Cabozantinib

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.

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.

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

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.

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.

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.

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.

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.

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.

There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients.

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

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

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.

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.

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects. 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.

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.

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.

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. Both men and women should be 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 as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

Cabozantinib as monotherapy

Summary of safety profile

The most common serious adverse drug reactions in the RCC population (≥1% incidence) are pneumonia, 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 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 common serious adverse drug reactions in the DTC population (≥1% incidence) are diarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep vein thrombosis, hypocalcaemia, osteonecrosis of jaw, pain, PPES, vomiting and renal impairment.

The most common serious adverse drug reactions in the NET population (≥1% incidence) are hypertension, fatigue, pulmonary embolism, vomiting, diarrhoea, nausea and embolism.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC, HCC, DTC and NET populations were diarrhoea, fatigue, nausea, decreased appetite, PPES and hypertension.

Tabulated list of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC, DTC and NET (n=1355) or reported after post-marketing use of cabozantinib are listed in Table 1. 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 1. Adverse drug reactions (ADRs) reported in clinical trials or after post-marketing use in patients treated with cabozantinib in monotherapy:

^* See section Description of selected adverse reactions for further characterisation.
^a including polyneuropathy; peripheral neuropathy is mainly sensory
^b Including epistaxis as the most commonly reported adverse reaction
^c All venous thrombosis including deep vein thrombosis
^d Based on reported adverse reactions
^e Impaired healing, incision site complication and wound dehiscence
^f Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption.
^g Fatal cases have been reported.

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, hyponatraemia, 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 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 reactions with cabozantinib in combination with nivolumab:

Adverse reaction frequencies presented in Table 2 may not be fully attributable to cabozantinib alone but may contain contributions from the underlying disease or from nivolumab used in a combination.
^a Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb
^b Fatal cases have been reported
^c With prior or concomitant immune checkpoint inhibitor exposure
^d Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption
^e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain
^f Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements with the exception of weight decreased, blood cholesterol increased and hypertriglyceridaemia

Description of selected adverse reactions

Data for the following reactions are based on patients who received cabozantinib 60 mg orally once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC, in HCC following prior systemic therapy, in DTC in patient refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy, in progressive NET following prior systemic therapy or in patients who received cabozantinib 40 mg orally once daily in combination with nivolumab in first-line advanced RCC.

Gastrointestinal (GI) perforation

In the RCC study (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.

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

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

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

In the NET study (CABINET), GI perforations were reported in 1.3% of cabozantinib-treated patients (3/227). Events were Grade 3, 4 and 5. Median time to onset was 21.6 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

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. In the NET study (CABINET), hepatic encephalopathy was reported in 0.9% of cabozantinib-treated patients (2/227); There was one Grade 3 event (0.4%) for which median time to onset was 14.3 weeks.

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR, CABOSUN and CA2099ER) and in the DTC study (COSMIC-311).

Diarrhoea

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

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

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

In 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 the NET study (CABINET), diarrhoea was reported in 63% of cabozantinib treated patients (144/227); Grade 3 events in 8.4%, no Grade 4 events. Median time to onset of Grade 3 events was 5.1 weeks.

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

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

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

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

In 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 the NET study (CABINET), fistulas (two anal and one biliary fistula) were reported in 1.3% (3/227) of the cabozantinib treated patients. Anal fistula events were Grade 1 and 3, biliary fistula was Grade 2. Median time to onset was 19.3 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

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

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

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

In 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 11.5 weeks.

In the NET study (CABINET), the incidence of severe haemorrhagic events (grade ≥3) was 1.8% in cabozantinib-treated patients (4/227). Median time to onset was 14.1 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)

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 in one patient in the NET study (CABINET). PRES has been rarely reported 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 2.3 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 RCC study (METEOR), the incidence of hypothyroidism was 21% (68/331).

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

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

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

In the NET study (CABINET), the incidence of hypothyroidism was 26% (59/227) in cabozantinib-treated patients, all grade 1-2.

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

Paediatric population

In study ADVL1211, a limited dose-escalation study of cabozantinib in paediatric and adolescent patients with recurrent or refractory solid tumours including CNS tumours, 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%), neutrophil count decreased (very common, 35.9%), and lipase increased (very common, 33.3%) were observed at 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 as grade ¾ of these ADRs. The adverse events reported are in line qualitatively with the recognised safety profile for cabozantinib in adult populations. However, the small numbers of subjects preclude a conclusive assessment of trends and frequencies and further comparison with the recognised safety profile of cabozantinib.

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

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