CABOMETYX SIDE EFFECTS
- Generic Name: cabozantinib tablets
- Brand Name: Cabometyx
- Drug Class: Antineoplastic Tyrosine Kinase Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
- Hemorrhage
- Perforations and Fistulas
- Thrombotic Events
- Hypertension and Hypertensive Crisis
- Diarrhea
- Palmar-plantar Erythrodysesthesia
- Hepatotoxicity
- Adrenal Insufficiency
- Proteinuria
- Osteonecrosis of the Jaw
- Impaired Wound Healing
- Reversible Posterior Leukoencephalopathy Syndrome
- Thyroid Dysfunction
- Hypocalcemia
Clinical Trial Experience
The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to CABOMETYX: as a single agent in 409 patients with RCC enrolled in randomized, active-controlled trials (CABOSUN, METEOR), 467 patients with HCC enrolled in a randomized, placebo-controlled trial (CELESTIAL), and 125 patients with DTC enrolled in a randomized, placebo-controlled trial (COSMIC-311), and in combination with nivolumab 240 mg/m² every 2 weeks in 320 patients with RCC enrolled in a randomized, active-controlled trial (CHECKMATE-9ER).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Renal Cell Carcinoma
METEOR
The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 mg once daily and 322 patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator. The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus.
Adverse reactions which occurred in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency, were: diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia (PPE), hypertension, vomiting, weight decreased, and constipation. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of patients were hypertension, diarrhea, fatigue, PPE, hyponatremia, hypophosphatemia, hypomagnesemia, lymphopenia, anemia, hypokalemia, and increased GGT.
The dose was reduced in 60% of patients receiving CABOMETYX and in 24% of patients receiving everolimus. Twenty percent (20%) of patients received CABOMETYX 20 mg once daily as their lowest dose. The most frequent adverse reactions leading to dose reduction in patients treated with CABOMETYX were: diarrhea, PPE, fatigue, and hypertension. Adverse reactions leading to dose interruption occurred in 70% patients receiving CABOMETYX and in 59% patients receiving everolimus. Adverse reactions led to study treatment discontinuation in 10% of patients receiving CABOMETYX and in 10% of patients receiving everolimus. The most frequent adverse reactions leading to permanent discontinuation in patients treated with CABOMETYX were decreased appetite (2%) and fatigue (1%).
Table 1: Adverse Reactions Occurring in ≥ 10% Patients Who Received CABOMETYX in METEOR
| Adverse Reaction | CABOMETYX (n=331) 1 |
Everolimus (n=322) |
||
| All Grades2 | Grade 3-4 | All Grades2 | Grade 3-4 | |
| Percentage (%) of Patients | ||||
| Gastrointestinal | ||||
| Diarrhea | 74 | 11 | 28 | 2 |
| Nausea | 50 | 4 | 28 | <1 |
| Vomiting | 32 | 2 | 14 | <1 |
| Stomatitis | 22 | 2 | 24 | 2 |
| Constipation | 25 | <1 | 19 | <1 |
| Abdominal pain3 | 23 | 4 | 13 | 2 |
| Dyspepsia | 12 | <1 | 5 | 0 |
| General | ||||
| Fatigue | 56 | 9 | 47 | 7 |
| Mucosal inflammation | 19 | <1 | 23 | 3 |
| Asthenia | 19 | 4 | 16 | 2 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 46 | 3 | 34 | <1 |
| Skin and Subcutaneous Tissue | ||||
| Palmar-plantar erythrodysesthesia | 42 | 8 | 6 | <1 |
| Rash 4 | 23 | <1 | 43 | <1 |
| Dry skin | 11 | 0 | 10 | 0 |
| Vascular | ||||
| Hypertension 5 | 39 | 16 | 8 | 3 |
| Investigations | ||||
| Weight decreased | 31 | 2 | 12 | 0 |
| Nervous System | ||||
| Dysgeusia | 24 | 0 | 9 | 0 |
| Headache | 11 | <1 | 12 | <1 |
| Dizziness | 11 | 0 | 7 | 0 |
| Endocrine | ||||
| Hypothyroidism | 21 | 0 | <1 | <1 |
| Respiratory, Thoracic, and Mediastinal | ||||
| Dysphonia | 20 | <1 | 4 | 0 |
| Dyspnea | 19 | 3 | 29 | 4 |
| Cough | 18 | <1 | 33 | <1 |
| Blood and Lymphatic | ||||
| Anemia | 17 | 5 | 38 | 16 |
| Musculoskeletal and Connective Tissue | ||||
| Pain in extremity | 14 | 1 | 8 | <1 |
| Muscle spasms | 13 | 0 | 5 | 0 |
| Arthralgia | 11 | <1 | 14 | 1 |
| Renal and Urinary | ||||
| Proteinuria | 12 | 2 | 9 | <1 |
| 1 One subject randomized to everolimus received cabozantinib. 2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 3 Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower 4 Includes the following terms: rash, rash erythematous, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, genital rash, intermittent leg rash, rash on scrotum and penis, rash maculo-papular, rash pruritic, contact dermatitis, dermatitis acneiform 5 Includes the following terms: hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation |
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Other clinically important adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis cholestatic (<1%).
Table 2: Laboratory Abnormalities Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR
| Laboratory Abnormality | CABOMETYX (n=331) |
Everolimus (n=322) |
||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| Percentage (%) of Patients | ||||
| Chemistry | ||||
| Increased AST | 74 | 3 | 40 | <1 |
| Increased ALT | 68 | 3 | 32 | <1 |
| Increased creatinine | 58 | <1 | 71 | 0 |
| Increased triglycerides | 53 | 4 | 73 | 13 |
| Hypophosph atemia | 48 | 8 | 36 | 5 |
| Hyperglycemia | 37 | 2 | 59 | 8 |
| Hypoalbuminemia | 36 | 2 | 28 | <1 |
| Increased ALP | 35 | 2 | 29 | 1 |
| Hypomagnesemia | 31 | 7 | 4 | <1 |
| Hyponatremia | 30 | 8 | 26 | 6 |
| Increased GGT | 27 | 5 | 43 | 9 |
| Hematology | ||||
| Leukopenia | 35 | <1 | 31 | <1 |
| Neutropenia | 31 | 2 | 17 | <1 |
| Anemia1 | 31 | 4 | 71 | 17 |
| Lymphopenia | 25 | 7 | 39 | 12 |
| Thrombocytopenia | 25 | <1 | 27 | <1 |
| ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase. NCI CTCAE, Version 4.0 1 Based on laboratory abnormalities |
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CABOSUN
The safety of CABOMETYX was evaluated in CABOSUN, a randomized, open-label trial in patients with advanced renal cell carcinoma, in which 78 patients received CABOMETYX 60 mg once daily and 72 patients received sunitinib 50 mg once daily (4 weeks on treatment followed by 2 weeks off), until disease progression or unacceptable toxicity. The median duration of treatment was 6.5 months (range 0.2 – 28.7) for patients receiving CABOMETYX and 3.1 months (range 0.2 – 25.5) for patients receiving sunitinib.
Within 30 days of treatment, there were 4 deaths in patients treated with CABOMETYX and 6 deaths in patients treated with sunitinib. Of the 4 patients treated with CABOMETYX, 2 patients died due to gastrointestinal perforation, 1 patient had acute renal failure, and 1 patient died due to clinical deterioration. All Grade 3-4 adverse reactions were collected in the entire safety population. The most frequent Grade 3-4 adverse reactions (≥5%) in patients treated with CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope.
The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced in 46% of patients receiving CABOMETYX and in 35% of patients receiving sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in 71% of patients receiving sunitinib. Based on patient disposition, 21% of patients receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to an adverse reaction.
Table 3: Grade 3-4 Adverse Reactions Occurring in ≥ 1% Patients Who Received CABOMETYX in CABOSUN
| Adverse Reaction | CABOMETYX (n = 78) |
Sunitinib (n = 72) |
| Grade 3-41 | Grade 3-41 | |
| Percentage (%) of Patients | ||
| Patients with any Grade 3-4 Adverse Reaction | 68 | 65 |
| Gastrointestinal | ||
| Diarrhea | 10 | 11 |
| Stomatitis | 5 | 6 |
| Nausea | 3 | 4 |
| Vomiting | 1 | 3 |
| Constipation | 1 | 0 |
| General | ||
| Fatigue | 6 | 17 |
| Pain | 5 | 0 |
| Metabolism and Nutrition | ||
| Hyponatremia2 | 9 | 8 |
| Hypophosphatemia2 | 9 | 7 |
| Decreased appetite | 5 | 1 |
| Dehydration | 4 | 1 |
| Hypocalcemia2 | 3 | 0 |
| Hypomagnesemia2 | 3 | 0 |
| Hyperkalemia2 | 1 | 3 |
| Skin and Subcutaneous Tissue | ||
| Palmar-plantar erythrodysesthesia | 8 | 4 |
| Skin ulcer | 3 | 0 |
| Vascular | ||
| Hypertension3 | 28 | 21 |
| Hypotension | 5 | 1 |
| Angiopathy | 1 | 1 |
| Investigations | ||
| Increased ALT2 | 5 | 0 |
| Weight decreased | 4 | 0 |
| Increased AST 2 | 3 | 3 |
| Increased blood creatinine 2 | 3 | 3 |
| Lymphopenia 2 | 1 | 6 |
| Thrombocytopenia 2 | 1 | 11 |
| Nervous System | ||
| Syncope | 5 | 0 |
| Respiratory, Thoracic, and Mediastinal | ||
| Dyspnea | 1 | 6 |
| Dysphonia | 1 | 0 |
| Blood and Lymphatic | ||
| Anemia | 1 | 3 |
| Psychiatric | ||
| Depression | 4 | 0 |
| Confusional state | 1 | 1 |
| Infections | ||
| Lung infection | 4 | 0 |
| Musculoskeletal and Connective Tissue | ||
| Back pain | 4 | 0 |
| Bone pain | 3 | 1 |
| Pain in extremity | 3 | 0 |
| Arthralgia | 1 | 0 |
| Renal and Urinary | ||
| Renal failure acute | 4 | 1 |
| Proteinuria | 3 | 1 |
| ALT, alanine aminotransferase; AST, aspartate aminotransferase 1 NCI CTCAE Version 4.0 2 Laboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values 3 Includes the following term: hypertension |
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CHECKMATE-9ER
The safety of CABOMETYX with nivolumab was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received CABOMETYX 40 mg orally once daily with nivolumab 240 mg over 30 minutes every 2 weeks (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320). CABOMETYX could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in CABOMETYX and nivolumab-treated patients. In this trial, 82% of patients in the CABOMETYX and nivolumab arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 48% of patients receiving CABOMETYX and nivolumab. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either CABOMETYX or nivolumab occurred in 20% of patients: 8% CABOMETYX only, 7% nivolumab only, and 6% both drugs due to the same adverse reaction at the same time. Adverse reactions leading to dose interruption or reduction of either CABOMETYX or nivolumab occurred in 83% of patients: 46% CABOMETYX only, 3% nivolumab only, and 21% both drugs due to the same adverse reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ≥20% of patients treated with CABOMETYX and nivolumab were diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Table 4: Adverse Reactions in >15% of Patients Receiving CABOMETYX and Nivolumab – CHECKMATE-9ER
| Adverse Reaction | CABOMETYX and Nivolumab (n=320) |
Sunitinib (n=320) |
||
| Grades 1-4 | Grades 3-4 | Grades 1-4 | Grades 3-4 | |
| Percentage (%) of Patients | ||||
| Gastrointestinal | ||||
| Diarrhea | 64 | 7 | 47 | 4.4 |
| Nausea | 27 | 0.6 | 31 | 0.3 |
| Abdominal paina | 22 | 1.9 | 15 | 0.3 |
| Vomiting | 17 | 1.9 | 21 | 0.3 |
| Dyspepsiab | 15 | 0 | 22 | 0.3 |
| General | ||||
| Fatiguec | 51 | 8 | 50 | 8 |
| Hepatobiliary | ||||
| Hepatotoxicityd | 44 | 11 | 26 | 5 |
| Skin and Subcutaneous Tissue | ||||
| Palmar-plantar erythrodysesthesia | 40 | 8 | 41 | 8 |
| Stomatitise | 37 | 3.4 | 46 | 4.4 |
| Rashf | 36 | 3.1 | 14 | 0 |
| Pruritus | 19 | 0.3 | 4.4 | 0 |
| Vascular | ||||
| Hypertensiong | 36 | 13 | 39 | 14 |
| Endocrine | ||||
| Hypothyroidismh | 34 | 0.3 | 30 | 0.3 |
| Musculoskeletal and Connective Tissue | ||||
| Musculoskeletal paini | 33 | 3.8 | 29 | 3.1 |
| Arthralgia | 18 | 0.3 | 9 | 0.3 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 28 | 1.9 | 20 | 1.3 |
| Nervous System Disorders | ||||
| Dysgeusia | 24 | 0 | 22 | 0 |
| Headache | 16 | 0 | 12 | 0.6 |
| Respiratory, Thoracic and Mediastinal | ||||
| Coughj | 20 | 0.3 | 17 | 0 |
| Dysphonia | 17 | 0.3 | 3.4 | 0 |
| Infections and Infestations | ||||
| Upper respiratory tract infectionk | 20 | 0.3 | 8 | 0.3 |
| Toxicity was graded per NCI CTCAE v4. a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b Includes gastroesophageal reflux disease. c Includes asthenia. d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. e Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes blood pressure increased, blood pressure systolic increased. h Includes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, rhinitis. |
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Table 5: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients Receiving CABOMETYX and Nivolumab – CHECKMATE-9ER
| Laboratory Abnormality | CABOMETYX and Nivolumab | Sunitinib | ||
| Grades 1-4 | Grades 3-4 | Grades 1-4 | Grades 3-4 | |
| Percentage (%) of Patients | ||||
| Chemistry | ||||
| Increased ALT | 79 | 9.8 | 39 | 3.5 |
| Increased AST | 77 | 7.9 | 57 | 2.6 |
| Hypophosphatemia | 69 | 28 | 48 | 10 |
| Hypocalcemia | 54 | 1.9 | 24 | 0.6 |
| Hypomagnesemia | 47 | 1.3 | 25 | 0.3 |
| Hyperglycemia | 44 | 3.5 | 44 | 1.7 |
| Hyponatremia | 43 | 11 | 36 | 12 |
| Increased lipase | 41 | 14 | 38 | 13 |
| Increased amylase | 41 | 10 | 28 | 6 |
| Increased alkaline phosphatase | 41 | 2.8 | 37 | 1.6 |
| Increased creatinine | 39 | 1.3 | 42 | 0.6 |
| Hyperkalemia | 35 | 4.7 | 27 | 1 |
| Hypoglycemia | 26 | 0.8 | 14 | 0.4 |
| Hematology | ||||
| Lymphopenia | 42 | 6.6 | 45 | 10 |
| Thrombocytopenia | 41 | 0.3 | 70 | 9.7 |
| Anemia | 37 | 2.5 | 61 | 4.8 |
| Leukopenia | 37 | 0.3 | 66 | 5.1 |
| Neutropenia | 35 | 3.2 | 67 | 12 |
| a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: CABOMETYX and nivolumab group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). | ||||
Hepatocellular Carcinoma
The safety of CABOMETYX was evaluated in CELESTIAL, a randomized, double-blind, placebo-controlled trial in which 704 patients with advanced hepatocellular carcinoma were randomized to receive CABOMETYX 60 mg orally once daily (n=467) or placebo (n=237) until disease progression or unacceptable toxicity. The median duration of treatment was 3.8 months (range 0.1 – 37.3) for patients receiving CABOMETYX and 2.0 months (range 0.0 – 27.2) for patients receiving placebo. The population exposed to CABOMETYX was 81% male, 56% White, and had a median age of 64 years.
Adverse reactions occurring in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, decreased appetite, PPE, fatigue, nausea, hypertension, and vomiting. Grade 3-4 adverse reactions which occurred in ≥ 5% of patients were PPE, hypertension, fatigue, diarrhea, asthenia, and decreased appetite. There were 6 adverse reactions leading to death in patients receiving CABOMETYX (hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, upper gastrointestinal hemorrhage).
The median average daily dose was 35.8 mg for CABOMETYX. The dose was reduced in 62% of patients receiving CABOMETYX; 33% of patients required a reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leading to dose reduction of CABOMETYX were: PPE, diarrhea, fatigue, hypertension, and increased AST. Adverse reactions leading to dose interruption occurred in 84% patients receiving CABOMETYX. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 16% of patients. The most frequent adverse reactions leading to permanent discontinuation of CABOMETYX were PPE (2%), fatigue (2%), decreased appetite (1%), diarrhea (1%), and nausea (1%).
Table 6: Adverse Reactions Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL1
| Adverse Reaction | CABOMETYX (n = 467) |
Placebo (n =237) |
||
| All Grades2 | Grade 3-4 | All Grades2 | Grade 3-4 | |
| Percentage (%) of Patients | ||||
| Gastrointestinal | ||||
| Diarrhea | 54 | 10 | 19 | 2 |
| Nausea | 31 | 2 | 18 | 2 |
| Vomiting | 26 | <1 | 12 | 3 |
| Stomatitis | 13 | 2 | 2 | 0 |
| Dyspepsia | 10 | 0 | 3 | 0 |
| General | ||||
| Fatigue | 45 | 10 | 30 | 4 |
| Asthenia | 22 | 7 | 8 | 2 |
| Mucosal inflammation | 14 | 2 | 2 | <1 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 48 | 6 | 18 | <1 |
| Skin and Subcutaneous Tissue | ||||
| Palmar-plantar erythrodysesthesia | 46 | 17 | 5 | 0 |
| Rash3 | 21 | 2 | 9 | <1 |
| Vascular | ||||
| Hypertension4 | 30 | 16 | 6 | 2 |
| Investigations | ||||
| Weight decreased | 17 | 1 | 6 | 0 |
| Nervous System | ||||
| Dysgeusia | 12 | 0 | 2 | 0 |
| Endocrine | ||||
| Hypothyroidism | 8 | <1 | <1 | 0 |
| Respiratory, Thoracic, and Mediastinal | ||||
| Dysphonia | 19 | 1 | 2 | 0 |
| Dyspnea | 12 | 3 | 10 | <1 |
| Musculoskeletal and Connective Tissue | ||||
| Pain in extremity | 9 | <1 | 4 | 1 |
| Muscle spasms | 8 | <1 | 2 | 0 |
| 1 Includes terms with a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4) 2 NCI CTCAE Version 4.0 3 Includes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected 4 Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased |
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Table 7: Laboratory Abnormalities Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL1
| Laboratory Abnormality | CABOMETYX N=467 |
Placebo N=237 |
||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| Percentage of Patients | ||||
| Chemistry | ||||
| Increased LDH | 84 | 9 | 29 | 2 |
| Increased ALT | 73 | 12 | 37 | 6 |
| Increased AST | 73 | 24 | 46 | 19 |
| Hypoalbuminemia | 51 | 1 | 32 | 1 |
| Increased ALP | 43 | 8 | 38 | 6 |
| Hypophosphatemia | 25 | 9 | 8 | 4 |
| Hypokalemia | 23 | 6 | 6 | 1 |
| Hypomagnesemia | 22 | 3 | 3 | 0 |
| Increased amylase | 16 | 2 | 9 | 2 |
| Hypocalcemia | 8 | 2 | 0 | 0 |
| Hematology | ||||
| Decreased platelets | 54 | 10 | 16 | 1 |
| Neutropenia | 43 | 7 | 8 | 1 |
| Increased hemoglobin | 8 | 0 | 1 | 0 |
| 1 Includes laboratory abnormalities with a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4) ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, blood lactate dehydrogenase | ||||
Differentiated Thyroid Cancer
The safety of CABOMETYX was evaluated in COSMIC-311, a randomized, double-blind, placebo-controlled trial in which 187 patients with advanced differentiated thyroid cancer were randomized to receive CABOMETYX 60 mg orally once daily (n=125) or placebo (n=62) with supportive care until disease progression or unacceptable toxicity. At the time of the primary efficacy analysis, the median duration of treatment was 4.4 months (range 0.0 – 15.7) for patients receiving CABOMETYX and 2.3 months (range 0.3 – 11.6) for patients receiving placebo. The median age was 66 years (range 32 to 85 years), 55% were female, 70% were White, 18% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib.
Adverse reactions occurring in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, PPE, fatigue, hypertension, and stomatitis. Grade 3-4 adverse reactions which occurred in ≥ 5% of patients were PPE, hypertension, fatigue, diarrhea, and stomatitis. Serious adverse reactions occurred in 34% of patients who received CABOMETYX. Serious adverse reactions in ≥2% included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal adverse reactions occurred in 1.6% of patients in the CABOMETYX arm, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%).
The median average daily dose was 42.0 mg for CABOMETYX. The dose was reduced in 56% of patients receiving CABOMETYX; 22% of patients required a second dose reduction. The most frequent adverse reactions (≥5%) leading to dose reduction of CABOMETYX were PPE, diarrhea, fatigue, proteinuria, and decreased appetite. Dose interruptions occurred in 72% patients receiving CABOMETYX. Adverse reactions requiring dosage interruption in ≥5% of patients were PPE, diarrhea, dyspnea, hypertension, decreased appetite and proteinuria. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 5% of patients.
Table 8: Adverse Reactions Occurring in ≥ 5% of CABOMETYX-Treated Patients in COSMIC-3111
| Adverse Reaction | CABOMETYX (N=125) |
Placebo (N=62) |
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| All Grades2 | Grade 3-4 | All Grades2 | Grade 3-4 | |
| Percentage of Patients | ||||
| Gastrointestinal | ||||
| Diarrhea | 51 | 7 | 3 | 0 |
| Nausea | 24 | 3 | 2 | 0 |
| Vomiting | 14 | 1 | 8 | 0 |
| Stomatitis3 | 26 | 5 | 3 | 0 |
| Dry mouth | 10 | 1 | 2 | 0 |
| General | ||||
| Fatigue4 | 42 | 10 | 23 | 0 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 23 | 3 | 16 | 0 |
| Skin and Subcutaneous Tissue | ||||
| Palmar-plantar erythrodysesthesia | 46 | 10 | 0 | 0 |
| Vascular | ||||
| Hypertension5 | 30 | 10 | 5 | 3 |
| Investigations | ||||
| Weight decreased | 18 | 1 | 5 | 0 |
| Nervous System | ||||
| Dysgeusia | 10 | 0 | 0 | 0 |
| Headache | 10 | 2 | 2 | 0 |
| Respiratory, Thoracic, and Mediastinal | ||||
| Dysphonia | 10 | 0 | 2 | 0 |
| Pulmonary embolism | 5 | 2 | 0 | 0 |
| Renal and Urinary | ||||
| Proteinuria | 15 | 1 | 3 | 0 |
| 1 Includes terms that are more frequent in the CABOMETYX arm and have a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4) 2 NCI CTCAE Version 5.0 3 Includes the following terms: mucosal inflammation, stomatitis 4 Includes the following terms: fatigue, asthenia 5 Includes the following terms: hypertension, blood pressure increased, hypertensive crisis |
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Table 9: Laboratory Abnormalities Occurring in ≥ 10% of CABOMETYX-Treated Patients in COSMIC-3111
| Laboratory Abnormality | CABOMETYX N=125 |
Placebo N=62 |
||
| All Grades | Grade 3 or 4 | All Grades | Grade 3 or 4 | |
| Percentageof Patients | ||||
| Chemistry | ||||
| LDH increased2 | 90 | 10 | 32 | 3 |
| AST increased | 77 | 1 | 18 | 0 |
| ALT increased | 66 | 2 | 11 | 0 |
| Hypocalcemia | 36 | 9 | 10 | 2 |
| ALP increased | 34 | 0 | 15 | 0 |
| GGT increased | 26 | 2 | 21 | 2 |
| Hypomagnesemia | 25 | 2 | 5 | 0 |
| Hypoalbuminemia | 19 | 1 | 7 | 0 |
| Hypokalemia | 18 | 1 | 3 | 0 |
| Hyponatremia | 15 | 0 | 10 | 2 |
| Hyperbilirubinemia | 12 | 0 | 5 | 0 |
| Hematology | ||||
| Leukocytes decreased | 38 | 2 | 7 | 2 |
| Neutrophils decreased | 31 | 2 | 5 | 2 |
| Platelets decreased | 26 | 0 | 5 | 0 |
| 1 Includes laboratory abnormalities that are more frequent in the CABOMETYX arm and have a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4) 2 Sponsor-defined grades for LDH were as follows: Grade 1 (> ULN to ≤ 2 x ULN), Grade 2 (> 2 x ULN to ≤ 3 x ULN), Grade 3 (> 3 x ULN). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; LDH, blood lactate dehydrogenase |
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Postmarketing Experience
The following adverse reactions have been identified during postapproval use of CABOMETYX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Vascular Disorders
Arterial (including aortic) aneurysms, dissections, and rupture
SRC: NLM .