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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
Jon Zugazagoitia, Irene Ferrer, Luis Paz-Ares
No abstract text is available yet for this article.
October 14, 2016: Lancet Oncology
Fedor V Moiseyenko, Vladimir M Moiseyenko, Svetlana N Aleksakhina, Vyacheslav A Chubenko, Nikita M Volkov, Kseniya S Kozyreva, Michail M Kramchaninov, Alexandr S Zhuravlev, Kseniya V Shelekhova, Alexandr O Ivantsov, Aigul R Venina, Elena V Preobrazhenskaya, Natalia V Mitiushkina, Aglaya G Iyevleva, Evgeny N Imyanitov
BACKGROUND: Discontinuation of gefitinib treatment is often accompanied by a disease flare. Some studies have demonstrated a benefit of the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) beyond progression; however, long-term results of these investigations remain limited. PATIENTS AND METHODS: We observed 70 patients with EGFR-mutated (EGFR-M+) non-small cell lung cancer (NSCLC) receiving single-agent gefitinib in a routine clinical setting; 56 patients were experiencing RECIST progression at the time of the analysis...
2016: Oncology Research and Treatment
Magda Bahcall, Taebo Sim, Cloud P Paweletz, Jyoti D Patel, Ryan S Alden, Yanan Kuang, Adrian G Sacher, Nam Doo Kim, Christine Lydon, Mark M Awad, Michael T Jaklitsch, Lynette M Sholl, Pasi A Jänne, Geoffrey R Oxnard
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped and understanding of mechanisms of resistance to MET TKIs is limited. Here we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib, responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib...
September 30, 2016: Cancer Discovery
Hannah A Scarborough, Barbara A Helfrich, Matias Casas-Selves, Alwin Schuller, Shaun E Grosskurth, Jihye Kim, Aik-Choon Tan, Daniel C Chan, Zhiyong Zhang, Vadym Zaberezhnyy, Paul A Bunn, James DeGregori
PURPOSE: The emergence of EGFR-inhibitors such as gefitinib, erlotinib and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR-inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
Sinead A Noonan, Peter B Sachs, D Ross Camidge
INTRODUCTION: Osimertinib is an EGFR inhibitor licensed for the treatment of EGFR-mutant, T790M-positive NSCLC. Previously unreported, frequent transient asymptomatic pulmonary opacities were noted in patients during osimertinib therapy at the University of Colorado. METHODS: Computed tomography imaging and clinical notes on patients with NSCLC who had been treated with osimertinib at the University of Colorado were retrospectively reviewed. RESULTS: Transient asymptomatic pulmonary opacities developed in seven of 20 patients (35%) while they were receiving osimertinib...
September 13, 2016: Journal of Thoracic Oncology
Nobuaki Mamesaya, Hirotsugu Kenmotsu, Mineo Katsumata, Takashi Nakajima, Masahiro Endo, Toshiaki Takahashi
We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field...
September 6, 2016: Investigational New Drugs
Xiao Xu, Long Mao, Wanhong Xu, Wei Tang, Xiaoying Zhang, Biao Xi, Rongda Xu, Xin Fang, Jia Liu, Ce Fang, Li Zhao, Xiaobo Wang, Ji Jiang, Pei Hu, Hongyun Zhao, Li Zhang
AC0010 is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR active and T790M mutations with up to 298-fold increase in potency compared to wild-type EGFR. In a xenografte model, oral administration of AC0010 at daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR active and T790M mutations for over 143 days with no weight loss...
August 29, 2016: Molecular Cancer Therapeutics
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
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
Daniel B Costa
The most frequent epidermal growth factor receptor (EGFR) mutations found by traditional or comprehensive molecular profiling of lung adenocarcinomas include indels of exon 19 (the exon 19 deletion delE746_A750 being the most common) and the exon 21 L858R point mutation. The current approval labels for first line palliative gefitinib 250 mg/day, erlotinib 150 mg/day and afatinib 40 mg/day for advanced lung cancers require the presence of the aforementioned classical/sensitizing EGFR mutations. Other gefitinib, erlotinib and afatinib sensitizing mutations include exon 18 indels, G719X, exon 19 insertions, A763_Y764insFQEA, S768I and L861Q; for which off-label EGFR kinase inhibitor use is generally agreed upon by thoracic oncologists...
June 2016: Translational Lung 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
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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