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https://www.readbyqxmd.com/read/28219203/-precision-first-line-therapy-for-advanced-non-small-cell-lung-cancer-patients-harboring-egfr-mutation
#1
D M Yuan, Y Song
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become the preferred treatment option for advanced non-small-cell lung cancer (NSCLC) patients with activating mutations in epidermal growth factor receptor (EGFR) according to major practice guidelines. Gefitinib, elortinib and icotinib formed the cornerstone of first-line EGFR-TKIs in the clinical practice in our country. Now, with the continuously emerging of new types of EGFR-TKIs and ever-increasing publication of clinical trial results on afatinib, AZD9291 and other TKIs, we have more first-line choices for patients with EGFR mutations...
February 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28061471/transformation-to-small-cell-carcinoma-as-an-acquired-resistance-mechanism-to-azd9291-a-case-report
#2
Lin Li, Hui Wang, Chao Li, Zheng Wang, Ping Zhang, Xu Yan
AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months' treatment of AZD9291 with hepatic metastasis...
January 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28029074/a-rational-approach-to-target-the-epidermal-growth-factor-receptor-in-glioblas
#3
Madan M Kwatra
Glioblastoma (GBM) is a deadly brain cancer, and all attempts to control it have failed so far. However, the future looks bright, as we now know the molecular landscape of GBM through the work of The Cancer Genome Atlas (TCGA) program. GBMs exhibit significant inter- and intra-tumoral heterogeneity, and to control this type of tumor, a personalized approach is required. One target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But all attempts to target it have been unsuccessful...
December 26, 2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28009438/population-pharmacokinetics-and-exposure-response-of-osimertinib-in-patients-with-non-small-cell-lung-cancer
#4
Kathryn Brown, Craig Comisar, Han Witjes, John Maringwa, Rik de Greef, Karthick Vishwanathan, Mireille Cantarini, Eugène Cox
AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response (ER) relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (N = 748) and one healthy volunteer study (N = 32), after single or multiple once-daily dosing of 20 to 240 mg osimertinib. Non-linear mixed effects modelling was used to characterise the popPK...
December 23, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27923714/acquired-braf-v600e-mutation-as-resistant-mechanism-after-treatment-with-osimertinib
#5
Chao-Chi Ho, Wei-Yu Liao, Chih-An Lin, Jin-Yuan Shih, Chong-Jen Yu, James Chih-Hsin Yang
INTRODUCTION: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment. METHODS: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib...
March 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27885838/osimertinib-for-egfr-t790m-mutation-positive-non-small-cell-lung-cancer
#6
Kenzo Soejima, Hiroyuki Yasuda, Toshiyuki Hirano
Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3(rd) generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1(st) or 2(nd) generation EGFR-TKIs...
January 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27861144/inhibition-of-oxidative-phosphorylation-suppresses-the-development-of-osimertinib-resistance-in-a-preclinical-model-of-egfr-driven-lung-adenocarcinoma
#7
Matthew J Martin, Cath Eberlein, Molly Taylor, Susan Ashton, David Robinson, Darren Cross
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27835594/characterization-of-osimertinib-azd9291-resistant-non-small-cell-lung-cancer-nci-h1975-osir-cell-line
#8
Zheng-Hai Tang, Xiao-Ming Jiang, Xia Guo, Chi Man Vivienne Fong, Xiuping Chen, Jin-Jian Lu
Osimertinib (OSI, also known as AZD9291) is the newest FDA-approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. However, resistance to OSI is likely to progress and the study of potential OSI-resistant mechanisms in advanced is necessary. Here, the OSI-resistant NCI-H1975/OSIR cells were established. After cells developed resistance to OSI, cell proliferation was decreased while cell migration and invasion were increased...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27821604/targeting-the-gatekeeper-osimertinib-in-egfr-t790m-mutation-positive-non-small-cell-lung-cancer
#9
Ferdinandos Skoulidis, Vassiliki A Papadimitrakopoulou
In 2015, the FDA approved an unprecedented number of new therapies for non-small cell lung cancer (NSCLC), among them therapies addressing specific genomic tumor subsets in the setting of development of resistance to first-line targeted therapy. Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy. It received breakthrough therapy designation, priority review status, and accelerated approval from the FDA...
November 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27793905/isoflavone-extracts-enhance-the-effect-of-epidermal-growth-factor-receptor-inhibitors-in-nsclc-cell-lines
#10
Rita Ambrosio, Maria Neve Ombra, Cesare Gridelli, Gianluca Picariello, Michele DI Stasio, Maria G Volpe
AIM: We investigated the effects of the pharmacological inhibition in vitro of epidermal growth factor receptor (EGFR) in combination with isoflavones. MATERIALS AND METHODS: Four anticancer drugs (erlotinib, gefitinib, afatinib and AZD9291) were combined with soy and red clover isoflavone extracts and used in cellular proliferation assays. The antitumor activity of inhibitors alone and in combination with isoflavone extracts was compared on three non-small cell lung cancer (NSCLC) cell lines with affiant EGFR genotype: A549 (EGFR wt); H1795 (EGFR T790M); HCC827 (EGFR del E746-A750)...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27770386/mechanisms-of-resistance-to-third-generation-egfr-tyrosine-kinase-inhibitors
#11
REVIEW
Shuhang Wang, Yongping Song, Feifei Yan, Delong Liu
The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy...
October 21, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27751847/osimertinib-for-pretreated-egfr-thr790met-positive-advanced-non-small-cell-lung-cancer-aura2-a-multicentre-open-label-single-arm-phase-2-study
#12
Glenwood Goss, Chun-Ming Tsai, Frances A Shepherd, Lyudmila Bazhenova, Jong Seok Lee, Gee-Chen Chang, Lucio Crino, Miyako Satouchi, Quincy Chu, Toyoaki Hida, Ji-Youn Han, Oscar Juan, Frank Dunphy, Makoto Nishio, Jin-Hyoung Kang, Margarita Majem, Helen Mann, Mireille Cantarini, Serban Ghiorghiu, Tetsuya Mitsudomi
BACKGROUND: Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS: In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27660466/osimertinib-making-a-breakthrough-in-lung-cancer-targeted-therapy
#13
REVIEW
Haijun Zhang
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for advanced non-small-cell lung cancer that harbors sensitizing EGFR mutations (EGFRm(+)) such as exon 19 deletions and L858R substitutions in exon 21. However, acquired resistance to EGFR TKIs is mostly driven by a second-site EGFR T790M mutation, which negates their inhibitory activity. Osimertinib (AZD9291, Tagrisso™), an oral, third-generation EGFR TKI, has been designed to target the EGFR T790M mutation, while sparing wild-type EGFR...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27649127/osimertinib-azd9291-a-mutant-selective-egfr-inhibitor-reverses-abcb1-mediated-drug-resistance-in-cancer-cells
#14
Xiao-Yu Zhang, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Leli Zeng, Megan Xu, Xiu-Qi Wang, Dong-Hua Yang, Zhe-Sheng Chen
In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine...
September 15, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27641462/-osimertinib-tagrisso-%C3%A2-activity-indication-and-modality-of-use-in-non-small-cell-lung-cancer
#15
Etienne Giroux Leprieur, Alexis B Cortot, Jacques Cadranel, Marie Wislez
The acquisition of a resistance EGFR mutation in exon 20 (T790M) occurs in half of the cases of secondary resistance to EGFR tyrosine kinase inhibitors (TKI), given in first-line treatment in advanced EGFR-mutated non-small cell lung cancers (NSCLC). Osimertinib (AZD9291, Tagrisso(®)) is a third-generation, irreversible EGFR TKI, active in case of T790M mutation. A large phase I trial showed the efficacy of osimertinib after failure of first-generation EGFR TKI (erlotinib, gefitinib), with response rate at 51% and up to 61% in case of T790M mutation...
October 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/27612423/differential-protein-stability-of-egfr-mutants-determines-responsiveness-to-tyrosine-kinase-inhibitors
#16
Paramita Ray, Yee Sun Tan, Vishal Somnay, Ranjit Mehta, Merna Sitto, Aarif Ahsan, Shyam Nyati, John P Naughton, Alexander Bridges, Lili Zhao, Alnawaz Rehemtulla, Theodore S Lawrence, Dipankar Ray, Mukesh K Nyati
Non-small cell lung cancer (NSCLC) patients carrying specific EGFR kinase activating mutations (L858R, delE746-A750) respond well to tyrosine kinase inhibitors (TKIs). However, drug resistance develops within a year. In about 50% of such patients, acquired drug resistance is attributed to the enrichment of a constitutively active point mutation within the EGFR kinase domain (T790M). To date, differential drug-binding and altered ATP affinities by EGFR mutants have been shown to be responsible for differential TKI response...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27486808/rapid-intracranial-response-to-osimertinib-in-a-patient-with-epidermal-growth-factor-receptor-t790m-positive-adenocarcinoma-of-the-lung
#17
Hermann Reichegger, Wolfram Jochum, Diana Förbs, Claudia Hader, Martin Früh
BACKGROUND: Osimertinib (AZD9291, Tagrisso) is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). CASE REPORT: Our report demonstrates that osimertinib is able to inhibit the growth of a radiotherapy- and surgery-refractory EGFR T790M-positive brain metastasis in a patient with lung adenocarcinoma. CONCLUSION: These data show that re-biopsy in EGFR-mutated non-small cell lung cancer patients with acquired TKI resistance should be performed...
2016: Oncology Research and Treatment
https://www.readbyqxmd.com/read/27469903/liquid-chromatography-tandem-mass-spectrometric-assay-for-the-t790m-mutant-egfr-inhibitor-osimertinib-azd9291-in-human-plasma
#18
Johannes J M Rood, Mark T J van Bussel, Jan H M Schellens, Jos H Beijnen, Rolf W Sparidans
A method for the quantitative analysis by ultra-performance liquid chromatography-tandem mass spectrometry of the highly selective irreversible covalent inhibitor of EGFR-TK, osimertinib in human plasma was developed and validated, using pazopanib as an internal standard. The validation was performed in a range from 1 to 1000ng/ml, with the lowest level corresponding to the lower limit of quantitation. Gradient elution was performed on a 1.8μm particle trifunctional bonded C18 column by 1% (v/v) formic acid in water, and acetonitrile as mobile phase...
September 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27450722/met-gene-amplification-and-protein-hyperactivation-is-a-mechanism-of-resistance-to-both-first-and-third-generation-egfr-inhibitors-in-lung-cancer-treatment
#19
Puyu Shi, You-Take Oh, Guojing Zhang, Weilong Yao, Ping Yue, Yikun Li, Rajani Kanteti, Jacob Riehm, Ravi Salgia, Taofeek K Owonikoko, Suresh S Ramalingam, Mingwei Chen, Shi-Yong Sun
The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance...
October 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27448564/egfr-c797s-mutation-mediates-resistance-to-third-generation-inhibitors-in-t790m-positive-non-small-cell-lung-cancer
#20
REVIEW
Shuhang Wang, Stella T Tsui, Christina Liu, Yongping Song, Delong Liu
T790M mutation is the most common mechanism for resistance to first- and second-generation tyrosine kinase inhibitors (TKI) for epidermal growth factor receptor (EGFR). Several third-generation EGFR mutant selective TKIs are being explored to conquer this resistance. AZD9291 (osimertinib, tagrisso) has been approved for treatment of the metastatic EGFR T790M mutation-positive non-small cell lung cancer. Resistance to AZD9291 has been described. C797S mutation was reported to be a major mechanism for resistance to T790M-targeting EGFR inhibitors...
July 22, 2016: Journal of Hematology & Oncology
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