Impact of EGFR mutations on treatment of non-small cell lung cancer

Somatic mutations in the epidermal growth factor receptor (EGFR) have been identified in advanced non-small cell lung cancer (NSCLC) patients who achieve dramatic clinical and radiographic responses to treatment with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Retrospective studies comparing outcomes of patients with and without EGFR mutations treated with EGFR-TKIs demonstrate that patients with EGFR mutations live significantly longer than those without mutations. In addition, patients with NSCLC and a somatic deletion mutation of exon 19 exhibit longer survival than patients with point mutations of exon 21. Secondary resistance mutations have also been identified. Patients exhibiting a somatic sensitizing mutation of EGFR who achieve partial response to gefitinib or erlotinib therapy eventually develop clinical resistance to treatment with EGFR-TKI. Approximately half of these resistant patients develop a detectable secondary acquired resistance mutation (T790M) in their tumor. New irreversible EGFR inhibitors have in vitro and in vivo evidence of antitumor activity against lung cancer cells harboring both the sensitizing and resistance mutations. These findings suggest that patients with advanced NSCLC bearing somatic EGFR mutations should receive treatment with an EGFR-TKI included as at least part of their initial therapy. Trials are starting to test the irreversible EGFR inhibitors in patients with NSCLC after they develop resistance to their initial treatment with gefitinib or erlotinib.