Cabometyx Adverse Reactions

Cabozantinib as monotherapy: Summary of safety profile: The most common serious adverse drug reactions in the RCC population (≥1% incidence) are abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and palmar-plantar erythrodysaesthesia syndrome (PPES).
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, fatigue, nausea, decreased appetite, PPES, hypertension, weight decreased, vomiting, dysgeusia, constipation and AST increased. Hypertension was observed more frequently in the treatment naïve RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).
The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, decreased appetite, PPES, fatigue, nausea, hypertension and vomiting.
The most common serious adverse drug reactions in the DTC population (≥1% incidence) are diarrhoea, pulmonary embolism, dyspnoea, deep vein thrombosis, hypertension and hypocalcaemia.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the DTC population included diarrhoea, PPES, hypertension and fatigue.
Tabulated list of adverse reactions: Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC and DTC (n=1043) or reported after post-marketing use of cabozantinib are listed in Table 8. 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. (See Table 8.)

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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 PI for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, refer to the nivolumab PI.
In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n=320), with a minimum follow‑up of 16 months, the most common serious adverse drug reactions (≥1% incidence) are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting, dehydration.
The most frequent adverse reactions (≥25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decrease appetite, nausea, abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Tabulated list of adverse reactions: Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 9, 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. (See Table 9.)

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Description of selected adverse reactions: Data for the following reactions are based on patients who received CABOMETYX 60 mg orally once daily as monotherapy in pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC, in HCC following prior systemic therapy and in DTC in patient refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy or in patients who received CABOMETYX 40 mg orally once daily in combination with nivolumab in first-line advanced RCC (see Pharmacology: Pharmacodynamics under Actions).
Gastrointestinal (GI) perforation (see Precautions): In the study in RCC following prior VEGF-targeted therapy (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.
In the treatment-naïve RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.
In the HCC study (CELESTIAL), GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks.
In the DTC study (COSMIC-311), GI perforation Grade 4 was reported in one patient (0.8%) of cabozantinib-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 4 and one event was Grade 5 (fatal).
Fatal perforations have occurred in the cabozantinib clinical program.
Hepatic encephalopathy (see Precautions): 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 Precautions): In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.
In the treatment-naïve RCC study (CABOSUN), diarrhoea was reported in 73% of cabozantinib-treated patients (57/78); Grade 3-4 events in 10%.
In the HCC study (CELESTIAL), diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3-4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.
In the DTC study (COSMIC-311), diarrhoea was reported in 51% of cabozantinib-treated patients (64/125); Grade 3-4 events in 7.2%. Diarrhoea led to dose reduction and interruption in 13/125 (10%) and 20/125 (16%) of subjects respectively.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidence of diarrhoea was reported in 64.7% (207/320) of treated patients; Grade 3-4 events in 8.4% (27/320). Median time to onset of all events was 12.9 weeks. Dose delay or reduction occurred in 26.3% (84/320) and discontinuation in 2.2% (7/320) of patients with diarrhoea, respectively.
Fistulas (see Precautions): In the study in RCC following prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder were Grade 2. Median time to onset was 30.3 weeks.
In the treatment-naïve RCC study (CABOSUN), no cases of fistulas were reported.
In the HCC study (CELESTIAL), fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.
In the DTC study (COSMIC-311), no cases of fistulas were reported in cabozantinib-treated patients.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.
Fatal fistulas have occurred in the cabozantinib clinical program.
Haemorrhage (see Precautions): In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of severe haemorrhagic events (Grade ≥3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.
In the treatment-naïve RCC study (CABOSUN), the incidence of severe haemorrhagic events (Grade ≥3) was 5.1% (4/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.
In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (Grade ≥3) was 2.4% in cabozantinib-treated patients (3/125). Median time to onset was 14 weeks.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥Grade 3 haemorrhage was in 1.9% (6/320) of treated patients.
Fatal haemorrhages have occurred in the cabozantinib clinical program.
Posterior reversible encephalopathy syndrome (PRES) (see Precautions): 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 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 0-1 in 91% with median time to resolution of 2.29 weeks (range: 0.4 to 108.1 weeks).
Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either cabozantinib (n=10) or nivolumab (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥2 increased ALT or AST was observed in 4 patients receiving cabozantinib, in 3 patients receiving nivolumab and 8 patients receiving both cabozantinib and nivolumab.
Hypothyroidism: In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).
In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).
In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (3/125), all Grade 1-2, none requiring modification of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.