Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

Abstract

Summary Background Pembrolizumab immunotherapy has been associated with hepatotoxicity in 1%‐10% of oncology patients treated in clinical trials. Aim To describe the incidence, phenotypes and outcomes of liver injury in a large cohort of solid organ tumour patients receiving pembrolizumab Methods Liver injury was defined by serum alanine aminotransferase, alkaline phosphatase, and/or total bilirubin levels exceeding threshold values. The likelihood of drug‐induced liver injury was adjudicated by expert opinion. Results Seventy (14.3%) of the 491 pembrolizumab‐treated patients developed liver injury at a median of 62 days (6‐478) and 71.4% had a cholestatic injury profile at onset. The median age, gender and tumour types of liver injury patients were similar to those without, but hepatic metastases (53% vs 21%, P < 0.01) and prior systemic and liver‐directed therapy (71% vs 53%, P < 0.01) were more commonly observed in liver injury patients. During follow‐up, liver injury patients were less likely to experience tumour remission (10% vs 40.4%) and had higher mortality (67.1% vs 33.7%). Only 20 (28.6%) liver injury cases were adjudicated as probable drug‐induced hepatotoxicity; these patients were significantly more likely to present with an hepatocellular/mixed injury pattern (65% vs 12%), to receive corticosteroids (55% vs 12%) and had lower mortality (45% vs 76%) during follow‐up. Conclusions Oncology patients treated with pembrolizumab who develop liver injury experience poorer outcomes during follow‐up. The low incidence of confirmed drug hepatotoxicity highlights the need for thorough medical evaluation before initiating corticosteroids to optimise patient care.

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

“…Among the various toxicities, work-up and management of liver injury is challenging for different reasons [82], including the use of ICIs in hepatocellular carcinoma [83] and chronic hepatitis B infection, as well as the common presence of hepatic metastasis [84,85]. Moreover, the type of liver injury does not affect work-up, whereas thresholds of liver function tests represent the main criteria for diagnosis and relevant management.…”

Metastatic Merkel Cell Carcinoma Masquerading as Multiple Immune-Related Adverse Events

“…Within this subset, only 29% of cases, 4.1% of the 491 cases overall, were adjudicated as likely to be drug-related on expert review (i.e., given Drug-Induced Liver Injury Network (DILIN) expert opinion scale scores of 1, definite, 2, highly likely, or 3, probable); most of the remainder were attributed to hepatic involvement by malignancy. The authors suggested an increased emphasis on contrast-enhanced cross-sectional scans and early biopsy in the setting of liver enzyme abnormalities as possible strategies to help reduce diagnostic uncertainty and avoid unnecessary empiric immunosuppression [ 11 ]. Proceeding with such a “prospectively obtained” liver biopsy in our case, where the patient could not undergo contrast-enhanced study due to acute kidney injury, might have expedited diagnosis of diffuse progression, prompting earlier goals of care discussion with the patient and family.…”

“…Labs were consistent with a cholestatic pattern of injury ( R = 1.2). Although checkpoint inhibitors are more associated with the hepatocellular pattern of injury, there are multiple case reports of pembrolizumab inducing cholestatic injury, even after a single dose [ 11 , 16 , 17 ].…”

Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

“…One study involving 491 patients treated with pembrolizumab noted 14% of patients with liver injury, a majority of which was attributed to hepatic metastases rather than DILI; those with liver injury had lower tumor response and higher mortality, likely due to more advanced cancer before treatment. Therefore, thorough assessment for other etiologies of liver injury should be completed to not only assist with diagnosis but also with management regarding appropriate use of immunosuppressive therapy …”