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Monotherapy Safety

No new safety signals observed between METEOR and CABOSUN trials1

The CABOSUN safety profile for 1L aRCC was generally consistent with that of the initial CABOMETYX product approval, which was supported by results from the METEOR trial.

Adverse Reactions Occurring in ≥10% of Patients in the CABOMETYX Arm of the METEOR Trial1

    Percentage (%) of Patients
  CABOMETYX (n=331)* everolimus (n=322)
All Grades Grade 3-4 All Grades Grade 3-4
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 pain 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 23 <1 43 <1
Dry skin 11 0 10 0
Vascular        
Hypertension 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
*

One subject randomized to everolimus received CABOMETYX

NCI-CTCAE v4.0.1

These ARs are grouped terms. For details, please see full Prescribing Information.1


Laboratory Abnormalities Occurring in ≥25% of Patients in the CABOMETYX Arm of the METEOR Trial1

    Percentage (%) of Patients
  CABOMETYX (n=331) everolimus (n=322)
All Grades Grade 3-4 All Grades Grade 3-4
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
Hypophosphatemia 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
Anemia§ 31 4 71 17
Lymphopenia 25 7 39 12
Thrombocytopenia 25 <1 27 <1
§

Based on laboratory abnormalities.1


Grade 3-4 Adverse Reactions (ARs) Occurring in >1% of Patients Who Received CABOMETYX in the CABOSUN Trial1||

  No. (%)
  CABOMETYX (n=78) sunitinib (n=72)
PATIENTS WITH ANY GRADE 3-4 AR 53 (68) 47 (65)
Gastrointestinal    
Diarrhea 8 (10) 8 (11)
Stomatitis 4 (5) 4 (6)
Nausea 2 (3) 3 (4)
General    
Fatigue 5 (6) 12 (17)
Pain 4 (5) 0
Metabolism and Nutrition    
Decreased appetite 4 (5) 1 (1)
Dehydration 3 (4) 1 (1)
Skin and Subcutaneous Tissue    
PPE 6 (8) 3 (4)
Skin ulcer 2 (3) 0
Vascular    
Hypertension 22 (28) 15 (21)
Hypotension 4 (5) 1 (1)
Investigations    
Weight decreased 3 (4) 0
Nervous System    
Syncope 4 (5) 0
Psychiatric    
Depression 3 (4) 0
Infections    
Lung infection 3 (4) 0
Musculoskeletal and Connective Tissue    
Back pain 3 (4) 0
Bone pain 2 (3) 1 (1)
Pain in extremity 2 (3) 0
Renal and Urinary    
Renal failure acute 3 (4) 1 (1)
||

National Center Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0)

  • The following Grade 3-4 ARs were seen in 1% of patients receiving CABOMETYX: dyspnea (vs 6% with sunitinib), anemia (vs 3% with sunitinib, vomiting (vs 3% with sunitinib), angiopathy (vs 1% with sunitinib), confusional state (vs 1% with sunitinib), arthralgia (vs )% with sunitinib), constipation (vs 0% with sunitinib), and dysphonia (vs 0% with sunitinib).1


The overall efficacy results in the METEOR and CABOSUN trials were achieved in the context of dose modifications

  2L
(METEOR)
vs everolimus
1L
(CABOSUN)
vs sunitinib
Dose withholds 70%
59%
73%
71%
Median duration of each dose withhold 7 days NA
Dose reductions 60%
24%
46%
35%
Discontinuations 10%
10%
21%
22%
Mean average daily dose2 45 mg 49 mg

Download the CABOMETYX Treatment Management Guide


1L=first-line; 2L=second-line; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AR=adverse reaction; aRCC=advanced renal cell carcinoma; AST=aspartate aminotransferase; GGT=gamma-glutamyl transferase; NA=not available; NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PPE=palmar-plantar erythrodysesthesia; RCC=renal cell carcinoma.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2021.
  2. Data on file. Exelixis, Inc.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

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

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

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

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.