Hiroyuki Uetake1, Kenichi Sugihara2, Kei Muro3, Toshiyuki Sunaya4, Yuka Horiuchi-Yamamoto5, Hajime Takikawa6. 1. Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. 2. Tokyo Medical and Dental University, Tokyo, Japan. 3. Department of Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Aichi, Japan. 4. Clinical Statistics, Product Development, Bayer Yakuhin, Ltd., Osaka, Japan. 5. Pharmacovigilance, Medical Affairs, Bayer Yakuhin, Ltd., Osaka, Japan. Electronic address: yuka.yamamoto@bayer.com. 6. Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Abstract
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.
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.
Authors: Tom Luedde; Jonel Trebicka; Frank Erhard Uschner; Florian Schueller; Ivelina Nikolova; Sabine Klein; Robert Schierwagen; Fernando Magdaleno; Stefanie Gröschl; Sven Loosen; Thomas Ritz; Christoph Roderburg; Michael Vucur; Glen Kristiansen; Twan Lammers Journal: Oncotarget Date: 2018-11-16