Is lenvima (lenvatinib) more likely to cause hepatic failure in a patient with hepatocellular carcinoma (HCC) than the cancer itself, after 4 months of treatment?

From the Guidelines

The hepatic failure experienced by the patient after 4 months of Lenvima (lenvatinib) treatment is more likely due to the medication than the underlying hepatocellular carcinoma (HCC).

Reasons for Lenvima-Induced Hepatic Failure

• Lenvima is known to cause hepatotoxicity as a significant adverse effect, with liver failure reported in clinical trials, such as the REFLECT trial, which compared lenvatinib to sorafenib for the treatment of patients with advanced HCC 1.
• The temporal relationship between starting Lenvima and the development of hepatic failure (4 months) suggests drug-induced liver injury rather than natural cancer progression.
• While HCC can cause liver failure, this typically occurs over a longer timeframe or in very advanced disease.
• Lenvima works by inhibiting multiple tyrosine kinase receptors involved in tumor angiogenesis, but these same mechanisms can impair normal liver function and repair processes.

Evidence from Clinical Trials

• The REFLECT trial, which was powered for noninferiority, showed equal efficacy between lenvatinib and sorafenib, with median OS of 13.6 vs 12.3 months, respectively 1.
• However, the trial also reported more serious adverse events (SAEs) and a higher rate of discontinuation due to adverse events in the lenvatinib arm, which may be related to hepatotoxicity 1.

Management and Recommendations

• Management should include immediate discontinuation of Lenvima and supportive care for hepatic failure.
• Patients with pre-existing liver dysfunction from underlying cirrhosis (common in HCC patients) are particularly vulnerable to Lenvima-induced hepatotoxicity due to reduced hepatic reserve.
• Regular liver function monitoring is crucial for patients on Lenvima, as recommended by the drug's package insert.

From the FDA Drug Label

Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1. 4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0. 5% of patients. In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients.

The development of hepatic failure in a patient with hepatocellular carcinoma (HCC) after 4 months of treatment with lenvatinib (LENVIMA) is likely due to the medication rather than the cancer itself because:

• Hepatic adverse reactions have been reported in clinical studies with LENVIMA, including serious and fatal events.
• The incidence of Grade 3 to 5 hepatic failure was 3% in LENVIMA-treated patients in the REFLECT (HCC) study, which is a significant adverse reaction.
• The drug label recommends monitoring liver function prior to initiating LENVIMA and regularly during treatment, and withholding or discontinuing the medication in case of hepatic failure, indicating a potential causal relationship between the medication and hepatic adverse reactions 2.

From the Research

Hepatic Failure Due to Lenvima

The development of hepatic failure in a patient with hepatocellular carcinoma (HCC) after 4 months of lenvima treatment can be attributed to the medication rather than the cancer itself for several reasons:

• Lenvima's side effect profile: Studies have shown that lenvima can cause hepatic toxicity, leading to hepatic failure in some cases 3, 4.
• Dose and treatment duration: The patient's treatment duration and dose of lenvima may have contributed to the development of hepatic failure, as higher doses and longer treatment durations can increase the risk of hepatic toxicity 4.
• Liver function at baseline: Patients with impaired liver function at baseline, such as those with Child-Pugh class B or C liver cirrhosis, may be more susceptible to lenvima-induced hepatic toxicity 4.
• Comparison to cancer progression: While HCC can cause hepatic failure, the relatively short timeframe of 4 months suggests that lenvima may have played a role in the development of hepatic failure, rather than the cancer itself 5.

Key Findings

Some key findings from the studies include:

• Lenvima can cause hepatic toxicity, leading to hepatic failure in some cases 3, 4.
• Patients with impaired liver function at baseline may be more susceptible to lenvima-induced hepatic toxicity 4.
• The tolerability and toxicity of lenvima are similar in patients with Child-Pugh class A and class B liver cirrhosis, but patients with less impaired liver function have a better survival benefit 4.
• Lenvima has a generally manageable tolerability profile, but hepatic toxicity is a potential side effect 3.