Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.

Molecular pathology of lung cancer: key to personalized medicine

“…179 Approximately 10-25% of EGFR-mutant lung adenocarcinomas do not respond to an EGFR TKI. 15 In addition to the previously mentioned mutations, even rarer primary mutations, such as D761Y, G719C, and E709A mutations, have also been shown to be insensitive to EGFR TKIs, and even more so when co-occurring with other genetic alterations. 196 Primary TKI resistance may also be mediated by the presence of other genetic alterations that affect signaling downstream from EGFR, such as mutation of KRAS, PIK3CA, and loss of PTEN expression.…”

“…The exon 20 insertions frequently associated with EGFR-TKI non-responsiveness, including D770-N771insNPG, D770-N771insSVQ, D770-N771insG, and point mutations, including T790M, V769L, and N771T. 15,67 The most important mutation in exon 20 is T790M, which is associated with a small fraction of adenocarcinomas with primary resistance to EGFR TKI and over one-half of the patients with acquired resistance to EGFR TKI ( Figure 2). 12,[67][68][69][70][71] A comprehensive literature review by Yamamoto et al 33 indicated that 569 mutations were found in 2880 lung cancer patients (20%).…”

“…13,15,22,38,193 A subset of lung adenocarcinomas show primary resistance to EGFR TKI therapy, even in the presence of an activating mutation in EGFR. 194 The most commonly found mutations associated with TKI drug sensitivity include exon 19 deletions downstream of the lysine residue at position 745 (DE746-A750), point mutations in exon 21 (L858R and L861Q and L861R), in exon 18 (G719A/C/S), and in exon 20 (V765A, T783A, and S768I).…”

“…[10][11][12][13] EGFR and members of its family have an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility, and neovascularization. [12][13][14][15][16] EGFR alterations have been implicated in the pathogenesis and progression of many malignancies. 13,[17][18][19][20][21] The incidence of EGFR mutations in unselected tumors with non-small cell histology ranges from 10 to 50%, depending upon the ethnic makeup of the patient population and the detection methods used for mutation analysis; 95% of such mutations have been found in adenocarcinomas.…”

“…5,28,29,[37][38][39] Recent studies have provided more compelling evidence of the clinical benefits of anti-EGFR treatment in the appropriate setting. 13,15,22,38,[40][41][42][43][44][45][46][47][48] Evidence from the large phase III randomized Iressa Pan-Asia Study trial and other phase III trials have prompted the American Society of Clinical Oncology to issue a provisional clinical opinion recommending the testing of EGFR mutational status in patients being considered for first line EGFR TKI therapy owing to their demonstrated benefit on progression-free survival. 22,41 Of note, they caution that no definitive benefit has been shown in patients treated with first-line TKIs in regards to overall survival.…”