Reply to M.C. Garassino et al

Abstract

The question raised by Garassino et al whether chemotherapy should be preferred in patients with epidermal growth factor receptor (EGFR) wild-type non–small-cell lung cancer (NSCLC) is relevant, given that approximately 85% to 90% of patients belong in this category in the western world. Interestingly, gefitinib is registered in Europe only for patients with mutant EGFR NSCLC, whereas erlotinib is registered for patients with NSCLC regardless of mutation status in both Europe and United States. There is little data in support of EGFR tyrosine kinase inhibitors (TKIs) being given to patients with wildtype EGFR and some evidence that there is actually a detriment in comparison with chemotherapy in the first-line setting. There is a need to assess the value, if any, of using an EGFR TKI in any line of treatment of NSCLC in patients with wild-type EGFR. Patients with wild-type EGFR include patients whose tumor is KRAS mutant, a setting in which EGFR TKIs are essentially inactive, if not detrimental. Although it is clear that EGFR TKIs improve progression-free survival in the first-line treatment of patients with mutant EGFR, on the basis of several randomized comparisons, as delineated in the recently published American Society of Clinical Oncology provisional clinical opinion, there are insufficient data in subsequent lines of treatment. Garassino et al are to be commended, as they are in fact currently conducting a prospective randomized study in second-line treatment of advanced NSCLC, in which patients with wild-type EGFR are being randomly assigned to receive docetaxel or erlotinib (NCT00637910; Tarceva Italian Lung Optimization Trial [TAILOR] study). EGFR mutation status for patients in whom treatment has failed is often based on archival tissue available from the diagnostic specimen. Because the mutational status may change under the pressure of systemic treatment and lead to resistance, the data obtained with pretreatment archival material may not be reliable. Although there may be differences among EGFR TKIs in terms of activity on wild-type EGFR cells, these differences are trivial in comparison with presence versus absence of EGFR-activating mutations. Treating patients with advanced NSCLC with EGFR TKIs in the absence of EGFR mutation testing or in wild-type EGFR is questionable and needs to be studied more. Fortunately, we are finally in an era in the treatment of patients with NSCLC when we have TKIs that are exquisitely active in specific subsets of patients. The availability of drugs on the market that hardly have an impact on survival but may have substantial toxicity should not be a reason to treat all unselected patients until the end of their lives.