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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...
December 2, 2016: Expert Review of Clinical Pharmacology
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
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
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 front-line targeted therapy. Osimertinib (TagrissoTM, AZD9291) is indicated for patients with metastatic EGFR (epidermal growth factor receptor) T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy and received breakthrough therapy designation, priority review status, and accelerated approval...
November 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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)...
November 2016: Anticancer Research
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
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...
October 14, 2016: Lancet Oncology
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
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...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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...
September 15, 2016: Bulletin du Cancer
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...
September 6, 2016: Oncotarget
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
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
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
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...
2016: Journal of Hematology & Oncology
James W T Yates, Susan Ashton, Darren Cross, Martine J Mellor, Steve J Powell, Peter Ballard
Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines...
October 2016: Molecular Cancer Therapeutics
Peter Ballard, James W T Yates, Zhenfan Yang, Dong-Wan Kim, James Chih-Hsin Yang, Mireille Cantarini, Kathryn Pickup, Angela Jordan, Mike Hickey, Matthew Grist, Matthew Box, Peter Johnström, Katarina Varnäs, Jonas Malmquist, Kenneth S Thress, Pasi A Jänne, Darren Cross
PURPOSE: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. EXPERIMENTAL DESIGN: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sai-Hong Ignatius Ou, Nikita Agarwal, Siraj M Ali
Third-generation EGFR TKI has been approved in the US and EU for the treatment of EGFR mutant T790M+ NSCLC patients that are resistant to first- or second generation EGFR TKIs. Here we report a patient who developed resistance to osimertinib after a confirmed partial response for 9 months. Pre-osimertinib and post-osimertinib tumor biopsy revealed the emergence of high level of MET amplification (30 copies) post osimertinib treatment. Patient was treated with single agent crizotinib, a known MET inhibitor, with transient symptomatic benefit...
August 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Puey Ling Chia, Hongdo Do, Adrienne Morey, Paul Mitchell, Alexander Dobrovic, Thomas John
AZD9291, a T790M specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated impressive response rates in tumours harbouring the EGFR T790M resistance mutation. Emergence of resistance to AZD9291 has been shown to occur through several different mechanisms including the development of new mutations (e.g. C797S) in the EGFR tyrosine kinase domain. We studied two patients with paired tumour biopsies and blood samples pre- and post-progression on AZD9291 to explore possible resistance mechanisms...
August 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Geoffrey R Oxnard, Kenneth S Thress, Ryan S Alden, Rachael Lawrance, Cloud P Paweletz, Mireille Cantarini, James Chih-Hsin Yang, J Carl Barrett, Pasi A Jänne
PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. METHODS: Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation...
October 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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