Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan.

BACKGROUND: Sorafenib is a multi-kinase inhibitor currently approved in Japan for unresectable and/or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. Although drug-induced lung injury has recently been the focus of interest in Japanese patients treated with molecular targeting agents, the clinical features of patients receiving sorafenib remain to be completely investigated. METHODS: All-patient post-marketing surveillance data was obtained within the frame of Special Drug Use Investigation; between April 2008 and March 2011, we summarized the clinical information of 62 cases with drug-induced lung injury among approximately 13,600 sorafenib-treated patients in Japan. In addition, we summarized the results of evaluation by a safety board of Japanese experts in 34 patients in whom pulmonary images were available. For the calculation of reporting frequency, interim results of Special Drug Use Investigation were used. RESULTS: In the sets of completed reports (2,407 in renal cell carcinoma and 647 in hepatocellular carcinoma), the reporting frequency was 0.33 % (8 patients; fatal, 4/8) and 0.62 % (4 patients; fatal, 2/4), respectively. Major clinical symptoms included dyspnea, cough, and fever. Evaluation of the images showed that 18 cases out of 34 patients had a pattern of diffuse alveolar damage. The patients with hepatocellular carcinoma showed a greater incidence and earlier onset of lung injury than those with renal cell carcinoma. CONCLUSION: Although the overall reporting frequency of sorafenib-induced lung injury is not considered high, the radiological diffuse alveolar damage pattern led to a fatal outcome. Therefore, early recognition of sorafenib-induced lung injury is crucial for physicians and patients.

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

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.