189P - Reduced CYP2D6 Function Potentiates the Gefitinib-Induced Rash in Patients with Non-Small Cell Lung Cancer

Abstract

ABSTRACT Background Rash, liver dysfunction, and diarrhea are known as adverse events of erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportion of adverse events compared to those with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib and not of erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events between in the gefitinib and erlotinib therapies. Methods The frequency of each adverse event was evaluated during the period that the patients received EGFR-TKI therapy. CYP2D6 phenotypes were determined from the CYP2D6 genotype using real-time polymerase chain reaction methods, which are able to determine single nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of adverse events with each factor, including CYP2D6 activities as well as treatment types. Results Patients were identified through a query of patient information for subjects prospectively enrolled in the Medical Information System within Osaka City University Hospital between January 1999 and February 2012 that tracks all of the patients referred for CYP2D6 sequencing from our hospital. A total of 232 patients received gefitinib therapy, and 86 patients received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR 0.44, 95% confidence interval [CI] 0.21-0.94, p = 0.03), and not of diarrhea ≥ grade 2 (OR 0.49, 95%CI 0.17-1.51, p = 0.20) and liver dysfunction ≥ grade 2 (OR 1.08, 95%CI 0.52-2.34, p = 0.84) in gefitinib cohort. No associations were observed between any adverse events in erlotinib cohorts and CYP2D6 phenotypes (rash: OR 1.77, 95%CI 0.54-6.41, p = 0.35; diarrhea: OR 1.08, 95%CI 0.21-7.43, p = 0.93; and liver dysfunction: OR 0.93, 95%CI 0.20-5.07, p = 0.93). Conclusions CYP2D6 may relate to the metabolism of gefitinib and not of erlotinib. CYP2D6 phenotypes are one of promising factors for the development of rash in gefitinib therapy. Disclosure All authors have declared no conflicts of interest.