Activation of epidermal growth factor receptor (EGFR) bypass signaling pathway is an uncommon cause of acquired resistance to ALK TKIs.<h4>Method</h4>We present two patients with <i>EML4-ALK</i> rearranged NSCLC, developing an acquired <i>EGFR</i> resistance mutation after receiving multiple lines of ALK TKIs.<h4>Results</h4>While preclinical models have showed encouraging data, there is a critical need for clinical studies on treatment strategies to overcome this drug resistance. This evidence concerns the gene EGFR and non-small cell lung carcinoma.