Resistance to third-generation inhibitors occurs after 9–13 months of treatment and is mediated by the development of secondary mutations (L858R/C797S) when used as first-line treatment for EGFR-positive NSCLC with common mutations, and tertiary mutations (L858R/T790M/C797S) when used in patients that harbor the T790M mutant after treatment with first and second generation inhibitors by replacing the cysteine covalently bound by the Michael acceptor with a less reactive serine residue [77,196,197,198]. Here, EGFR is linked to non-small cell lung carcinoma.