Hepatic toxicity during regorafenib treatment in patients with metastatic gastrointestinal stromal tumors

Abstract

Regorafenib is a multi-target tyrosine kinase inhibitor that has been approved for the treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors (GIST). Severe hepatobiliary toxicity has been reported in patients with colorectal cancer treated with regorafenib, but not in those with GIST. Therefore, the aim of the present study was to investigate the incidence and clinical course of regorafenib-associated hepatic toxicity (HT) in patients with GIST in a real-world setting. Patients with metastatic GIST treated with regorafenib between September 2012 and May 2014 at three German tertiary care centers were followed up until August 2017. Patient records were retrospectively analyzed and descriptive statistics were employed. HT was defined as alterations in the serum values of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase and bilirubin (according to the Common Terminology Criteria for Adverse Events, version 4.0), and/or corresponding clinical signs. The time to clinical progression and the overall survival were calculated by Kaplan-Meier curves. Overall, 21 patients were treated with regorafenib and 5 (23.5%) of those heavily pretreated patients suffered from severe HT during regorafenib treatment. In 4 (80%) of these cases, regorafenib treatment was continued, optimizing individual treatment benefit. Clinical monitoring and adequate therapy management are crucial for ensuring continuation of regorafenib treatment in order to achieve an optimal clinical outcome.

Multikinase-Inhibitor Screening in Drug-resistant Osteosarcoma Patient-derived Orthotopic Xenograft Mouse Models Identifies the Clinical Potential of Regorafenib

“…Study drugs. The following drugs were used in the present study: Cisplatinum (Bristol Myers Squibb, New York, NY, USA) a standard first-line treatment for osteosarcoma; pazopanib (GlaxoSmithKline Plc., London, UK), an MKI approved for softtissue sarcoma and RCC (20); sunitinib (Pfizer Inc., New York, NY, USA), an MKI approved for gastrointestinal stromal tumors (GIST) and RCC (21); sorafenib (Bayer AG, Leverkusen, Germany), an MKI approved for RCC, HCC, and thyroid carcinoma (22); crizotinib (Pfizer Inc.), an MKI approved for non-small-cell lung cancer and anaplastic large-cell lymphoma (23); and regorafenib (Bayer AG), an MKI approved for metastatic colorectal cancer, GIST, and metastatic HCC (24).…”

Health-Related Quality of Life and Side Effects in Gastrointestinal Stromal Tumor (GIST) Patients Treated with Tyrosine Kinase Inhibitors: A Systematic Review of the Literature

“…Other frequently reported adverse events were diarrhea, fatigue, hoarseness, hypertension, and oral mucositis. One study [ 147 ] specifically investigated the incidence of regorafenib-associated hepatic toxicity, in which 5 of the 21 metastatic GIST patients developed (laboratory) hepatic toxicity. In a single-center retrospective study of 28 patients, toxicity and efficacy of regorafenib in fractioned dosing, 160 mg a day for the first 3 weeks of every 4-week cycle, was compared to continuous dosing of 120 mg a day.…”

Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay

“…An example compound showing the need for early, biologically relevant, safety assessment as well as efficacy testing was Regorafenib. This compound made it into clinical trials based on classical preclinical models, but was later found to cause hypertension [ 33 – 35 ] and hepatotoxicity [ 36 ] in the clinic. In our screen, the compound showed major anti-angiogenic efficacy ( Z * = − 17.7) but also showed significant toxicity (Medium toxicity).…”