KRAS Wild-Type Lung Cancer: A Moving Target in an Era of Genotype Migration

The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the management of advanced lung cancer ranks among one of the few most important advances in solid tumor oncology over the past decade. In recent years, much has been learned about how to most effectively use first-generation EGFR TKIs like erlotinib and gefitinib for non–small-cell lung cancer (NSCLC). We know that EGFR TKIs should be administered instead of first-line chemotherapy to patients with lung cancers carrying EGFR exon 19 or 21 mutations, because this leads to longer median progression-free survival (PFS) and improved quality of life. We know that patients with EGFR-mutant lung cancer with poor performance status should be offered treatment with EGFR TKIs, because this can lead to dramatic responses with marked and durable improvement in performance status. Furthermore, patients with KRASmutant lung cancers rarely respond to EGFR TKIs, and some investigators suspect that such patients may gain no benefit from these agents at all. We are also learning much about continuation of TKIs postprogression in some patients with EGFR-mutant lung cancers, which may prolong the duration of benefit from the drugs. One setting in which the published evidence is inadequate is in the application of predictive biomarkers to guide EGFR TKI therapy in previously treated NSCLC. The BR.21 trial resulted in the initial US Food and Drug Administration approval of erlotinib for previously treated NSCLC by showing a 2-month improvement in median survival over placebo in previously treated NSCLC. A biomarker analysis of this trial was later published, which found that only high EGFR copy number was predictive of survival benefit from erlotinib. However, retrospective EGFR genotyping could only be performed for 204 of the 731 BR.21 patients (28%), and an analysis of PFS was not performed. When one looks as a group at the biomarker analyses from several randomized trials studying erlotinib or gefitinib in previously treated NSCLC (Table 1), it is clear that patients with EGFR-mutant disease have the longest PFS and highest response rates with erlotinib and gefitinib, followed by those with KRAS wild-type disease (including EGFR-mutant disease), whereas those with KRAS-mutant and EGFR wild-type disease (including KRAS-mutant disease) do the least well. The article by Ramalingam et al in Journal of Clinical Oncology adds thought-provoking data to this discussion, with the first randomized data on irreversible EGFR TKIs in patients with lung cancer without previous TKI exposure. In this randomized phase II study for patients with NSCLC experiencing progression during chemotherapy, erlotinib was compared with dacomitinib, an irreversible inhibitor of multiple ERBB-family kinases. Although erlotinib has been found to maximally inhibit the mutant EGFR kinase, dacomitinib irreversibly inhibits EGFR, human epidermal growth factor receptor 2, and ERBB4 at nanomolar concentrations. The authors found a significant improvement in PFS with dacomitinib in the intention-to-treat population (P .012) and in patients with KRAS wild-type lung cancers (P .006). The broader inhibitory activity of dacomitinib