSwere consistent.

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

Cabozantinib 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 RCCsubjects1.00.90.80.70.60.50.40.30.2

CABOMETYX0.1

Sunitinib0.00 3 6 9 12 15 18 21 24 27 30

Months

Number at risk:

CABOMETYX

Sunitinib

Probability of Progression-free Survival

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

CABOMETYX Sunitinib(N=79) (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 censoringb 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 indicatesprogression-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 mgintravenously every 2 weeks for the first-line treatment of advanced/metastatic RCC was evaluated ina 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 conditionsrequiring 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 despiteantihypertensive therapy, active brain metastases and uncontrolled adrenal insufficiency. Patientswere 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 incombination 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 continueduntil disease progression or unacceptable toxicity with nivolumab administration up to 24 months.

Treatment beyond initial Investigator-assessed RECIST version 1.1-defined progression waspermitted if the patient had a clinical benefit and was tolerating study drug, as determined byinvestigator. First tumour assessment post-baseline was performed at 12 weeks (± 7 days) followingrandomisation. 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 determinedby 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 was61 years (range: 28-90) with 38.4%  65 years of age and 9.5%  75 years of age. The majority ofpatients were male (73.9%) and white (81.9%). Eight percent of patients were Asian, 23.2% and76.5% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. Patient distributionby 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% ofpatients had PD-L1 expression ≥ 1%. 11.5% of patients had tumours with sarcomatoid features. Themedian duration of treatment was 14.26 months (range: 0.2-27.3 months) in cabozantinib withnivolumab-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 patientsrandomised 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 18.1months) are shown in Table 7.

Table 7: Efficacy results (CA2099ER)nivolumab + cabozantinib sunitinib(n = 323) (n = 328)

PFS per BICR

Events 144 (44.6%) 191 (58.2%)

Hazard ratioa 0.5195% 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 0.6098.89% 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% orindeterminate) 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 Lairdh 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. sunitinibregardless of tumour PD L1 expression. Median PFS for tumour PD L1 expression ≥ 1% was 13.08for 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 forthe 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. sunitinibregardless of the (IMDC) risk category. Median PFS for the favourable risk group was not reached forcabozantinib 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 cabozantinibin 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 withnivolumab 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 of16 months and a median follow-up of 23.5 months (see figures 4 and 5). The PFS hazard ratio was0.52 (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 theoriginal results. With the updated analysis, median PFS is reached for the favourable risk group.

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

Progression-free Survival per BICR (months)

Number of subjects at risk

Nivolumab + cabozantinib323 280 236 201 166 145 102 56 26 5 2 0

Sunitinib328 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)

Sunitinib (events: 206/328), median and 95.0% CI:8.31 (6.93, 9.69)

Probability of progression-free survival

Figure 5 : Kaplan Meier curves of OS (CA2099ER)

Overall Survival (Months)

Number of subjects at risk

Nivolumab + cabozantinib323 308 295 283 269 255 220 147 84 40 10 0

Sunitinib328 295 272 254 236 217 189 118 62 22 4 0

Nivolumab + cabozantinib (events: 86/323), median and 95% CI: NE

Sunitinib (events: 116/328), median 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 curativetreatment and who had previously received sorafenib for advanced disease were randomized (2:1) toreceive cabozantinib (N=470) or placebo (N=237). Patients could have received one other priorsystemic therapy for advanced disease in addition to sorafenib. Randomization was stratified byaetiology 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 macrovascularinvasions (Yes, No).

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints wereprogression-free survival (PFS) and objective response rate (ORR), as assessed by the investigatorusing Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments wereconducted every 8 weeks. Subjects continued blinded study treatment after radiological diseaseprogression 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 theblinded treatment phase.

Probability of survival

The baseline demographic and disease characteristics were similar between the cabozantinib andplacebo 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%) hadmacroscopic vascular invasion and/ or extra-hepatic tumour spread, 41% had alfa-fetoprotein (AFP)levels ≥400μg/L, 44% had been treated by loco-regional transarterial embolisation or chemoinfusionprocedures, 37% had radiotherapy prior to cabozantinib treatment. Median duration of sorafenibtreatment was 5.32 months. Seventy-two percent (72%) of patients had received 1 and 28% hadreceived 2 prior systemic therapy regimens for advanced disease.

A statistically significant improvement in OS was demonstrated for cabozantinib 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 Placebo(N=470) (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 ofpercent 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 model3 as assessed by investigator per RECIST 1.14 stratified Cochran-Mantel-Haenszel (CMH) test

Figure 6: Kaplan-Meier curve of overall survival (CELESTIAL)1.00.90.80.70.60.50.40.30.2

CABOMETYX0.1

Placebo0.00 6 12 18 24 30 36 42

Number at risk: Months

CABOMETYX

Placebo

Figure 7: Kaplan Meier curve for progression-free survival (CELESTIAL)1.00.9 CABOMETYX0.8 Placebo0.70.60.50.40.30.20.10.00 6 12 18 24 30 36

Number at risk: Months

CABOMETYX

Placebo

The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancertherapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receivingthese therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use

Probability of Progression-Free Survival Probability of Survivalof NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan- Meier estimates formedian duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placeboarm, 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 negativeeffect of cabozantinib versus placebo on the EQ-5D utility index score was observed during the firstweeks of treatment. Only limited QoL data are available after this period.

Differentiated thyroid carcinoma (DTC)

Placebo -Controlled study in adult patients who have received prior systemic therapy and arerefractory or not eligible to radioactive iodine (COSMIC-311)

The safety and efficacy of CABOMETYX was evaluated in COSMIC-311, a randomised (2:1),double-blind, placebo-controlled, multicenter trial in adult patients with locally advanced ormetastatic disease with differentiated thyroid cancer that had progressed following up to two prior

VEGFR-targeting therapy (including, but not limited to, lenvatinib or sorafenib) and were radioactiveiodine-refractory or not eligible. Patients with measurable disease and documented radiographicprogression per RECIST 1.1 per the Investigator, during or following treatment with VEGFR-targeting TKI, were randomised (N=258) to receive cabozantinib 60 mg orally once daily (N=170) orplacebo (N=88).

Randomisation was stratified by prior receipt of lenvatinib (yes vs. no) and age (≤ 65 years vs. > 65years). Eligible patients randomised to placebo were allowed to cross-over to cabozantinib uponconfirmation of progressive disease by blinded independent radiology review committee (BIRC).

Subjects continued blinded study treatment as long as they experienced clinical benefit or until therewas unacceptable toxicity. The primary efficacy outcome measures were progression-free survival(PFS) in the ITT population, and objective response rate (ORR) in the first 100 randomised patients,as assessed by BIRC per RECIST 1.1. Tumour assessments were conducted every 8 weeks afterrandomisation during the first 12 months on study, then every 12 weeks thereafter. Overall survival(OS) was an additional endpoint.

The primary analysis of PFS included 187 randomised patients, 125 to cabozantinib and 62 toplacebo. Baseline demographics and disease characteristics were generally balanced for bothtreatment groups. The median age was 66 years (range 32 to 85 years), 51% being ≥ 65 years of age,13% being ≥ 75 years of age. The majority of patients were white (70%), 18% of patients were Asianand 55% were female. Histologically, 55% had a confirmed diagnosis of papillary thyroid carcinoma,48% had follicular thyroid carcinoma including 17% patients with Hürthle cell thyroid cancer.

Metastases were present in 95% of the patients: lungs in 68%, lymph nodes in 67%, bone in 29%,pleura in 18% and liver in 15%. Five patients had not received prior RAI due to ineligibility, 63% hadreceived prior lenvatinib, 60% had received prior sorafenib and 23% had received both sorafenib andlenvatinib. Baseline ECOG performance status was 0 (48%) or 1 (52%).

The median duration of treatment was 4.4 months in the cabozantinib arm and 2.3 months in theplacebo arm.

The results of the primary analysis (with a cut-off date of 19 August 2020 and median follow up 6.2months for the PFS), and the updated analysis (with a cut-off date of 08 February 2021 and medianfollow-up 10.1 months for the PFS) are presented in Table 9. The trial did not demonstrate astatistically significant improvement in ORR for patients randomised to cabozantinib (n=67)compared with placebo (n=33): 15% vs. 0%. The trial demonstrated a statistically significantimprovement in PFS (median follow up 6.2 months) for patients randomised to cabozantinib (n=125)compared with placebo (n=62).

An updated analysis of PFS and OS (median follow up 10.1 months) was performed including 258randomised patients, 170 to cabozantinib and 88 to placebo.

The overall survival analysis was confounded as placebo-treated subjects with confirmed diseaseprogression had the option to cross over to cabozantinib.

Table 9: Efficacy Results from COSMIC-311

Primary Analysis1 (ITT) Updated Analysis2 (Full ITT)

CABOMETYX Placebo CABOMETYX Placebo(n=125) (n=62) (n=170) (n=88)

Progression-Free

Survival*

Number of Events, (%) 31 (25) 43 (69) 62 (36) 69 (78)

Progressive Disease 25 (20) 41 (66) 50 (29) 65 (74)

Death 6 (4.8) 2 (3.2) 12 (7.1) 4 (4.5)

Median PFS in Months(96% CI) NE (5.7, NE) 1.9 (1.8, 3.6) 11.0 (7.4, 13.8) 1.9 (1.9, 3.7)

Hazard Ratio (96% CI)3 0.22 (0.13, 0.36) 0.22 (0.15, 0.32)p-value4 < 0.0001

Overall Survival

Events, n (%) 17 (14) 14 (23) 37 (22) 21 (24)

Hazard Ratio3 (95% CI) 0.54 (0.27, 1.11) 0.76 (0.45, 1.31)

Primary Analysis1

Objective responserate (ORR)5

CABOMETYX Placebo(n=67) (n=33)

Overall response, (%) 10 (15) 0 (0)

Complete response 0 0

Partial response 10 (15) 0

Stable disease 46 (69) 14 (42)

Progressive disease 4 (6) 18 (55)

* The primary analysis of PFS included censoring for new anti-cancer treatment. Results for PFS with and without censoringfor new anti-cancer treatment were consistent.

CI, confidence interval; NE, not evaluable1 The cut-off date of the primary analysis is 19 August 2020.2 The cut-off date of the secondary analysis is 08 February 2021.3 Estimated using the Cox proportional-hazard model.4 Log-rank test stratified by receipt of prior lenvatinib (yes vs. no) and age (≤ 65 years vs. > 65 years) as stratification factors(per IXRS data).5 Based on the first 100 patients included in the study with a median follow-up of 8.9 months, n=67 in CABOMETYX groupand n=33 in placebo group. The improvement in ORR was not statistically significant.

Figure 8: Kaplan-Meier Curve of Progression-Free Survival in COSMIC-311 (updated analysis[cut-off date: 08 February 2021], N=258)

CABOMETYX

Placebo

Months

Number at risk:

CABOMETYX

Placebo

The European Medicines Agency has deferred the obligation to submit the results of some studieswith CABOMETYX in one or more subsets of the paediatric population in treatment of solidmalignant tumours (see section 4.2 for information on paediatric use).

ADVL 1211

A phase 1 study (ADVL1211) of cabozantinib in paediatric patients with solid tumours has beenconducted by the Children Oncology Group (COG). Eligible patients were ≥2 years and ≤18 years. Thisstudy enrolled patients at 3 dose levels: 30 mg/m2, 40 mg/m2, and 55 mg/m2 once daily on a continuousdosing schedule (weekly dosing by BSA and rounded to the nearest 20 mg). Cabozantinib was dosedbased on body surface area (BSA) according to a dosing nomogram

The objective was to define dose limiting toxicities (DLTs), to determine the recommended phase 2dose (RP2D), to obtain preliminary pharmacokinetics data in children and to explore efficacy in solidtumours. Forty-one patients were enrolled, of whom 36 were fully evaluable. Patients had a variety ofsolid tumours: MTC (n=5), osteosarcoma (n=2), EWS (n=4), rhabdomyosarcoma (RMS) (n=2), othersoft tissue sarcoma (STS) (n=4), Wilms tumour (WT) (n=2), hepatoblastoma (n=2), HCC (n=2), RCC(n=3), central nervous system (CNS) tumours (n=9), and others (n=6).

Of the 36 subjects in the evaluable population, four subjects (11.1%) had best overall response of PRand eight subjects (22.2%) had SD (lasting at least 6 cycles). Of the 12 subjects with PR or SD greaterthan or equal to 6 cycles 10 subjects were in the cabozantinib 40 mg/m2 or 55 mg/m2 groups (sevenand three, respectively).

Based on central review, partial responses were seen in 2/5 patients with MTC, one patient with Wilmstumour, and one patient with clear cell sarcoma.

ADVL1622

ADVL1622 assessed the activity of cabozantinib in selected pediatric solid tumors. This multicenter,open label two-stage phase 2 trial included the following solid tumour strata: non-osteosarcoma strata

Probability of Progression-Free Survival(including Ewing sarcoma, rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcomas(NRSTS) and Wilms tumour), osteosarcoma stratum and rare solid tumours strata (including medullarythyroid carcinoma (MTC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC),hepatoblastoma, adrenocortical carcinoma and other solid tumours). Cabozantinib was administeredorally once daily on a continuous dosing schedule of 28-day cycles at a dose of 40 mg/m2/day(cumulative weekly dose of 280 mg/m2 using a dosing nomogram). Subjects were ≥2 and ≤30 years ofage at the time of study entry for all strata except upper age limit of ≤18 years of age for MTC, RCCand HCC.

For non-osteosarcoma and rare tumors strata the primary endpoint was the objective response rate(ORR). For the osteosarcoma stratum, a two-stage design that incorporated dual endpoints of objectiveresponse (CR + PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1criteria and treatment success as defined by SD for ≥4 months was utilized. The PK of cabozantinib inpediatric and adolescent subjects was assessed (please refer to section 5.2)

Efficacy Results Summary

At the data cutoff date (30 June 2021), 108/109 subjects had received at least one dose of cabozantinib.

Each statistical cohort in the non-osteosarcoma strata included 13 subjects. No responses were observedin these statistical cohorts. The osteosarcoma stratum included in total 29 subjects including 17 children(aged 9 to 17 years) and 12 adults (aged 18 to 22 years).

In the osteosarcoma stratum, all subjects had received prior systemic therapy A PR was observed in oneadult and one child. The Disease Control Rate (DCR) was 34.5% (95% CI: 17.9, 54.3).

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

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

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative tofasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There isno 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 formulationsfollowing a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tabletformulation compared to the capsule formulation was observed. A less than 10% difference in the

AUC was observed between cabozantinib tablet and capsule formulations.

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) wasestimated to be 212 L.

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 monohydroxysulfate, 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 inhibitionpotency 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 CYP3A4inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalysed human livermicrosomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6,

CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. Aneutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation(ie, a <20% reduction).

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthyvolunteers following oral administration of a range of doses from 20 to 140 mg, the plasma terminalhalf-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state wasestimated to be 2.48 L/hr. Within a 48-day collection period after a single dose of 14C-cabozantinib inhealthy volunteers, approximately 81% of the total administered radioactivity was recovered with54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios ofgeometric LS mean for total plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, forsubjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to140.11%), for subjects with moderate renal impairment compared to subjects with normal renalfunction. The geometric LS means for unbound plasma cabozantinib AUC0-inf was 0.2% higher forsubjects with mild renal impairment (90% CI 55.9% to 180%) and 17% higher (90% CI 65.1% to209.7%) for subjects with moderate renal impairment compared to subjects with normal renalfunction. Subjects with severe renal impairment have not been studied.

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects andcancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasmaexposure was observed amongst subjects with normal liver function (n=1425) and mild hepaticimpairment (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. Thepharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

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

Paediatrics

Data obtained from simulation performed with the population pharmacokinetic model developed inhealthy subjects as well as adult patients with different type of malignancies show that in adolescentpatients aged 12 years and older, a dose of 40 mg of cabozantinib once daily for patients < 40 kg, or adose of 60 mg once daily in patients ≥ 40 kg results in a similar plasma exposure attained in adultstreated with 60 mg of cabozantinib once daily (see section 4.2).

In the two clinical studies conducted by the COG in paediatric patients with solid tumours (ADVL1211and ADVL1622), cabozantinib was dosed based on body surface area (BSA) according to a dosingnomogram, using available 20 mg and 60 mg tablets intended for adults. Among the 55 patients, medianage was 13 years (range: 4 to 18 years). A population PK analysis was built using PK data collected inboth studies. The PK of cabozantinib was adequately described by a two-compartment model with first-order elimination and first-order absorption processes. There was no evidence that age, sex, raceethnicity and tumour type affected cabozantinib PK in children and adolescent patients. Only BSA wasfound to be a significant predictor of cabozantinib PK. No dose dependency was seen in the developedmodel across the three tested dose levels (30, 40 and 55 mg/m²). The exposures in children andadolescent subjects following an administration of a BSA-based dose of 40mg/m² are similar toexposures in adults with a fixed dose of 60mg QD.

Adverse reactions not observed in clinical trials, but seen in animals at exposure levels similar toclinical 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 GItract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observedadverse effect level (NOAEL) for these findings were below human clinical exposure levels atintended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicityassays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2transgenic 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 orin combination with malignant pheochromocytoma/complex malignant pheochromocytoma of theadrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinicalrelevance 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 theintended human therapeutic exposure.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesiswas observed in male dogs at exposure levels below human clinical exposure levels at intendedtherapeutic dose.

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

Juvenile rats (comparable to a >2 year-old paediatric population) administered cabozantinib showedincreased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductivesystem (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content anddensity, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries anddecreased haematopoiesis appeared to be transient, while effects on bone parameters and liverpigmentation were sustained. Juvenile rats (correlating to a <2- year paediatric population) showedsimilar treatment-related findings, with additional findings in male reproductive system (degenerationand/or atrophy of seminiferous tubules in testes, reduced luminal sperm in epididymis), and appearedto be more sensitive to cabozantinib-related toxicity at comparable dose levels.

Tablet content

Microcrystalline cellulose

Anhydrous lactose

Hydroxypropyl cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Hypromellose 2910

Titanium dioxide (E171)

Triacetin

Iron oxide yellow (E172)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

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

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

Ipsen Pharma70 rue Balard75015 Paris

France

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

Date of first authorisation: 09 September 2016

Date of latest renewal: 21 April 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.