EGFRMutations in Non–Small-Cell Lung Cancer

Mutations in the epidermal growth factor receptor (EGFR), most commonly deletions in exon 19 affecting the amino acid motif LREA (delE746-750) or substitution of arginine for leucine at position 858 (L858R) in exon 21, are present in approximately 17% of tumors in patients with pulmonary adenocarcinoma and lead to constitutive activation of the EGFR tyrosine kinase. 1 These activating EGFR mutations are associated with high response rates to EGFR tyrosine kinase inhibitor (TKI) therapy, with combined results from 21 studies from 2004 to 2006 showing responses in 210 of 268 patients (78%). 2 These response rates observed in patients with EGFR-mutant tumors receiving TKIs were much higher than what had been described in patients treated with standard platinum-doublet chemotherapy.Follow-up studies directly comparing the 2 treatment strategies in patients with advancedstage non-small-cell lung cancer harboring activating EGFR mutations confirmed the superiority of EGFR TKI therapy to chemotherapy in this patient population as described herein.In the Iressa Pan-Asia Study (IPASS), patients with previously untreated advanced-stage pulmonary adenocarcinoma who were never or light smokers were randomized to receive the EGFR TKI gefitinib or standard chemotherapy with carboplatin plus paclitaxel. 3 Progression-free survival (PFS), the primary end point of the study, was significantly improved with gefitinib therapy among patients with EGFRmutant tumors (hazard ratio [HR], 0.48; P < .001)but worse in those without EGFR mutations (HR, 2.85; P < .001).An updated analysis of the trial defined EGFR mutation as the strongest predictive biomarker for response to EGFR TKI therapy and median PFS. 4 Subsequent studies in Asia comparing the first-generation EGFR TKIs gefitinib or erlotinib to chemotherapy in previously untreated patients with EGFR-mutant lung cancer showed similar results, with increased response rates and PFS for patients treated with targeted therapy. [5]6][7] The European Tarceva vs Chemotherapy (EURTAC) trial was the first study comparing targeted therapy with an EGFR TKI to chemotherapy in a non-Asian population. 8 In this multicenter phase 3 trial, 173 patients with activating EGFR mutations were randomized to receive erlotinib or a platinumbased chemotherapy doublet.Erlotinib therapy was associated with improved median PFS, the primary end point of the study, compared with chemotherapy (9.7 vs 5.2 months; HR, 0.37; P < .001).There were no significant differences in the median overall survival (OS) in these studies, most likely as a result of crossover at progression.