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      Combined plasma and tissue genotyping of EGFR T790M benefits NSCLC patients: a real‐world clinical example

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          Abstract

          Acquired resistance to epidermal growth factor receptor ( EGFR)‐tyrosine kinase inhibitors ( TKIs) is a prevalent clinical problem in the management of advanced non‐small‐cell lung cancer ( NSCLC) with TKI‐sensitizing mutations in the EGFR gene. Third‐generation EGFRTKIs have demonstrated potent activity against TKI resistance mediated by the EGFR T790M mutation, and standard rebiopsy and liquid biopsy are utilized to assess the T790M status of the NSCLC patients who experienced progressive disease (PD). Here, we conducted a retrospective study to assess 375 patients whose initial biopsy indicated a TKI‐sensitizing mutation (either EGFR 19del or L858R) and who developed PD after treatment with first‐generation TKIs, and assayed for T790M status. We adopted a combination approach in which tissue rebiopsy is preferred, utilizing liquid biopsies when tissue rebiopsy is not feasible. We analyzed the potential predictive clinical factors affecting T790M detection, evaluated the standard rebiopsy and liquid biopsy methods in T790M genotyping, and reported the clinical performance of osimertinib. Our results suggested that primary EGFR 19del, brain metastasis, and longer progression‐free survival of initial EGFRTKI treatment are associated with acquired T790M resistance. T790M‐positive patients significantly benefited from osimertinib. In conclusion, the real‐world clinical adoption of the combination approach with both tissue rebiopsy and liquid biopsy for T790M genotyping may provide significant benefits to patients who have developed PD after first‐generation TKI treatments.

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          Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component.

          Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.
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            Plasma ctDNA Analysis for Detection of the EGFR T790M Mutation in Patients with Advanced Non-Small Cell Lung Cancer.

            Tumor biopsies for detecting EGFR mutations in advanced NSCLC are invasive, costly, and not always feasible for patients with late-stage disease. The clinical utility of the cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc., Pleasanton, CA) with plasma samples from patients with NSCLC at disease progression after previous EGFR tyrosine kinase inhibitor therapy was investigated to determine eligibility for osimertinib treatment.
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              Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies.

              The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research.
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                Author and article information

                Contributors
                jiemajm@sina.com
                yongjung125@sina.com
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                10 April 2019
                May 2019
                : 13
                : 5 ( doiID: 10.1002/mol2.2019.13.issue-5 )
                : 1226-1234
                Affiliations
                [ 1 ] Henan Cancer Hospital The Affiliated Cancer Hospital of Zhengzhou University China
                Author notes
                [*] [* ] Correspondence

                Y. Guo and J. Ma, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, Henan 450008, China

                Fax: +86‐0371‐65587686

                Tel: +86 0371‐65587686

                E‐mails: yongjung125@ 123456sina.com (YG); jiemajm@ 123456sina.com (JM)

                Article
                MOL212481
                10.1002/1878-0261.12481
                6487696
                30927306
                7c43c1f3-4bef-4a44-b3ae-5083e3d87cc9
                © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 July 2018
                : 21 February 2019
                : 05 March 2019
                Page count
                Figures: 3, Tables: 4, Pages: 9, Words: 6071
                Funding
                Funded by: Construction of Precision Medical Data Platform on Lung Cancer and other Common Malignancy
                Award ID: 161100311500
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                mol212481
                May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:29.04.2019

                Oncology & Radiotherapy
                egfr,liquid biopsy,nsclc,osimertinib,pfs,t790m
                Oncology & Radiotherapy
                egfr, liquid biopsy, nsclc, osimertinib, pfs, t790m

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