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World J Respirol. Jul 28, 2016; 6(2): 57-62
Published online Jul 28, 2016. doi: 10.5320/wjr.v6.i2.57
New era of epidermal growth factor receptor-tyrosine kinase inhibitors for lung cancer
Joana Espiga Macedo
Joana Espiga Macedo, Department of Medical Oncology, Centro Hospitalar de Entre Douro e Vouga, 4520-211 Santa Maria Da Feira, Portugal
Author contributions: Macedo JE contributed to article conception, writing, editing and reviewing the final approval of the article.
Conflict-of-interest statement: Macedo JE has received fees for serving as a speaker, such as consultant and/or an advisory board member for Celgene, Merck and Roche.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Joana Espiga Macedo, MD, Consultant of Medical Oncology, Department of Medical Oncology, Centro Hospitalar de Entre Douro e Vouga, Rua Dr. Cândido de Pinho, 4520-211 Santa Maria Da Feira, Portugal. joanamacedo@hotmail.com
Telephone: +351-93-6050138 Fax: +351-25-6373867
Received: August 27, 2015
Peer-review started: August 31, 2015
First decision: October 8, 2015
Revised: May 25, 2016
Accepted: June 27, 2016
Article in press: June 29, 2016
Published online: July 28, 2016
Processing time: 327 Days and 1.9 Hours
Abstract

Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor (EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors (TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase I clinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.

Keywords: Epidermal growth factor receptor-tyrosine kinase inhibitors; Clonal evolution; Non-small cell lung cancer; Acquired resistance

Core tip: Dramatic changes have occurred in the last decades, concerning the treatment of lung cancer. The knowledge of clinical, pathological and molecular pathways has allowed sub-classifying non-small cell lung cancer (NSCLC), to a point where it has never been reached. The determination of activating mutations of epidermal growth factor receptor (EGFR) has permitted the use of EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib in first, second and maintenance setting. However, acquired resistance develops at some stage of the disease, and second generation TKIs have been developed, but with similar results to traditional chemotherapy. With the arrival of third generation TKIs, a selective target mutational personalized therapy has accomplished better response rates, with a lower toxicity profile in phase I clinical trials. The question is should NSCLC patients with exon 19del and L858R point mutation in exon 21 be treated differently, once the driver oncogene is known? On the other hand, if patients with acquired resistance with EGFR T790M, should they also be treated targeting this predominant clone?