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      Remarkable response to dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR‐mutant non‐small cell lung cancer

      case-report

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          Abstract

          Dacomitinib, a second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor, is a standard therapeutic option for patients with EGFR‐mutant non‐small cell lung cancer (NSCLC). However, its efficacy in patients with central nervous system lesions is unclear. Here, we describe a case of EGFR‐mutant NSCLC whose neurological symptoms were due to leptomeningeal carcinomatosis that was successfully treated with dacomitinib. After initiation of dacomitinib, the neurological symptoms of the patient were remarkably improved and leptomeningeal dissemination and brain metastases were shown to have regressed on magnetic resonance imaging (MRI) scan. To our knowledge, this is the first report showing the efficacy of dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR‐mutant NSCLC. The current case suggests that dacomitinib is a novel treatment option for patients with EGFR‐mutant NSCLC accompanied by central nervous system lesions, even those with symptomatic leptomeningeal carcinomatosis.

          Key points
          Significant findings of the study

          This is the first report showing the efficacy of dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR‐mutant NSCLC.

          What this study adds

          The current case suggests that dacomitinib is a novel treatment option for patients with EGFR‐mutant NSCLC accompanied by CNS lesions, even in those with symptomatic leptomeningeal carcinomatosis.

          Abstract

          Although dacomitinib is a standard therapeutic option for patients with EGFR‐mutant non‐small cell lung cancer (NSCLC), its efficacy in patients with CNS lesions is unclear. Here, we describe a case of EGFR‐mutant NSCLC with leptomeningeal carcinomatosis that was successfully treated with dacomitinib.

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          Most cited references10

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          Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.

          Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC).
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            The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.

            Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the "gatekeeper" residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a "generic" resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
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              Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations.

              Leptomeningeal metastases (LM) have increased in patients with NSCLC, and prognostic factors and outcomes for LM with EGFR gene mutations have not been well studied.
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                Author and article information

                Contributors
                ootsubo@kokyu.med.kyushu-u.ac.jp
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                28 October 2020
                January 2021
                : 12
                : 1 ( doiID: 10.1111/tca.v12.1 )
                : 114-116
                Affiliations
                [ 1 ] Department of Respiratory Medicine Kitakyushu Municipal Medical Center Fukuoka Japan
                Author notes
                [*] [* ] Correspondence

                Kohei Otsubo, Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, 2‐1‐1 Bashaku, Kokurakita‐ku, Kitakyushu, Fukuoka 802‐0077, Japan.

                Tel: +81‐93‐541‐1831

                Fax: +81‐93‐533‐8718

                Email: ootsubo@ 123456kokyu.med.kyushu-u.ac.jp

                Author information
                https://orcid.org/0000-0002-9476-8840
                Article
                TCA13712
                10.1111/1759-7714.13712
                7779185
                33112047
                703dcb1f-e28a-456c-9bdd-2a3053d71903
                © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, 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
                : 12 September 2020
                : 05 October 2020
                : 05 October 2020
                Page count
                Figures: 2, Tables: 0, Pages: 3, Words: 1351
                Categories
                Case Report
                Case Reports
                Custom metadata
                2.0
                January 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:03.01.2021

                dacomitinib,egfr mutation,leptomeningeal carcinomatosis,non‐small cell lung cancer

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