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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
#1
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
#2
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...
August 14, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28794650/treating-egfr-mutation-resistance-in-non-small-cell-lung-cancer-role-of-osimertinib
#3
REVIEW
Valentina Mazza, Federico Cappuzzo
The discovery of mutations in EGFR significantly changed the treatment paradigm of patients with EGFR-mutant non-small cell lung cancer (NSCLC), a particular group of patients with different clinical characteristics and outcome to EGFR-wild-type patients. In these patients, the treatment of choice as first-line therapy is first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, or afatinib. Inevitably, after the initial response, all patients become refractory to these drugs...
2017: Application of Clinical Genetics
https://www.readbyqxmd.com/read/28794368/interstitial-lung-disease-induced-by-osimertinib-for-epidermal-growth-factor-receptor-egfr-t790m-positive-non-small-cell-lung-cancer
#4
Yoshiya Matsumoto, Tomoya Kawaguchi, Norio Yamamoto, Kenji Sawa, Naoki Yoshimoto, Tomohiro Suzumura, Tetsuya Watanabe, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Naruo Yoshimura, Yuko Kuwae, Kazuto Hirata
A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration...
August 10, 2017: Internal Medicine
https://www.readbyqxmd.com/read/28781309/congestive-heart-failure-during-osimertinib-treatment-for-epidermal-growth-factor-receptor-egfr-mutant-non-small-cell-lung-cancer-nsclc
#5
Hiromi Watanabe, Eiki Ichihara, Hirohisa Kano, Kiichiro Ninomiya, Mitsune Tanimoto, Katsuyuki Kiura
We herein report a case of congestive heart failure which developed during osimertinib treatment. A 78-year-old woman presented with mild exertional dyspnea three weeks after starting osimertinib for the treatment of epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer. She was diagnosed with congestive heart failure caused by the osimertinib. In contrast to trastuzumab, a human epidermal growth factor receptor 2 (HER2) monoclonal antibody that often causes cardiac dysfunction, the causal relationship between osimertinib and cardiotoxicity has so far received little attention and thus remains unclear...
August 15, 2017: Internal Medicine
https://www.readbyqxmd.com/read/28765329/overcoming-acquired-resistance-to-azd9291-a-third-generation-egfr-inhibitor-through-modulation-of-mek-erk-dependent-bim-and-mcl-1-degradation
#6
Puyu Shi, You-Take Oh, Liang Deng, Guojing Zhang, Guoqing Qian, Shuo Zhang, Hui Ren, Grant Wu, Benjamin Legendre, Emily Anderson, Suresh S Ramalingam, Taofeek K Owonikoko, Mingwei Chen, Shi-Yong Sun
<p>The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.</p> <br /><br />Experimental Design: <p>AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28754471/how-to-train-your-inhibitor-design-strategies-to-overcome-resistance-to-epidermal-growth-factor-receptor-inhibitors
#7
REVIEW
Sandra N Milik, Deena S Lasheen, Rabah A T Serya, Khaled A M Abouzid
Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015...
July 18, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28751247/brief-report-modulation-of-biomarker-expression-by-osimertinib-results-of-the-paired-tumor-biopsy-cohorts-of-the-aura-phase-i-trial
#8
Kenneth S Thress, Vivien Jacobs, Helen K Angell, James Chih-Hsin Yang, Lecia V Sequist, Fiona Blackhall, Wu-Chou Su, Martin Schuler, Jürgen Wolf, Kathryn A Gold, Mireille Cantarini, J Carl Barrett, Pasi A Jänne
INTRODUCTION: Osimertinib is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI and T790M resistance mutations. To enhance understanding of osimertinib's mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers post-osimertinib in paired clinical samples from the Phase I AURA trial. METHODS: Paired tumor biopsies were collected pre-study and following 15±7 days of osimertinib treatment (80 or 160 mg daily)...
July 24, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28736180/retreatment-with-osimertinib-following-pneumonitis
#9
Misako Nagasaka, Shirish M Gadgeel
No abstract text is available yet for this article.
July 6, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28730963/increased-expression-of-ire1%C3%AE-associates-with-the-resistant-mechanism-of-osimertinib-azd9291-resistant-non-small-cell-lung-cancer-hcc827-osir-cells
#10
Zheng-Hai Tang, Min-Xia Su, Xia Guo, Xiao-Ming Jiang, Lin Jia, Xiuping Chen, Jin-Jian Lu
BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay...
July 19, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28716641/synthesis-and-evaluation-of-osimertinib-derivatives-as-potent-egfr-inhibitors
#11
Hongying Gao, Zimo Yang, Xinglin Yang, Yu Rao
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28710746/osimertinib-a-review-in-t790m-positive-advanced-non-small-cell-lung-cancer
#12
REVIEW
Yvette N Lamb, Lesley J Scott
Osimertinib (Tagrisso™) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR TKI-sensitizing mutations and, crucially, the T790M mutation that often underlies acquired resistance to EGFR TKI therapy. Osimertinib has been approved in numerous countries for use in patients with T790M-positive advanced NSCLC. In the pivotal, international AURA3 trial in patients with T790M-positive advanced NSCLC who had disease progression after EGFR TKI therapy, osimertinib treatment significantly prolonged progression-free survival (PFS; primary endpoint) compared with platinum-pemetrexed therapy at the time of the primary analysis...
August 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28708233/treatment-in-egfr-mutated-non-small-cell-lung-cancer-how-to-block-the-receptor-and-overcome-resistance-mechanisms
#13
REVIEW
Claudia Proto, Giuseppe Lo Russo, Giulia Corrao, Monica Ganzinelli, Francesco Facchinetti, Roberta Minari, Marcello Tiseo, Marina Chiara Garassino
In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months...
July 31, 2017: Tumori
https://www.readbyqxmd.com/read/28701107/overcoming-resistance-to-egfr-tyrosine-kinase-inhibitors-in-lung-cancer-focusing-on-non-t790m-mechanisms
#14
Kenichi Suda, Christopher J Rivard, Tetsuya Mitsudomi, Fred R Hirsch
despite initial dramatic efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer patients, emergence of acquired resistance is almost inevitable. The EGFR T790M secondary mutation that accounts for ~50% of resistance is now treatable with osimertinib. However, for the remaining 50% of patients who develop resistance mechanisms other than T790M mutation, cytotoxic chemotherapies are still the standard of care and novel treatment strategies are urgently needed. Areas covered: In this review, we discuss current experimental and clinical evidence to develop better treatment strategies to overcome or prevent acquired resistance to EGFR-TKIs in lung cancers, focusing on non-T790M mechanisms...
July 17, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28699260/australian-recommendations-for-egfr-t790m-testing-in-advanced-non-small-cell-lung-cancer
#15
REVIEW
Thomas John, Jeffrey J Bowden, Stephen Clarke, Stephen B Fox, Kerryn Garrett, Keith Horwood, Christos S Karapetis
First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line therapy in patients with non-small cell lung cancer (NSCLC) harboring a sensitizing mutation in the EGFR gene. Unfortunately, resistance to these therapies often occurs within 10 months of commencing treatment and is mostly commonly due to the development of the EGFR T790M mutation. Treatment with the third-generation EGFR TKI, osimertinib can prolong progression free survival in patients with the T790M mutation, so it is important to determine the resistance mechanism in order to plan ongoing therapeutic strategies...
August 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28680534/nsclc-depend-upon-yap-expression-and-nuclear-localization-after-acquiring-resistance-to-egfr-inhibitors
#16
Marc McGowan, Lilach Kleinberg, Ann Rita Halvorsen, Åslaug Helland, Odd Terje Brustugun
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes...
March 2017: Genes & Cancer
https://www.readbyqxmd.com/read/28676222/optimal-management-of-egfr-mutant-non-small-cell-lung-cancer-with-disease-progression-on-first-line-tyrosine-kinase-inhibitor-therapy
#17
REVIEW
Bin-Chi Liao, Chia-Chi Lin, Jih-Hsiang Lee, James Chih-Hsin Yang
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, and the second-generation EGFR-TKI, afatinib, have all been approved as standard first-line treatments for advanced EGFR-mutant non-small cell lung cancer (NSCLC) based on superior progression-free survival results compared to platinum doublet chemotherapy regimens. Acquired resistance to an EGFR-TKI inevitably develops after a period of effective drug treatment. After tumor progression, many combination therapy regimens that include an EGFR-TKI, or EGFR-TKI monotherapy, have been tested in prospective trials with the aim of extending survival...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28662863/lung-adenocarcinoma-harboring-egfr-t790m-and-in%C3%A2-trans-c797s-responds-to-combination-therapy-of-first-and-third-generation-egfr-tkis-and-shifts-allelic-configuration-at-resistance
#18
Zhen Wang, Jin-Ji Yang, Jie Huang, Jun-Yi Ye, Xu-Chao Zhang, Hai-Yan Tu, Han Han-Zhang, Yi-Long Wu
INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as EGFR C797S. In vitro study proved that cells harboring EGFR C797S in trans with T790M are sensitive to a combination of first- and third-generation EGFR tyrosine kinase inhibitors. However, this has not been reported clinically. METHODS: We performed capture-based sequencing on longitudinal plasma samples obtained at various treatment milestones from a patient with advanced lung adenocarcinoma who was undergoing targeted therapy...
June 27, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28625657/synergy-between-next-generation-egfr-tyrosine-kinase-inhibitors-and-mir-34a-in-the-inhibition-of-non-small-cell-lung-cancer
#19
Jane Zhao, Adriana Guerrero, Kevin Kelnar, Heidi J Peltier, Andreas G Bader
OBJECTIVES: EGFR tyrosine kinase inhibitors (TKIs) are widely used to treat NSCLC, primarily patients with activating mutations, with more limited response in wild-type disease. However, even with EGFR-mutated disease, many patients fail to respond, most who initially respond fail to respond completely, and almost all develop resistance and inevitably progress. New therapeutic options that improve these outcomes could provide substantial clinical benefit. We previously demonstrated strong synergistic effects between erlotinib and the tumor suppressor microRNA miR-34a, sensitizing NSCLC cells with primary resistance (EGFR wild-type) and restoring sensitivity in cells with acquired resistance...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625644/treatment-options-for-egfr-mutant-nsclc-with-cns-involvement-can-patients-bloom-with-the-use-of-next-generation-egfr-tkis
#20
REVIEW
Chee-Seng Tan, Byoung Chul Cho, Ross A Soo
With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of CNS metastases has been observed during the course of the disease. CNS metastases remains a therapeutically challenging subset of patient to treat owing to the blood-brain barrier (BBB). Prior to routine EGFR mutation testing, surgical resection, stereotactic radiosurgery and/or whole brain radiation therapy (WBRT) were the main treatment options whereas treatment options for patients with leptomeningeal metastases (LM) included intra-thecal chemotherapy, WBRT, and ventriculo-peritoneal shunting...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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