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Child-Pugh B: Retrospective exploratory subgroup analysis

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OS and PFS were assessed in CELESTIAL patients who progressed from Child-Pugh A to Child-Pugh B status by week 81,2

*

The observed outcomes should be interpreted with caution because of the relatively small size of the Child-Pugh B subgroup.2 No statistical procedure was employed for controlling type I error. Results should be hypothesis generating.3

†

At the time of the first Child-Pugh assessment at Week 8 after randomization by the investigator, 51/470 patients in the CABOMETYX arm and 22/237 patients in the placebo arm had Child-Pugh B cirrhosis (ie, Child-Pugh B subgroup). Available values for the central laboratory-determined Child-Pugh B score points included Child-Pugh B7 (n=26 CABOMETYX arm, 11 placebo), B8 (11 CABOMETYX arm, 3 placebo), and B9 (3 CABOMETYX arm, 5 placebo).2 Child-Pugh grading was investigator assessed and scoring was by Exelixis, Inc. (study sponsor); some discrepancies between grading and scoring results existed.

Select safety results in the Child-Pugh B subgroup2

 

Patients (%)
 

CABOMETYX
(n=51)

Placebo
(n=22)

All Grades

Grade 3-4

All Grades

Grade 3-4

All-causality AR

        

Any reaction

51 (100)

36 (71)

22 (100)

13 (59)

Fatigue

29 (57)

10 (20)

9 (41)

4 (18)

Ascites

17 (33)

7 (14)

12 (55)

5 (23)

AST increased

11 (22)

7 (14)

2 (9.1)

1 (4.5)

Thrombocytopenia

11 (22)

6 (12)

0 (0)

0 (0)

Anemia

6 (12)

5 (9.8)

5 (23)

4 (18)

Blood bilirubin increased

11 (22)

5 (9.8)

3 (14)

0 (0)

Dyspnea

10 (20)

5 (9.8)

7 (32)

0 (0)

Blood ALP increased

4 (7.8)

4 (7.8)

0 (0)

0 (0)

Hypertension

9 (18)

4 (7.8)

0 (0)

0 (0)

PPE

15 (29)

4 (7.8)

1 (4.5)

0 (0)

Platelet count decreased

6 (12)

4 (7.8)

0 (0)

0 (0)

Portal vein thrombosis

4 (7.8)

4 (7.8)

0 (0)

0 (0)

Pulmonary embolism

4 (7.8)

4 (7.8)

0 (0)

0 (0)

Asthenia

12 (24)

3 (5.9)

3 (14)

0 (0)

Decreased appetite

30 (59)

3 (5.9)

5 (23)

0 (0)

Diarrhea

24 (47)

3 (5.9)

6 (27)

1 (4.5)

General physical health deterioration

5 (9.8)

3 (5.9)

2 (9.1)

2 (9.1)

Hepatic encephalopathy

4 (7.8)

3 (5.9)

0 (0)

0 (0)

Hyperbilirubinemia

4 (7.8)

3 (5.9)

1 (4.5)

0 (0)

Nausea

23 (45)

3 (5.9)

6 (27)

0 (0)

Pain

3 (5.9)

3 (5.9)

0 (0)

0 (0)

Pneumonia

4 (7.8)

3 (5.9)

1 (4.5)

0 (0)

Abdominal pain

11 (22)

2 (3.9)

10 (45)

3 (14)

Hepatic failure

3 (5.9)

1 (2.0)

3 (14)

3 (14)

Sepsis

1 (2.0)

1 (2.0)

2 (9.1)

2 (9.1)

Additional reactions of interest

        

ALT increased

7 (14)

2 (3.9)

1 (4.5)

0 (0)

Hyponatremia

5 (9.8)

2 (3.9)

0 (0)

0 (0)

Neutrophil count decreased

2 (3.9)

1 (2.0)

0 (0)

0 (0)

Hypoalbuminemia

17 (33)

1 (2.0)

2 (9.1)

0 (0)

Chronic hepatic failure

0 (0)

0 (0)

1 (4.5)

0 (0)

61%
of Child-Pugh B patients

Dose reductions with CABOMETYX2,3
(14% with placebo)

18%
of Child-Pugh B patients

Discontinuations with CABOMETYX due to treatment-related ARs2
(5% with placebo)

Patients who progressed to Child-Pugh B received a median average daily dose of 37 mg2

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ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CI=confidence interval; HR=hazard ratio; OS=overall survival; PFS=progression-free survival; PPE=palmar-plantar erythrodysesthesia.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  2. El-Khoueiry AB, Meyer T, Cheng AL, et al. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child–Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomized controlled trial. BMC Cancer. 2022;22(1):377.
  3. 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.

Thromboembolic Events: CABOMETYX can cause arterial or venous thromboembolic events. 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.

Cardiac Failure: CABOMETYX can cause severe and fatal cardiac failure. Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue depending on the severity.

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, 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® (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 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, 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® (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 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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