Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy
Mariacarmela Santarpia,1 Alessia Liguori,1 Niki Karachaliou,2 Maria Gonzalez-Cao,3 Maria Grazia Daffinà,1 Alessandro D’Aveni,1 Grazia Marabello,1 Giuseppe Altavilla,1 Rafael Rosell3–5 1Medical Oncology Unit, Department of Human Pathology “G. Barresi&rdquo...
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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2017
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| Acceso en línea: | https://doaj.org/article/4766e798cf9941aea5df612b6b3c637f |
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| Sumario: | Mariacarmela Santarpia,1 Alessia Liguori,1 Niki Karachaliou,2 Maria Gonzalez-Cao,3 Maria Grazia Daffinà,1 Alessandro D’Aveni,1 Grazia Marabello,1 Giuseppe Altavilla,1 Rafael Rosell3–5 1Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy; 2Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, 3Department of Oncology, Institute of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, 4Cancer Biology and Precision Medicine Program, Germans Trias i Pujol Research Institute, 5Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Spain Abstract: The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I–III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients. Keywords: osimertinib, T790M mutation, epidermal growth factor receptor, tyrosine kinase inhibitors |
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