Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash

Michael Steffens; Tanusree Paul; Vivien Hichert; Catharina Scholl; Dirk von Mallek; Christoph Stelzer; Fritz Sörgel; Bärbel Reiser; Christian Schumann; Stefan Rüdiger; Stefan Boeck; Volker Heinemann; Volker Kächele; Thomas Seufferlein; Julia Stingl

doi:10.1016/j.ejca.2015.11.022

Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash

Eur J Cancer. 2016 Mar:55:131-9. doi: 10.1016/j.ejca.2015.11.022. Epub 2016 Jan 25.

Authors

Affiliations

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.

PMID: 26820683
DOI: 10.1016/j.ejca.2015.11.022

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.

Keywords: EGFR inhibitor-induced skin rash; Erlotinib metabolic ratio; Erlotinib/O-desmethyl-erlotinib ratio; Predictive biomarker.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / blood
Adenocarcinoma / drug therapy*
Adenocarcinoma / enzymology
Adenocarcinoma / mortality
Adenocarcinoma / pathology
Adult
Aged
Aged, 80 and over
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / adverse effects*
Antineoplastic Agents / blood
Antineoplastic Agents / pharmacokinetics
Biotransformation
Carcinoma, Non-Small-Cell Lung / blood
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / pathology
Dealkylation
Disease Progression
Disease-Free Survival
Drug Dosage Calculations
Drug Monitoring / methods
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Erlotinib Hydrochloride / administration & dosage
Erlotinib Hydrochloride / adverse effects*
Erlotinib Hydrochloride / blood
Erlotinib Hydrochloride / pharmacokinetics
Exanthema / chemically induced*
Exanthema / diagnosis
Female
Germany
Humans
Kaplan-Meier Estimate
Lung Neoplasms / blood
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Male
Middle Aged
Pancreatic Neoplasms / blood
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / enzymology
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology
Predictive Value of Tests
Proportional Hazards Models
Prospective Studies
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / adverse effects*
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / pharmacokinetics
Severity of Illness Index

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Erlotinib Hydrochloride
EGFR protein, human
ErbB Receptors