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Targeting EGFR in Lung Cancer: Current Standards and Developments

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Abstract

Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15–40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.

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Authors and Affiliations

  1. Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain

    Asunción Díaz-Serrano, Elisabeth Jiménez, Jon Zugazagoitia & Luis Paz-Ares Rodríguez

  2. Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain

    Asunción Díaz-Serrano, Pablo Gella, Elisabeth Jiménez, Jon Zugazagoitia & Luis Paz-Ares Rodríguez

  3. Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, CT, 06520, USA

    Jon Zugazagoitia

  4. Medicine School, Universidad Complutense de Madrid, Madrid, Spain

    Luis Paz-Ares Rodríguez

  5. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Jon Zugazagoitia & Luis Paz-Ares Rodríguez

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  1. Asunción Díaz-Serrano
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Luis Paz-Ares has received consulting fees or honorarium from Roche, AstraZeneca, Pfizer, Boehringer Mannheim, Lilly, MSD, Merck, Novartis, and Astellas. Asunción Díaz-Serrano, Pablo Gella, Elisabeth Jiménez, and Jon Zugazagoitia declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Díaz-Serrano, A., Gella, P., Jiménez, E. et al. Targeting EGFR in Lung Cancer: Current Standards and Developments. Drugs 78, 893–911 (2018). https://doi.org/10.1007/s40265-018-0916-4

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