CPNPC avançado com EGFRm
*Afatinib, erlotinib, and gefitinib
†Definido como gefitinibe e erlotinibe.
A resistência adquirida afeta pacientes que responderam inicialmente à terapia com TKI do EGFR de primeira geração†e, então, não mais responderam. A resistência adquirida ocorre na maior parte dos pacientes com CPNPC tratados com TKIs do EGFR de primeira geração† 12
‡Estudos publicados nos últimos quatro anos (erlotinibe, gefitinibe). Manuscrito principal, N ≥ 50. Biópsia de tecido em caráter prospectivo realizada na progressão da doença. Desfecho primário = examinar os mecanismos moleculares da resistência adquirida; metodologia relatada.
Resistant Mechanisms to EGFR TKIs
Resistant Mechanisms to EGFR TKIs
Steric hindrance, which reduces receptor binding of reversible EGFR TKIs22
Increased binding affinity of EGFR for ATP, resulting in reduced TKI potency23
Obstáculo estérico, que reduz a ligação aos receptores de TKIs do EGFR reversíveis22
Afinidade de ligação aumentada do EGFR por ATP, resultando em potência reduzida do TKI23
1. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 2. American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Published 2014. Accessed March 20, 2015. 3. Kris MG, et al.Identification of driver mutations in tumour specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC) ASCO meeting abstract. J Clin Oncol. 2011;29(suppl):CRA7506. 4. Langer CJ. Epidermal growth factor receptor inhibition in mutation-positive non–small-cell lung cancer. is afatinib better or simply newer? J Clin Oncol.2013;27:3303-3306. 5. Cheng L,et al. Molecular pathology of lung cancer: key to personalized medicine.Mod Pathol. 2012;20:347-369. 6. Shigematsu H, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339-346. 7. Sekine I, et al. Emerging ethnic differences in lung cancer therapy. Br J Cancer. 2008;99:1757-1762. 8. Hirsch FR, et al. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009;10:432-433. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-small Cell Lung Cancer v6.2015. © National Comprehensive Cancer Network,Inc 2015. All rights reserved. Accessed May 18, 2015.To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®,NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 10. Sequist LV, etal.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. 11. Mok TS,et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 12. Nurwidya F, et al. Molecular mechanisms contributing to resistance to tyrosine kinase-targeted therapy for non-small cell lung cancer. Cancer Biol Med. 2012;9(1):18-22. 13. Yu HA, et al. Analysis of tumour specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 14. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 15. Cortot AB, Janne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respi Rev. 2014;23:356-366. 16. Oxnard GR, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumours harboring the T790M mutation. Clin Cancer Res. 2011;17:1616-1622. 17. Sun JM, et al. Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer. 2013;82:294-298. 18. Kuiper JL, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014;85:19-24. 19. Li W, et al. T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 2014;84:295-300. 20. Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012;11(3)784-791. 21. Chmielecki J,et al.Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3:90ra59. 22. Kobayashi S, et al.EGFR mutation and resistance of non–small-cell lung cancer to gefitinib.N Engl J Med. 2005;352(8):786-792. 23. Yun CH, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070-2075. 24. Pao W, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:225-235.