Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 19 in-frame insertions have been described in about 1% of EGFR-mutant lung cancers. They appear to be more common in nonsmoking women. These exon 19 insertions appear to be sensitizing mutations and have been shown to respond to TKIs in some studies.