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Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib.
Target Oncol. 2019 02; 14(1):75-83.TO

Abstract

BACKGROUND

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.

OBJECTIVE

To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.

PATIENTS AND METHODS

In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.

RESULTS

Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.

CONCLUSION

EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

Authors+Show Affiliations

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140, Vienna, Austria. maximilian.hochmair@wienkav.at.Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140, Vienna, Austria.Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140, Vienna, Austria. Cardiothoracic and Vascular Center, Sigmund Freud University, Kelsenstrasse 2, 1030, Vienna, Austria.Department of Radiology, Comprehensive Cancer Center, Medical University of Vienna, Währingergürtel 18-22, 1090, Vienna, Austria.Department of Internal Medicine 1, Wilhelminen Hospital, Montleartstraβe 37, 1160, Vienna, Austria.Boehringer Ingelheim RCV GmbH & Co. KG, Doktor-Boehringer-Gasse 5-11, 1120, Vienna, Austria.Boehringer Ingelheim RCV GmbH & Co. KG, Doktor-Boehringer-Gasse 5-11, 1120, Vienna, Austria.Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30539501

Citation

Hochmair, Maximilian J., et al. "Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients With Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib." Targeted Oncology, vol. 14, no. 1, 2019, pp. 75-83.
Hochmair MJ, Buder A, Schwab S, et al. Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib. Target Oncol. 2019;14(1):75-83.
Hochmair, M. J., Buder, A., Schwab, S., Burghuber, O. C., Prosch, H., Hilbe, W., Cseh, A., Fritz, R., & Filipits, M. (2019). Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib. Targeted Oncology, 14(1), 75-83. https://doi.org/10.1007/s11523-018-0612-z
Hochmair MJ, et al. Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients With Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib. Target Oncol. 2019;14(1):75-83. PubMed PMID: 30539501.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib. AU - Hochmair,Maximilian J, AU - Buder,Anna, AU - Schwab,Sophia, AU - Burghuber,Otto C, AU - Prosch,Helmut, AU - Hilbe,Wolfgang, AU - Cseh,Agnieszka, AU - Fritz,Richard, AU - Filipits,Martin, PY - 2018/12/13/pubmed PY - 2020/1/7/medline PY - 2018/12/13/entrez SP - 75 EP - 83 JF - Targeted oncology JO - Target Oncol VL - 14 IS - 1 N2 - BACKGROUND: Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. OBJECTIVE: To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. PATIENTS AND METHODS: In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. RESULTS: Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. CONCLUSION: EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment. SN - 1776-260X UR - https://www.unboundmedicine.com/medline/citation/30539501/Liquid_Biopsy_Based_Identification_of_EGFR_T790M_Mutation_Mediated_Resistance_to_Afatinib_Treatment_in_Patients_with_Advanced_EGFR_Mutation_Positive_NSCLC_and_Subsequent_Response_to_Osimertinib_ L2 - https://dx.doi.org/10.1007/s11523-018-0612-z DB - PRIME DP - Unbound Medicine ER -