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The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies has been studied as a strategy to improve the outcome of first-line chemotherapy in patients with NSCLC. The present review updates the findings from phase III trials.Cetuximab improved survival when combined with first-line chemotherapy and this benefit was limited to patients with high EGFR expression in their tumors. A Southwest Oncology Group study currently prospectively evaluates the predictive biomarkers for cetuximab. In the SQUIRE phase III trial, necitumumab added to cisplatin and gemcitabine increased the survival in patients with advanced squamous cell NSCLC. The INSPIRE trial studied chemotherapy with and without necitumumab in patients with nonsquamous NSCLC but was prematurely halted because of increased thromboembolic events with chemotherapy and necitumumab.EGFR monoclonal antibodies improved the outcome including survival in selected patients with advanced NSCLC. Prospective validation of predictive biomarkers is ongoing.