Historical development of EGFR-targeted therapy

The high expression of epidermal growth factor receptor (EGFR) in carcinomas from multiple tissue sites led to preclinical studies and early trials assessing the efficacy of EGFR inhibitors in multiple cancer types. In these early studies, one class of EGFR inhibitors that targets the tyrosine kinase domain of the receptor proved effective in some patients with lung adenocarcinoma. It was later shown that mutations in the tyrosine kinase (TK) domain rather than the EGFR expression predicted response to this class of drugs. First-, second-, and third-generation EGFR TKIs (tyrosine kinase inhibitors) were successively developed and became the standard of care in the treatment of patients with EGFR-mutated lung cancer. Despite the improvements in survival achieved by these drugs, patients still face challenges as mechanisms of resistance eventually develop and lead to disease progression. This chapter will outline important preclinical studies and clinical trials that led to the development and approval of EGFR TKIs for their clinical uses. Later chapters will focus on the mechanisms of resistance to EGFR TKIs, potential new drug targets, and recent trials involving this class of drugs.