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Safety data for CABOMETYX® (cabozantinib) aRCC monotherapy

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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 (ARs) 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 0% with sunitinib), constipation (vs 0% with sunitinib), and dysphonia (vs 0% with sunitinib).1

Laboratory-related Grade 3-4 ARs occurring in ≥1% of patients who received CABOMETYX in the CABOSUN Trial1¶

 

No. (%)

 

CABOMETYX (n=78)

sunitinib (n=72)

Metabolism and nutrition

  

Hyponatremia

7 (9)

6 (8)

Hypophosphatemia

7 (9)

5 (7)

Hypocalcemia

2 (3)

0

Hypomagnesemia

2 (3)

0

Hyperkalemia

1 (1)

2 (3)

Investigations

  

Increased ALT

4 (5)

0

Increased AST

2 (3)

2 (3)

Increased blood creatinine

2 (3)

2 (3)

Lymphopenia

1 (1)

4 (6)

Thrombocytopenia

1 (1)

8 (11)

Renal and urinary

  

Proteinuria

2 (3)

1 (1)

ARs were graded according to NCI–CTCAE v4.0.

Laboratory abnormalities are reported as ARs and not based on shifts in laboratory values.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
See Monotherapy Dosing & Administration

Download the CABOMETYX Treatment Management Guide

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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.
  2. Data on file. Exelixis, Inc.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

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

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thrombotic Events: CABOMETYX can cause arterial or venous thromboembolic event. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) 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; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. 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. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. 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. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4).

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

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

ADVERSE REACTIONS

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

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

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 or Moderate CYP3A4 Inducers: If coadministration with strong or moderate 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.

Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

Please see 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 adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). 

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extrapancreatic neuroendocrine tumors (epNET)​. 

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). 

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

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

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

CABOMETYX® (cabozantinib) is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). 

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extrapancreatic neuroendocrine tumors (epNET)​. 

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). 

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

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

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

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