Michael Steffens1, Tanusree Paul2, Vivien Hichert3, Catharina Scholl3, Dirk von Mallek3, Christoph Stelzer4, Fritz Sörgel5, Bärbel Reiser2, Christian Schumann6, Stefan Rüdiger7, Stefan Boeck8, Volker Heinemann8, Volker Kächele9, Thomas Seufferlein9, Julia Stingl3. 1. Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany. Electronic address: michael.steffens@bfarm-research.de. 2. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany. 3. Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany. 4. IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg, Germany. 5. IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg, Germany; Department of Pharmacology, University of Duisburg-Essen, Essen, Germany. 6. Department of Internal Medicine II, University of Ulm, Ulm, Germany; Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgäu, Kempten, Germany. 7. Department of Internal Medicine II, University of Ulm, Ulm, Germany. 8. Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany. 9. Department of Internal Medicine I, University of Ulm, Ulm, Germany.
Abstract
AIM: The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. METHODS: From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. RESULTS: Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)). CONCLUSION: The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.
AIM: The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancerpatients experiencing skin rash under treatment with EGFR inhibitors. METHODS: From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. RESULTS: Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancerpatients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)). CONCLUSION: The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.
Authors: Stefanie L Groenland; Ron H J Mathijssen; Jos H Beijnen; Alwin D R Huitema; Neeltje Steeghs Journal: Eur J Clin Pharmacol Date: 2019-06-07 Impact factor: 2.953
Authors: Remy B Verheijen; Huixin Yu; Jan H M Schellens; Jos H Beijnen; Neeltje Steeghs; Alwin D R Huitema Journal: Clin Pharmacol Ther Date: 2017-09-07 Impact factor: 6.875
Authors: Vivien Hichert; Catharina Scholl; Michael Steffens; Tanusree Paul; Christian Schumann; Stefan Rüdiger; Stefan Boeck; Volker Heinemann; Volker Kächele; Thomas Seufferlein; Julia Stingl Journal: Oncotarget Date: 2017-05-23