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https://www.readbyqxmd.com/read/29033419/successful-osimertinib-rechallenge-with-steroid-therapy-after-osimertinib-induced-interstitial-lung-disease-a-case-report
#1
Tatsunori Kiriu, Daisuke Tamura, Motoko Tachihara, Reina Sekiya, Daisuke Hazama, Masahiro Katsurada, Kyosuke Nakata, Tatsuya Nagano, Masatsugu Yamamoto, Hiroshi Kamiryo, Kazuyuki Kobayashi, Yoshihiro Nishimura
A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the EGFR was treated with EGFR-TKIs and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone...
October 16, 2017: Internal Medicine
https://www.readbyqxmd.com/read/29031620/targeting-non-small-cell-lung-cancer-with-small-molecule-egfr-tyrosine-kinase-inhibitors
#2
REVIEW
Mahaveer Singh, Hemant R Jadhav
Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790M mutants, sparing wild-type EGFR...
October 12, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28989039/first-line-osimertinib-in-patients-with-treatment-na%C3%A3-ve-somatic-or-germline-egfr-t790m-mutant-metastatic-nsclc
#3
Katerina Ancevski Hunter, David M Friedland, Liza C Villaruz, Timothy F Burns
INTRODUCTION: In rare cases, patients present with baseline (somatic or germline) Epidermal Growth Factor Receptor (EGFR) Thr790Met (T790M) mutations prior to EGFR tyrosine kinase inhibitor (TKI) treatment. This mutation confers resistance to first and second generation TKIs. Osimertinib is a third generation TKI that is FDA approved for use in patients with the EGFR T790M mutation and who have progressed on TKI treatment. To date, the only presented but unpublished experience with first-line osimertinib treatment in 5 patients with baseline T790M mutations who received osimertinib on an expansion cohort of the phase 1 AURA trial...
October 5, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28986130/covalent-binding-design-strategy-a-prospective-method-for-discovery-of-potent-targeted-anticancer-agents
#4
REVIEW
Luhong Wang, Jingyuan Zhao, Yao Yao, Changyuan Wang, Jianbin Zhang, Xiaohong Shu, Xiuli Sun, Yanxia Li, Kexin Liu, Hong Yuan, Xiaodong Ma
Cancer remains the most serious disease that threatens human health. Molecularly targeted cancer therapies, specifically small-molecule protein kinase inhibitors, form an important part of cancer therapy. Targeted covalent modification represents a proven approach to drug discovery with the recent FDA approvals of afatanib, ibrutinib, and osimertinib agents, which were designed to undergo an irreversible hetero-Michael addition reaction with a unique cysteine residue of a specific protein. Covalent inhibitors possess numerous advantages, including increased biochemical efficacy, longer duration of action, the high potential for improved therapeutic index due to lower effective dose, and the potential to inhibit certain drug resistance mechanisms...
September 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28965727/proteome-wide-map-of-targets-of-t790m-egfr-directed-covalent-inhibitors
#5
Sherry Niessen, Melissa M Dix, Sabrina Barbas, Zachary E Potter, Shuyan Lu, Oleg Brodsky, Simon Planken, Douglas Behenna, Chau Almaden, Ketan S Gajiwala, Kevin Ryan, RoseAnn Ferre, Michael R Lazear, Matthew M Hayward, John C Kath, Benjamin F Cravatt
Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities...
September 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28961841/dual-met-and-erbb-inhibition-overcomes-intratumor-plasticity-in-osimertinib-resistant-advanced-non-small-cell-lung-cancer-nsclc
#6
A Martinez-Marti, E Felip, J Matito, E Mereu, A Navarro, S Cedrés, N Pardo, A Martinez de Castro, J Remon, J M Miquel, A Guillaumet-Adkins, E Nadal, G Rodriguez-Esteban, O Arqués, R Fasani, P Nuciforo, H Heyn, A Villanueva, H G Palmer, A Vivancos
Background: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. Methods: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28887354/osimertinib-may-be-an-effective-first-line-therapy-in-egfr-mutant-nsclc
#7
(no author information available yet)
Osimertinib achieved objective responses in 77% of patients with treatment-naïve NSCLC.
September 8, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28884371/egfr-t790m-mutation-testing-of-non-small-cell-lung-cancer-tissue-and-blood-samples-artificially-spiked-with-circulating-cell-free-tumor-dna-results-of-a-round-robin-trial
#8
Jana Fassunke, Michaela Angelika Ihle, Dido Lenze, Annika Lehmann, Michael Hummel, Claudia Vollbrecht, Roland Penzel, Anna-Lena Volckmar, Albrecht Stenzinger, Volker Endris, Andreas Jung, Ulrich Lehmann, Silke Zeugner, Gustavo Baretton, Hans Kreipe, Peter Schirmacher, Thomas Kirchner, Manfred Dietel, Reinhard Büttner, Sabine Merkelbach-Bruse
The European Commision (EC) recently approved osimertinib for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutations. Besides tissue-based testing, blood samples containing cell-free circulating tumor DNA (ctDNA) can be used to interrogate T790M status. Herein, we describe the conditions and results of a round robin trial (RRT) for T790M mutation testing in NSCLC tissue specimens and peripheral blood samples spiked with cell line DNA mimicking tumor-derived ctDNA...
September 8, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28880737/cost-effectiveness-of-osimertinib-in-the-uk-for-advanced-egfr-t790m-non-small-cell-lung-cancer
#9
Evelina Bertranou, Carolyn Bodnar, Viktor Dansk, Alastair Greystoke, Samuel Large, Matthew Dyer
AIM: This study presents the cost-utility analysis that was developed to inform the NICE health technology assessment of osimertinib vs platinum-based doublet chemotherapy (PDC) in patients with EGFR-T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS AND MATERIALS: A partitioned survival model with three health states (progression-free, progressed disease, and death) from a UK payer perspective and over lifetime (15 years) was developed...
September 21, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/28880013/osimertinib-azd9291-decreases-programmed-death-ligand-1-in-egfr-mutated-non-small-cell-lung-cancer-cells
#10
Xiao-Ming Jiang, Yu-Lian Xu, Mu-Yang Huang, Le-Le Zhang, Min-Xia Su, Xiuping Chen, Jin-Jian Lu
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells...
September 7, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28860885/osimertinib-in-the-treatment-of-non-small-cell-lung-cancer-design-development-and-place-in-therapy
#11
REVIEW
Mariacarmela Santarpia, Alessia Liguori, Niki Karachaliou, Maria Gonzalez-Cao, Maria Grazia Daffinà, Alessandro D'Aveni, Grazia Marabello, Giuseppe Altavilla, Rafael Rosell
The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients...
2017: Lung Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28843359/combination-osimertinib-and-gefitinib-in-c797s-and-t790m-egfr-mutated-non-small-cell-lung-cancer
#12
Surein Arulananda, Hongdo Do, Ashan Musafer, Paul Mitchell, Alexander Dobrovic, Thomas John
INTRODUCTION: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib...
August 24, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28841389/osimertinib-as-first-line-treatment-of-egfr-mutation-positive-advanced-non-small-cell-lung-cancer
#13
Suresh S Ramalingam, James C-H Yang, Chee Khoon Lee, Takayasu Kurata, Dong-Wan Kim, Thomas John, Naoyuki Nogami, Yuichiro Ohe, Helen Mann, Yuri Rukazenkov, Serban Ghiorghiu, Daniel Stetson, Aleksandra Markovets, J Carl Barrett, Kenneth S Thress, Pasi A Jänne
Purpose The Osimertinib First Time in Patients Ascending Dose (AURA) study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort)...
August 25, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28839001/t790m-selective-egfr-tki-combined-with-dasatinib-as-an-optimal-strategy-for-overcoming-egfr-tki-resistance-in-t790m-positive-non-small-cell-lung-cancer
#14
Satomi Watanabe, Takeshi Yoshida, Hisato Kawakami, Naoki Takegawa, Junko Tanizaki, Hidetoshi Hayashi, Masayuki Takeda, Kimio Yonesaka, Junji Tsurutani, Kazuhiko Nakagawa
T790M mutation-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as co-oncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced anti-tumor activity in T790M-positive cells...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28838405/emergence-of-egfr-g724s-mutation-in-egfr-mutant-lung-adenocarcinoma-post-progression-on-osimertinib
#15
A Oztan, S Fischer, A B Schrock, R L Erlich, C M Lovly, P J Stephens, J S Ross, V Miller, S M Ali, S-H I Ou, L E Raez
Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28838400/emergence-of-fgfr3-tacc3-fusions-as-a-potential-by-pass-resistance-mechanism-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutated-nsclc-patients
#16
Sai-Hong Ignatius Ou, Leora Horn, Marcelo Cruz, Davood Vafai, Christine M Lovly, Allison Spradlin, Michael J Williamson, Ibiayi Dagogo-Jack, Adrienne Johnson, Vincent A Miller, Shirish Gadgeel, Siraj M Ali, Alexa B Schrock
Resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) with activating EGFR mutations generally involve development of acquired secondary or tertiary EGFR mutations, such as T790M or C797S. However, case reports have demonstrated that actionable receptor tyrosine kinase fusions such as EML4-ALK, CCDC6-RET, and FGFR3-TACC3 can potentially confer resistance to EGFR TKIs. We seeked to identify the prevalence of FGFR3-TACC3 fusion transcripts as resistance mechanism to EGFR TKIs...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28838392/detection-of-epidermal-growth-factor-receptor-gene-t790m-mutation-in-cytology-samples-using-the-cobas-%C3%A2-egfr-mutation-test
#17
Miyako Satouchi, Hiroshi Tanaka, Hiroshige Yoshioka, Tadasuke Shimokawaji, Keiko Mizuno, Koji Takeda, Ichiro Yoshino, Takashi Seto, Takayasu Kurata, Naoki Tashiro, Koichi Hagiwara
OBJECTIVE: Detection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28830985/characterization-of-in-vivo-resistance-to-osimertinib-and-jnj-61186372-an-egfr-met-bi-specific-antibody-reveals-unique-and-consensus-mechanisms-of-resistance
#18
Kristina B Emdal, Antje Dittmann, Raven J Reddy, Rebecca S Lescarbeau, Sheri L Moores, Sylvie Laquerre, Forest M White
Approximately 10% of non-small cell lung cancer (NSCLC) patients in the U.S. and 40% of NSCLC patients in Asia have activating EGFR mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be co-targeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival...
August 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28808573/osimertinib-induced-interstitial-lung-disease-in-a-patient-with-non-small-cell-lung-cancer-pretreated-with-nivolumab-a-case-report
#19
Osamu Takakuwa, Tetsuya Oguri, Takehiro Uemura, Kazuki Sone, Satoshi Fukuda, Minami Okayama, Yoshihiro Kanemitsu, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito, Ken Maeno, Akio Niimi
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene...
September 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28806116/systemic-therapy-for-stage-iv-non-small-cell-lung-cancer-american-society-of-clinical-oncology-clinical-practice-guideline-update
#20
Nasser Hanna, David Johnson, Sarah Temin, Sherman Baker, Julie Brahmer, Peter M Ellis, Giuseppe Giaccone, Paul J Hesketh, Ishmael Jaiyesimi, Natasha B Leighl, Gregory J Riely, Joan H Schiller, Bryan J Schneider, Thomas J Smith, Joan Tashbar, William A Biermann, Gregory Masters
Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development...
October 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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