S5732 Dabrafenib/Trametinib-Induced Immune-Related Cholangiopathy Managed With Systemic Corticosteroids and Tocilizumab

Introduction: BRAF and MEK inhibitors, such as dabrafenib and trametinib, offer effective treatment response and improved survival for BRAF V600E-mutant melanoma. These agents are associated with adverse effects, including transient elevations in liver function tests, predominantly in a hepatocellular pattern. However, biliary involvement is a rare but serious complication that can pose diagnostic and management challenges. We present a case of immune-related cholestatic liver injury associated with dabrafenib/trametinib therapy, successfully treated with systemic corticosteroids and tocilizumab. Case Description/Methods: A 65-year-old woman with BRAF V600E-mutant metastatic melanoma, previously treated with resection, radiation, and targeted therapy, presented with fevers and worsening liver function tests one week after restarting dabrafenib/trametinib. Serum studies were characteristic of cholestatic liver injury with aspartate aminotransferase 150 U/L, alanine aminotransferase 140 U/L, ALP 1547 U/L and total bilirubin 1.9 mg/dL. MRCP demonstrated gallbladder wall thickening and pericholecystic fluid, without ductal dilatation, raising concern for acute cholecystitis. However, a normal hepatobiliary scan and negative Murphy’s sign argued against this diagnosis. Despite initiation of empiric antibiotics, liver function tests continued to worsen, raising suspicion for drug-induced cholangiopathy. A liver biopsy was performed and histopathology revealed portal expansion with mixed inflammatory infiltrate consisting of lymphocytes, plasma cells, histiocytes, neutrophils and poorly formed granulomas. Bile ducts also showed focal epithelial injury. Special stains were negative for alternative diagnoses. Given the biopsy findings, immune-related cholangiopathy was diagnosed, triggered by reinitiation of dabrafenib/trametinib. These medications were discontinued with concurrent initiation of systemic corticosteroids and tocilizumab, resulting in stabilization of liver function tests. Discussion: This case illustrates the diagnostic complexity of cholestatic liver injury in the setting of targeted therapy. Though not commonly associated with severe cholangiopathy, dabrafenib/trametinib therapy may induce immune-mediated bile duct injury or direct hepatocellular toxicity in susceptible individuals. Early recognition of this rare complication of targeted therapy and distinction from infectious, obstructive, or other drug-induced etiologies is important for management and prognosis, with systemic corticosteroids and tocilizumab available as effective treatment options.