Rapid disease progression in epidermal growth factor receptor (EGFR) non–small-cell lung cancer treated with tyrosine kinase inhibitorss has been associated with concomitant mutations. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry in 51 tumor blocks, and it was correlated with overall response rate, overall survival, and progression-free survival. We point out that immunohistochemistry could be a valid tool to identify PTEN loss. Moreover, our results have shown worse outcomes in terms of progression-free survival, overall survival, and objective response rate in patients with concomitant EGFR mutation and PTEN loss. Furthermore, the coexistence of PTEN loss and IGFR overexpression identifies a potential prognostic ‘signature’ for a subgroup of patients with particularly poor prognosis.