Abstract 3588: Personalized medicine for non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib

Abstract

Erlotinib is an oral available, selective inhibitor of EGFR tyrosine kinase activity for the treatment of patients with NSCLC. Side effects, commonly seen as skin rash and diarrhea, occurred in 75% of patients. About 20% of patients needed erlotinib dose reduction from the standard dose of 150mg/day due to these toxicities. Since the severity of skin rash is strongly associated with improved clinical outcome, skin rash may be a surrogate marker of favorable clinical outcome. Erlotinib is a substrate for ABC transporters such as ABCB1 and ABCG2. However, it is unknown whether these polymorphisms affect the pharmacokinetics of erlotinib and influence the inter-individual variability in erlotinib toxicity. The purpose of this study is to evaluate the effects of ABC transporter polymorphism on erlotinib pharmacokinetics and the development of side effects, skin rash and diarrhea in Japanese patients with NSCLC. Methods: Thirty-one Patients were orally administered 150 mg erlotinib as a single treatment. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1(D1), 8(D8), and stable phase. DNA from plasma was screened for SNPs in the ABCB1 and ABCG2 genes using TaqMan assay or direct nucleotide sequencing. Results: The mean Cmax of D1 and D8 were 1.7 and 3.1 µg/ml, respectively. Trough concentration at D1, D8 and steady state were 0.7, 1.2 and 1.4 µg/ml, respectively. Skin rash occurred in 95% of patients. One patient (Cmax, 3.0 µg/ml at D1) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The Cmax and AUC on D1 was correlated with the severity of skin rash, however, Cmin were not correlated. Patients with homozygous variant for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type and heterozygous were associated with higher AUC and Cmin at D1 (31 vs 21, p=0.07; 1.1 vs 0.6 µg/ml, p=0.007). AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. ABCB1 polymorphism was associated with decreased ABCB1 function, resulting in the increased concentration of erlotinib. All five patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT developed higher grade 2 toxicity by day 7. Patients homozygous variant for ABCB1 developed toxicity significantly faster than those with at least one T allele (p=0.002). On the other hand, all three patients carrying without T allele had not experience toxicity. Conclusions: The present study suggests that ABCB1 polymorphism affects the pharmacokinetics of erlotinib and also influence the development of erlotinib toxicity. We proposed that prior to the Erlotinib treatment, the measuring of ABCB1 polymorphism may help to identify patients with NSCLC who can develop a severe toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3588.

Serum Concentrations of Erlotinib at a Dose of 25 mg Daily

“…All patients had stage IV NSCLCs and received erlotinib orally. Erlotinib (molecular weight of 429.90) was measured using high performance liquid chromatography (HPLC) with ultra-violet detection (5). The measured serum concentration of erlotinib, by HPLC, in both patients receiving 25 mg/day exceeded 0.4 µM (Table); while the concentration measured for the patient receiving 150 mg/day exceeded 4 µM.…”