Correlation between erlotinib pharmacokinetics, cutaneous toxicityand clinical outcomes in patients with advanced non-small cell lungcancer (NSCLC)

Objectives: An association between skin toxicity and outcome has been reported for NSCLC patientstreated with erlotinib. Several explanations have been suggested, including pharmacokinetic and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic andto correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients.Methods: Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line wereenrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serumand urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC–MS/MSanalysis, along with urinary 6-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of theCYP3A4/5 enzyme.Results: 56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were3.90 [2.13] mol/l and 0.37 [2.90] mol/mol creat in serum and urinary samples, respectively; at T2 drugconcentrations were significantly lower (2.02 [4.05] mol/l and 0.23 [4.47] mol/mol creat, respectively).Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade0–2 (6.84 [2.28] vs. 3.08 [1.97] mol/l, respectively, p = 0.004) and had longer progression-free and overallsurvival. An inverse correlation between erlotinib serum levels and urinary 6-hydroxycortisol/cortisolratio was observed in patients with grade 3 skin toxicity. Conclusions: These findings suggest that the pharmacokinetics and metabolism of erlotinib are relatedto skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters.