Purpose: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. Experimental Design: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. Results: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC 0-1 in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. C max in smokers was two-thirds of that in nonsmokers, and C 24h in smokers was 8.3-fold lower than in nonsmokers. The median C 24h of smokers at the 300 mg dose was slightly less than the C 24h of smokers at the 150 mg dose. The median C max was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. Conclusion: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC 0-1 and C 24h were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in C max was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.Although the recommendation to consider smoking status in clinical studies was made decades ago (1), the effect of smoking on pharmacokinetics has been studied for only a limited number of drugs (2 -5). Drugs for which patients' smoking status may have clinical significance include caffeine (6), chlordiazepoxide (7), chlorpromazine (8), diazepam (7), estradiol (9), flecainide (10, 11), haloperidol (12), heparin (13), imipramine (14), insulin (15), pentazocine (16), propoxyphene (7), propranolol (17), tacrine (4), and theophyline (18). Studies indicate that some of these drugs, including caffeine, imipramine, pentazocine, tacrine, and theophyline, are likely affected by induction of cytochrome P4501A enzymes.Erlotinib (TarcevaR, OSI Pharmaceuticals, Melville, NY; Roche, Basel, Switzerland; Genentech, South San Francisco, CA) is an orally active, potent selective inhibitor of the epidermal growth factor receptor tyrosine kinase (19). It is indicated for the treatment of patients with locally advanced or metastatic non -small cell lung cancer after failure of at least one prior chemotherapy regimen and in combination with gemcitabine for the treatment of patients with local advanced, unresectable, or metastatic pancreatic cancer. In the pivotal phase III non -small cell lung cancer trial, BR.21 (20), smoking history was the only factor with a significant and potentially clinically relevant interaction with treatment, indicating that erlotinib was more effective in never smokers than in current or former smokers. Further analyses have also shown that smoking hist...

A B S T R A C T PurposeErlotinib prolongs survival in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT ϩ erlotinib) in chemotherapy-naïve patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number. Patients and MethodsA total of 143 patients were randomly assigned to either erlotinib 150 mg daily orally until disease progression (PD) occurred or to chemotherapy with paclitaxel 200 mg/m 2 intravenously (IV) and carboplatin dosed by creatinine clearance (AUC 6) IV on day 1 intercalated with erlotinib 150 mg orally on days 2 through 15 every 3 weeks for four cycles followed by erlotinib 150 mg orally until PD occurred (CT ϩ erlotinib). The primary end point was 6-month progression-free survival (PFS); secondary end points included response rate, PFS, and survival. EGFR, KRAS mutation, EGFR fluorescent in situ hybridization and immunohistochemistry, and E-cadherin and vimentin protein levels were also assessed. ResultsSix-month PFS rates were 26% and 31% for the two arms (CT ϩ erlotinib and erlotinib alone, respectively). Both were less than the historical control of 45% (P ϭ .001 and P ϭ .011, respectively). Median PFS times were 4.57 and 2.69 months, respectively. Patients with tumors harboring EGFR activating mutations fared better on erlotinib alone (median PFS, 18.2 months v 4.9 months for CT ϩ erlotinib). ConclusionThe feasibility of a multicenter biomarker-driven study was demonstrated, but neither treatment arms exceeded historical controls. This study does not support combined chemotherapy and erlotinib in first-line treatment of EGFR-selected advanced NSCLC, and the patients with tumors harboring EGFR mutations had a better outcome on erlotinib alone.