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

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