Abstract
Before 2009, nonsmall cell lung cancer (NSCLC) was one disease entity treated by cytotoxic chemotherapy that provided a response rate of 20–35 % and a median survival time (MST) of 10–12 months. In 2004, it was found that activated mutations of the epidermal growth factor receptor (EGFR) gene were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Four phase III studies (North East Japan (NEJ) 002, West Japan Thoracic Oncology Group (WJTOG) 3405, OPTIMAL, and EUROTAC) prospectively compared TKI (gefitinib or erlotinib) with cytotoxic chemotherapy as first-line therapy in EGFR-mutated NSCLC. These studies confirmed that progression-free survival (PFS) with TKIs (as the primary endpoint) was significantly longer than that with standard chemotherapy (hazard ratio [HR] = 0.16–0.49) from 2009 to 2011. Although the NEJ 002 study showed identical overall survival (OS) between the arms (HR = 0.89), quality of life (QoL) was maintained much longer in patients treated with gefitinib. In conclusion, TKI should be considered as the standard first-line therapy in advanced EGFR-mutated NSCLC. Since 2009, a new step has been introduced in the treatment algorithm for advanced NSCLC.
Highlights
Recent sequencing of DNA to identify polymorphisms has catalyzed the quest for protein kinase “driver” mutations, K
Small molecule inhibitors that block binding of adenosine-5′-triphosphate (ATP) to the tyrosine kinase catalytic domain have been developed, and gefitinib and erlotinib are the first generation of such agents, which act as tyrosine kinase inhibitors (TKI) at the epidermal growth factor receptor (EGFR)
In 2004, three groups of researchers reported that activating mutations of EGFR detected by direct sequencing were present in a subset of nonsmall cell lung cancer (NSCLC) and that tumors with EGFR mutations were highly sensitive to EGFR-TKI [1,2,3]
Summary
Dysregulation of protein kinases is frequently observed in cancer cells; protein kinases are attractive targets in the development of anticancer drugs. In 2004, three groups of researchers reported that activating mutations of EGFR detected by direct sequencing were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR-TKI [1,2,3]. This knowledge is the first evidence for division of subpopulations in NSCLC and of the possibility of treating NSCLC patients individually, there have been two streams of clinical studies. Clinical efficacy of EGFR-TKIs such as gefitinib or erlotinib has been investigated initially. In order to develop personalized therapy in NSCLC, clinical efficacy of EGFR-TKIs has been indicated by molecular selection in phase 3 trials of NSCLC (Table 1) [15,16,17,18,19]
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