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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: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. 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 37% (16% 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. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX 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): PPE occurred in 45% 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.

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): 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, resume at a reduced dose. 

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. 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.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

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

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, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. 

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 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.

Indication

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

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

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