From the FDA Drug Label
A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2. 4% were Grade 3. KRAS inhibitors, such as LUMAKRAS, can cause hyperbilirubinemia.
- The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0,29) 1.
- Hyperbilirubinemia leading to dose interruption occurred in 1. 6% of patients. Monitoring of liver function tests, including total bilirubin, is recommended prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated 1.
From the Research
Yes, some KRAS inhibitors can cause hyperbilirubinemia as a side effect, specifically sotorasib and adagrasib, which are FDA-approved KRAS G12C inhibitors, have been associated with elevated bilirubin levels in clinical trials, with approximately 5% of patients experiencing grade 3 or higher hyperbilirubinemia with sotorasib, as reported in a study published in 2024 2. The mechanism behind the hyperbilirubinemia appears to be related to the inhibition of hepatic transporters responsible for bilirubin clearance, rather than direct hepatocellular injury. Some key points to consider when using KRAS inhibitors include:
- Monitoring liver function tests before and during treatment with these agents
- Dose reduction or temporary discontinuation may be necessary if a patient develops significant hyperbilirubinemia, according to the severity
- The hyperbilirubinemia is typically reversible upon dose modification or discontinuation of the medication
- Patients should be educated about potential symptoms of liver dysfunction, including yellowing of the skin or eyes, dark urine, or light-colored stools It's also worth noting that different KRAS inhibitors may have different safety profiles, as seen in a study comparing sotorasib and adagrasib, where adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with checkpoint inhibitors either sequentially or concurrently, as reported in a study published in 2024 2. Additionally, other studies have reported similar findings, with divarasib being 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib, and having a manageable toxicity profile, as reported in a study published in 2024 3. However, the most recent and highest quality study, published in 2024 2, provides the most relevant information on the safety profile of KRAS inhibitors, and clinicians should prioritize this study when making decisions about the use of these agents.