Introduction

Vismodegib is a kinase inhibitor active used in the therapy of unresectable or metastatic basal cell carcinoma. Vismodegib therapy is associated with a low rate or transient elevations in serum aminotransferase during therapy and has been linked to rare cases of clinically apparent acute liver injury.

Background

Vismodegib (vis” moe deg’ ib) is an orally available, kinase inhibitor with specific activity against a key step (activation of smoothened: SMO) in the hedgehog signaling pathway. Hedgehog is a key regulator of embryonic development, cell growth and differentiation. Mutations in this pathway have been identified in several malignant diseases including basal cell carcinoma. Clinical trials of vismodegib in patients with metastatic or locally advanced basal cell carcinoma reported at least partial responses in up to half of patients. Vismodegib, the first hedgehog pathway inhibitor, was approved for use in the United States in 2012. Current indications include metastatic or locally advanced, recurrent or unresectable basal cell carcinoma. Vismodegib is available in capsules of 150 mg under the brand name Erivedge. The typical dose is 150 mg once daily until disease progression or unacceptable toxicity occurs. Side effects are common and often dose limiting, although rarely life threatening. Common side effects include muscle spasms, alopecia, anorexia, dysguesia, weight loss, nausea, diarrhea, fatigue and arthralgias. Potential serious adverse events include severe weight loss, squamous cell skin cancer and embryo-fetal toxicity.

Hepatotoxicity

Most clinical trials of vismodegib included few patients and rates of liver tests abnormalities were usually not reported. The product label for vismodegib includes no mention serum enzyme elevations or hepatotoxicity. However, a subsequent review of all published studies of vismodegib mentions that liver enzyme elevations occurred in 1.4% of a total of 363 patients treated. Since its approval and more general use, reports of clinically apparent liver injury linked to vismodegib have appeared. In one report, an elderly man presented with fatigue, nausea and jaundice 41 days after starting vismodegib with a cholestatic pattern of serum enzyme elevations and rapid improvement on stopping (Case 1). In addition, review of 7 years of spontaneous adverse event reporting to the FDA revealed 94 reports of hepatotoxicity during vismodegib therapy, including 20 that were considered serious and 4 that resulted in hepatic failure. Thus, clinically apparent liver injury from vismodegib occurs, but is somewhat rare.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The cause of liver injury from vismodegib is unknown, but likely due to hypersensitivity. Vismodegib has a prolonged half-life (~19 days) and is metabolized at least in part in the liver via multiple cytochrome P450 enzymes, including CYP 3A4, 2C8, 2C9 and 2C19. While it theoretically should have several drug-drug interactions, there is little clinical data on its effects on other drugs or vice versa.

Outcome and Management

In using kinase inhibitors for treatment of cancer, monitoring of routine liver tests before starting and at intervals during therapy is warranted. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to temporary cessation. Restarting vismodegib after cessation for liver test abnormalities should be done with caution and only after the abnormalities have resolved or improved significantly. The various protein kinase inhibitors vary greatly in chemical structure and there is little evidence for cross sensitivity to the liver injury.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Case 1. Cholestatic hepatitis attributed to vismodegib therapy.

[Modified from: Ash MM, Jolly PS. Cholestatic hepatic injury associated with vismodegib, aspirin, and naproxen use: a case study and review of vismodegib safety. Int J Dermatol 2015; 54: 370-4. PubMed Citation]

A 72 year old man with multiple basal cell carcinomas developed worsening nausea, dysgeusia, anorexia, weight loss and muscle cramps followed by appearance of jaundice 5 to 6 weeks after starting vismodegib. He also had a sudden loss of voice, decreased fluid intake and melena without sore throat, fever or rash. He had no history of liver disease or alcohol abuse, and all liver tests had been normal before vismodegib therapy was begun (Table). Medications that he took chronically included tadalafil, amlodipine, and valsartan, and he had recently started naproxen and aspirin because of muscle cramps attributed to vismodegib. On presentation, he was jaundiced and had mild hepatic tenderness. Serum bilirubin was 10.7 mg/dL, ALT 525 U/L, AST 206 U/L, alkaline phosphatase 807 U/L, GGT 550 U/L and INR 1.1. He had a mild increase in serum creatinine (2.2 mg/dL), possibly due to dehydration. Vismodegib was stopped and he was admitted for evaluation and intravenous hydration. Imaging of the liver showed no evidence of gall stones or biliary obstruction. Symptoms and liver test abnormalities began to improve rapidly and two weeks later, jaundice had resolved and liver tests were minimally elevated. Six months later, routine liver tests were all within the normal range.