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Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms.
Tumori 2017; 103(4):325-337T

Abstract

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.

Authors+Show Affiliations

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.Thoracic Oncology Unit, Medical Oncology Unit, University Hospital of Parma, Parma - Italy.Thoracic Oncology Unit, Medical Oncology Unit, University Hospital of Parma, Parma - Italy.Thoracic Oncology Unit, Medical Oncology Unit, University Hospital of Parma, Parma - Italy.Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

28708233

Citation

Proto, Claudia, et al. "Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and Overcome Resistance Mechanisms." Tumori, vol. 103, no. 4, 2017, pp. 325-337.
Proto C, Lo Russo G, Corrao G, et al. Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms. Tumori. 2017;103(4):325-337.
Proto, C., Lo Russo, G., Corrao, G., Ganzinelli, M., Facchinetti, F., Minari, R., ... Garassino, M. C. (2017). Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms. Tumori, 103(4), pp. 325-337. doi:10.5301/tj.5000663.
Proto C, et al. Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and Overcome Resistance Mechanisms. Tumori. 2017 Jul 31;103(4):325-337. PubMed PMID: 28708233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment in EGFR-mutated non-small cell lung cancer: 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, Y1 - 2017/07/01/ PY - 2017/06/07/accepted PY - 2017/7/15/pubmed PY - 2017/8/18/medline PY - 2017/7/15/entrez SP - 325 EP - 337 JF - Tumori JO - Tumori VL - 103 IS - 4 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. SN - 2038-2529 UR - https://www.unboundmedicine.com/medline/citation/28708233/Treatment_in_EGFR_mutated_non_small_cell_lung_cancer:_how_to_block_the_receptor_and_overcome_resistance_mechanisms_ L2 - http://journals.sagepub.com/doi/full/10.5301/tj.5000663?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -