Originally published as JCO Early Release 10.1200/JCO.2008.19.3995 on January 21 2009

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Overcoming CYP1A1/1A2 Mediated Induction of Metabolism by Escalating Erlotinib Dose in Current Smokers

From the Northern Centre for Cancer Treatment, Newcastle Upon Tyne; Royal Marsden Hospital, Sutton; OSI Pharmaceuticals, Oxford; Ninewells Hospital, Dundee; Weston Park Hospital, University of Sheffield, Sheffield; Beatson Oncology Centre, Glasgow; Aberdeen Royal Infirmary, Aberdeen; Edinburgh Cancer Centre, Edinburgh, United Kingdom; Wake Forest University, Winston-Salem, NC; and OSI Pharmaceuticals Inc, Boulder, CO.

Corresponding author: Andrew N. Hughes, MBBS, PhD, Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Rd, Newcastle upon Tyne, NE4 6BE; e-mail: Andrew.Hughes{at}nuth.nhs.uk.

Purpose Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg.

Patients and Methods Cohorts of NSCLC patients currently smoking 10 cigarettes per day for 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity.

Results Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 µg/mL for 150 mg and 300 mg, respectively.

Conclusion The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

Supported by a grant from OSI Pharmaceuticals Inc.

Presented in part at the annual meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007; WCLC, Seoul, Korea, September 2-6, 2007; and Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, November 13-15, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00294736 [ClinicalTrials.gov] .

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