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      AZD9291-induced Acute Interstitial Lung Disease

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          Abstract

          To the Editor: A 32-year-old Chinese male patient with 1 week cough and dyspnea on exertion was presented to hospital. He was a metastatic lung adenocarcinoma patient with 3 years treatment history. In October 2012, the patient complained cough, short of breath, and thoracic computerized axial tomography scan (CAT-scan) revealed left lung hilum mass with the right lung multismall patches or opacities. Core needle biopsy on supraclavicular lymph nodes was performed and diagnosis of Stage IV (T3N3M1a) lung adenocarcinoma was made by radiologist, pathologist, and oncologist. Chemotherapy with cisplatin and pemetrexed was initiated and a partial response (PR) was reached. After 6 cycles of double-bullet chemotherapy, maintenance therapy with pemetrexed was used. In January 2014, positron emission tomography-computed tomography scan showed the right lung disease progression and bone metastasis. Fine needle aspiration (FNA) was performed on right lung node and genetic sequencing study showed epidermal growth factor receptor (EGFR) 19 del erlotinib (Tarceva, Roche, Switzerland) was administrated orally and both lung lesions became shrunk and a good PR was achieved after 1 month of erlotinib treatment. This result maintained 9.5 months until patient's lung disease progression and liver metastasis which were confirmed by CAT-scan and FNA. The 3rd line treatment with docetaxel (Qilu Pharmaceutical Co., China) and bevacizumab (Avastin, Roche, Switzerland) was administered, PR was reached. Patient's symptoms got severe and CAT-scan showed disease progression on both lungs after 4 months of above treatment. FNA was performed on the right lung lesion and gene panels were tested, it showed EGFR T790M, 19 del, and TP53 mutation. AZD9291 (Tagrisso, Osimertinib, AstraZeneca, UK) was used at a dose of 80 mg oral daily. The patient performed well and CAT-scan showed PR at 1 month follow-up, and the lesions continued remission on the last follow-up at 5.5 months therapy. The patient complained light cough and short of breath on exertion at 4.5 months of AZD9291 therapy. Physical examination was unremarkable; there were no rales or wheezes on chest auscultation. Oxygen saturation was 98%, blood works results were all within normal range. CAT-scan revealed interstitial lung fibrosis change on both lungs and obvious ground-glass opacities on the right upper lung [Figure 1a]. After carefully reviewed patient's history and series CAT-scans, drug-induced acute interstitial lung disease (ILD) was confirmed by pathologist, radiologist, and oncologist. Figure 1 CAT-scan revealed interstitial lung fibrosis change on both lungs. (a) 4.5 months after AZD9291 treatment, right upper lung interstitial fibrosis. (b) One month after AZD9291 dose reduction and dexamethasone treatment. Because AZD9291 was the 4th line therapy of this patient, stop taking it to avoid worsening ILD was quite dangerous for him. The aggressive treatment plan was immediately initiated with dose reduction to 80 mg every other day, low-dose continued oxygen inhalation, and high-dose corticosteroid (10 mg dexamethasone infusion once a day for 10 days). Patient's symptoms got improved, ground-glass opacities on the right lung were remarkable attenuated, and both lung fields got clearer on CAT-scan at 1 month follow-up [Figure 1b]. AZD9291 is an oral, potent, irreversible 3rd generation EGFR tyrosine kinase inhibitor (TKI), inhibits kinase activity. In vitro and in vivo studies, it showed strong inhibition lung cancer cells with EGFR sensitizing mutation or with T790M resistance mutation, but less activity on wild-type compare to the 1st generation gefitinib or erlotinib.[1] In patients with relapsed or metastasized disease after 1st generation TKI, its overall response rate (ORR) was around 50%; and patients with EGFR T790M mutation positive or negative had a 60% ORR and PFS 9.6 months or 21% ORR and PFS 2.8, respectively.[2] ILD is a rare complication during EGFR-TKI therapy, about 1–3% patients will acquire it. The mechanism of TKI-induced ILD is not very clear, TKI interrupting type II pneumocytes and alveolar wall repair may play an important role.[3] There is no standard guideline for the treatment of TKI-induced ILD; current management includes oxygen inhalation, drug discontinuation, and high-dose and prolongs corticosteroids or immunosuppressive. High-dose N-acetylcysteine alleviates pulmonary fibrosis in rats but needs further study in human.[4] The patient had been treated with multiline therapies, maintenance 3rd generation EGFR-TKI is the most reliable method to sustain patient's survival. We reduced 50% dosage of the drug administration according to the half-life and metabolic characters of it,[1] to maintain effective blood drug concentration and maximally reduce its side effects. Drug-induced ILD is a severe and a fatal complication if not intervened promptly. This case showed that early diagnosis and early intervention of this complication is critical important during TKI treatment of advanced nonsmall cell lung cancer. AZD9291 dose reduction and aggressive corticosteroid treatment could be a promising treatment option for patient who required 3rd generation TKI to maintain disease remission. Clinical physicians must cautiously weigh the benefits and risks of targeted therapies causing ILD in order to provide optimal treatments and favorable outcomes. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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          AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.

          The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
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            AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.

            First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. ©2014 American Association for Cancer Research.
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              Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.

              The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFR T790 M) ultimately emerged in most of these patients. The second and third-generation EGFR-TKIs were designed to have more potent inhibition of EGFR and to overcome EGFR T790 M. This review describes the recent developments of these novel EGFR-TKIs.
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                Author and article information

                Journal
                Chin Med J (Engl)
                Chin. Med. J
                CMJ
                Chinese Medical Journal
                Medknow Publications & Media Pvt Ltd (India )
                0366-6999
                20 June 2016
                : 129
                : 12
                : 1507-1508
                Affiliations
                Department of Oncology, Qingdao Central Hospital, Second Affiliated Hospital of Qingdao University, Qingdao, Shandong 266042, China
                Author notes
                Address for correspondence: Dr. You-Xin Ji, Department of Oncology, Qingdao Central Hospital, Second Affiliated Hospital of Qingdao University, Qingdao, Shandong 266042, China E-Mail: mdji001@ 123456gmail.com
                Article
                CMJ-129-1507
                10.4103/0366-6999.183426
                4910381
                27270553
                Copyright: © 2016 Chinese Medical Journal

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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