TY - JOUR
T1 - Treatment in EGFR-mutated non-small cell lung cancer
T2 - How to block the receptor and overcome resistance mechanisms
AU - Proto, Claudia
AU - Lo Russo, Giuseppe
AU - Corrao, Giulia
AU - Ganzinelli, Monica
AU - Facchinetti, Francesco
AU - Minari, Roberta
AU - Tiseo, Marcello
AU - Garassino, Marina Chiara
PY - 2017/7/1
Y1 - 2017/7/1
N2 - In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.
AB - In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.
KW - Epidermal growth factor receptor
KW - Non-small cell lung cancer
KW - Resistance mechanisms
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85027506932&partnerID=8YFLogxK
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U2 - 10.5301/tj.5000663
DO - 10.5301/tj.5000663
M3 - Review article
C2 - 28708233
AN - SCOPUS:85027506932
VL - 103
SP - 325
EP - 337
JO - Tumori
JF - Tumori
SN - 0300-8916
IS - 4
ER -