Clinical Features of Regorafenib-induced Liver Injury in Japanese Patients From Postmarketing Experience

To the best of our knowledge, this is the first report of an investigation of regorafenib-induced liver injury in patients with metastatic colorectal cancer using solicited postmarketing data from real-world clinical practice. Overall, the clinical features were comparable to those in the clinical trials, including idiosyncratic occurrence and hepatocellular type. Early recognition and timely drug withdrawal are crucial for preventing severe outcomes. Background: Regorafenib (Stivarga) is an oral multikinase inhibitor currently approved for patients with metastatic colorectal cancer or gastrointestinal stromal tumor. Although hepatotoxicity has been a known product profile feature of regorafenib since its initial approval, its clinical features are limited to those found in the clinical trials. Patients and Methods: The present study was conducted in 2 analysis sets: a safety analysis set for metastatic colorectal cancer from solicited postmarketing surveillance (PMS) in Japan (n = 1227) and an analysis set for serious hepatic adverse drug reactions (n = 210) from all patients registered for regorafenib use. Results: The features of liver injury compatible with current product labeling included the second cycle as the most frequently observed time to onset, hepatocellular type as the typical pattern of liver injury, idiosyncratic occurrence as the possible mechanism, and rare fatal outcomes (0.33%; 4 of 1227). In addition to the known features, the present study found unpredictability in the outcome of hepatic events using the onset values of liver chemistry tests and delayed improvement of hepatic parameters after drug withdrawal. Owing to multiple confounding factors in patients with advanced cancer, difficulty remains in the interpretation of exploration for background factors and evaluation using Hy's law in oncology products. Conclusion: Regorafenib-induced liver injury can be considered idiosyncratic and typically of hepatocellular type, with fatal outcomes rare. Early recognition and timely drug withdrawal are the most important strategies to prevent progression to severe outcomes. At occurrence, careful observation until improvement and monitoring for fulminant hepatic failure are also essential.