Is cabozantinib (Cometriq) associated with hepatotoxicity?

From the Guidelines

Yes, cabozantinib can cause hepatotoxicity, as evidenced by increased AST levels in 12% of patients compared to 7% in the placebo group, as reported in the 2020 study published in the Journal of Clinical Oncology 1.

Key Points to Consider

• Cabozantinib is a tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma.
• The medication has been associated with liver injury in some patients, highlighting the need for regular monitoring of liver function tests (LFTs) before and during treatment.
• Specifically, ALT, AST, and bilirubin should be checked at baseline, then every 2 weeks during the first 2 months of treatment, and monthly thereafter or as clinically indicated.
• If hepatotoxicity occurs, dosage modifications may be necessary, such as withholding cabozantinib until liver enzyme levels improve to Grade 1, then resuming at a reduced dose.
• The hepatotoxic effects of cabozantinib are thought to result from its inhibition of multiple receptor tyrosine kinases involved in tumor growth and angiogenesis, which can also affect normal hepatocyte function.
• Patients with pre-existing liver disease or hepatic impairment may be at increased risk and require closer monitoring, as suggested by the 2022 AGA clinical practice guideline on systemic therapy for hepatocellular carcinoma published in Gastroenterology 1.

Monitoring and Management

• Regular monitoring of LFTs is crucial to detect potential hepatotoxicity early.
• Dosage adjustments or temporary withholding of cabozantinib may be necessary to manage hepatotoxicity.
• Patients should be educated on the signs and symptoms of hepatotoxicity and the importance of adherence to the monitoring schedule.
• The decision to use cabozantinib should be made on a case-by-case basis, considering the potential benefits and risks, including the risk of hepatotoxicity, as outlined in the guidelines 1.

From the FDA Drug Label

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.

§ 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

Hepatotoxicity is a reported adverse reaction in patients treated with cabozantinib, as indicated by the presence of hepatotoxicity in the list of common adverse reactions.

• Key words: hepatotoxicity, liver injury, ALT increased, AST increased. The FDA drug label for cabozantinib 2 supports the answer that cabozantinib is hepatotoxic.

From the Research

Hepatotoxicity of Cabozantinib

• Cabozantinib has been associated with a higher risk of hepatotoxicity in cancer patients, as shown in a study published in 2024 3.
• The study found that patients receiving cabozantinib had a higher relative risk of all-grade and grade ≥3 elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared to those who did not receive cabozantinib.
• Another study published in 2019 found that higher cabozantinib exposure was predicted to increase the likelihood of adverse events, including hepatotoxicity, in patients with advanced hepatocellular carcinoma 4.
• However, a study published in 2022 found that cabozantinib improved overall survival and progression-free survival in patients with advanced hepatocellular carcinoma, regardless of albumin-bilirubin grade, with low rates of grade 3/4 adverse events associated with hepatic decompensation 5.
• Real-life clinical data from 2021 also showed that cabozantinib was effective and safe in patients with unresectable hepatocellular carcinoma, with most common treatment-related adverse events being fatigue, diarrhea, and anorexia, and most common treatment-related Grade 3-4 adverse events being fatigue, hand-foot skin reaction, and increased aminotransferases 6.
• A review published in 2020 highlighted the importance of patient selection and special considerations when using cabozantinib for the treatment of hepatocellular carcinoma, including previous tolerance of sorafenib, safety profile, and quality of life 7.

Key Findings

• Cabozantinib is associated with a higher risk of hepatotoxicity in cancer patients 3.
• Higher cabozantinib exposure is predicted to increase the likelihood of adverse events, including hepatotoxicity 4.
• Cabozantinib improves overall survival and progression-free survival in patients with advanced hepatocellular carcinoma, regardless of albumin-bilirubin grade 5.
• Real-life clinical data show that cabozantinib is effective and safe in patients with unresectable hepatocellular carcinoma 6.
• Patient selection and special considerations are important when using cabozantinib for the treatment of hepatocellular carcinoma 7.