Targeted therapy in lung cancer: the good, the bad, and the ugly.

Greater insight into the molecular mechanisms that underlie carcinogenesis and cancer progression has led to the introduction of targeted drugs in many cancers, including non–small-cell lung cancer (NSCLC). Despite the modest benefits observed to date, the approval of targeted drugs for the management of patients with NSCLC has generated tremendous excitement and hope regarding the outcomes of these patients in the future. The simple concept that underlies the development of these targeted drugs is the recognition (assumption!) that certain molecular targets have differential expression and relevance in malignant and normal tissues. Therefore, the expectation is that drugs targeting these molecular processes will affect malignant tissues significantly greater than normal tissues, resulting in a high therapeutic index. Significant clinical experience has been garnered in recent years regarding the therapeutic use of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors in the treatment of patients with NSCLC. This experience has educated the oncology community regarding adverse effects that practicing oncologists were not familiar with in the era of cytotoxic therapy as the sole systemic modality. In this issue of Clinical Lung Cancer, Ricciardi et al provide a thorough review of the adverse effects observed with these novel targeted drugs. These adverse effects have led to a greater understanding of the relevance of these molecular targets for normal physiologic functions and anatomic integrity. In addition, there is greater recognition of the importance of drug pharmacokinetics and off-target effects in the development of these adverse events. Appropriate understanding of the mechanisms that underlie these adverse effects could enable their appropriate management and thus provide patients an opportunity to remain on these treatments sufficiently long enough to derive clinical benefits from these targeted drugs. Dermatologic toxicities are the most common toxicities observed with EGFR inhibitors. The factors that influence the development of these dermatologic toxicities are not completely understood. However, it is recognized that the incidence of rash with EGFR tyrosine kinase inhibitors (TKIs) correlates with the dose and the drug levels achieved in an individual. The development of rash appears to occur when a certain threshold drug level is reached. In this regard, it is interesting that the incidence of rash in the ISEL (Iressa Survival Evaluation in Lung Cancer) study evaluating gefitinib was 36%, and the incidence rate in the BR.21 trial evaluating erlotinib was 76%.1,2 It is recognized that drug exposure (Cmax and area under the curve [AUC]) of gefitinib at clinical doses is much lower than that of erlotinib at erlotinib's dose of 150 mg.3,4 Gefitinib, unlike erlotinib, was dosed much lower than its maximum tolerated dose (MTD) based on data that the steady-state plasma concentration of gefitinib at 250 mg exceeded the IC90 inhibitory concentration of KB2 oral carcinoma cells and that the pharmacodynamic effect of the drug on skin was observed at this dose and lower doses.5,6 However, the gefitinib exposure achieved with this dose might not have exceeded the “threshold level” required in sufficient number of patients in the ISEL study to demonstrate an overall survival (OS) benefit. The importance of drug levels in the development of rash is also supported by the low incidence of rash in current smokers compared with never-smokers observed in BR.21. It was hypothesized that the induction of P450 enzymes CYP1A1 and CYP1A2 involved in the metabolism of erlotinib by components of cigarette smoke might reduce the drug levels in active smokers. This hypothesis was supported by a pharmacokinetic study among normal volunteers, demonstrating a lower AUC among smokers at the dose of 150 mg.7 Subsequent data generated in a phase I study in patients with NSCLC who are active smokers have shown that the MTD in current smokers for erlotinib is 300 mg daily.8 Retrospective analysis of BR.21 has shown that the efficacy of erlotinib is significantly lower in active smokers. It is possible that achieving adequate drug levels in active smokers could improve the efficacy of this drug. It is also important to recognize that certain drugs can induce or inhibit the activity of the P450 enzymes involved in the metabolism of erlotinib and thus influence drug levels and the development of dermatologic toxicities. Recent data have also shown that proton pump inhibitors might reduce the absorption of erlotinib, leading to reduced drug levels and, therefore, skin rash. It is quite possible that the 24% of patients on erlotinib in BR.21 who did not develop skin rash might have not achieved adequate drug levels because of one of these factors. Because development of skin rash correlates with the efficacy of erlotinib and because development of skin rash might correlate with adequate drug levels in a patient, it is extremely crucial that appropriate advice is given to patients regarding continued cigarette smoking or use of drugs that could interfere with the metabolism of EGFR TKIs. Development of skin rash also correlates with efficacy from monoclonal antibodies (MoAbs) editorial Clinical Lung Cancer, Vol. 10, No. 1, 10-12, 2009 DOI: 10.3816/CLC.2009.n.002