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https://www.readbyqxmd.com/read/28344665/treatment-choice-in-epidermal-growth-factor-receptor-mutation-positive-non-small-cell-lung-carcinoma-latest-evidence-and-clinical-implications
#1
REVIEW
Oscar Juan, Sanjay Popat
Discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the treatment of lung cancer. First-line treatment with EGFR TKIs (gefitinib, erlotinib and afatinib) has demonstrated a superior response rate and progression-free survival (PFS) compared with chemotherapy in EGFR-mutation positive patients. However, a number of open questions remain, such as choice between the three EGFR TKIs licensed, treatment of patients unsuitable for chemotherapy due to morbidity or advanced age, management of acquired resistance and optimal biological sample to determine EGFR status...
March 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28341106/the-apple-trial-feasibility-and-activity-of-azd9291-osimertinib-treatment-on-positive-plasma-t790m-in-egfr-mutant-nsclc-patients-eortc-1613
#2
Jordi Remon, Jessica Menis, Baktiar Hasan, Aleksandra Peric, Eleonora De Maio, Silvia Novello, Martin Reck, Thierry Berghmans, Bartosz Wasag, Benjamin Besse, Rafal Dziadziuszko
The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B...
March 1, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#3
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28302223/-current-status-and-prospect-of-t790m-mutation-in-non-small-cell-lung-cancer
#4
Qin Yu, Da Jiang, Ying Li
Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) is regarded as the main accepted first-line treatment on EGFR mutation in non-small cell lung cancer (NSCLC). Although targeted therapy for the first and two generation of TKIs may lead to longer progression-free survival (PFS) and better tolerance for patients, the long-term treatment will inevitably lead to drug resistance. Among them, more than 50% of acquired resistance is associated with T790M mutation. The latest guidelines from the National Comprehensive Cancer Network (NCCN) have been proposed that the three generation of TKI (Osimertinib) can be used in first-line TKI therapy progress with detecting T790M mutations in patients...
March 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28296233/sustained-response-to-standard-dose-osimertinib-in-a-patient-with-plasma-t790m-positive-leptomeningeal-metastases-from-primary-lung-adenocarcinoma
#5
Oscar Siu-Hong Chan, Warren Kam-Wing Leung, Rebecca Mei-Wan Yeung
A 44-year-old male, never smoker, suffers from stage IV adenocarcinoma of the right lung with epidermal growth factor receptor (EGFR) exon-21 L858R point mutation on initial presentation. After 23 months of treatment with gefitinib, intercalated with multiple courses of radiotherapy, leptomeningeal metastases (LMs) developed. Acquired T790M mutation was confirmed by the droplet digital polymerase chain reaction plasma EGFR test. After switching to osimertinib at the standard dose, his neurocognitive function improved clinically, coupled with sustained radiological improvement...
March 15, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28293555/second-line-treatment-of-non-small-cell-lung-cancer-clinical-pathological-and-molecular-aspects-of-nintedanib
#6
REVIEW
Luis Corrales, Amanda Nogueira, Francesco Passiglia, Angela Listi, Christian Caglevic, Marco Giallombardo, Luis Raez, Edgardo Santos, Christian Rolfo
Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel, gemcitabine, pemetrexed, and erlotinib and for patients with target-specific oncogenes afatinib, osimertinib, crizotinib, alectinib, and ceritinib. In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC)...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28287083/brigatinib-combined-with-anti-egfr-antibody-overcomes-osimertinib-resistance-in-egfr-mutated-non-small-cell-lung-cancer
#7
Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28284589/osimertinib-improves-progression-free-survival-in-nsclc
#8
Sheila Pinion
No abstract text is available yet for this article.
March 8, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28274957/an-acquired-her2-t798i-gatekeeper-mutation-induces-resistance-to-neratinib-in-a-patient-with-her2-mutant-driven-breast-cancer
#9
Ariella B Hanker, Monica Red Brewer, Jonathan H Sheehan, James P Koch, Gregory R Sliwoski, Rebecca Nagy, Richard Lanman, Michael F Berger, David M Hyman, David B Solit, Jie He, Vincent Miller, Richard E Cutler, Alshad S Lalani, Darren Cross, Christine M Lovly, Jens Meiler, Carlos L Arteaga
We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding...
March 8, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28274743/tolerable-and-effective-combination-of-full-dose-crizotinib-and-osimertinib-targeting-met-amplification-sequentially-emerging-after-t790m-positivity-in-egfr-mutant-non-small-cell-lung-cancer
#10
Emily R York, Marileila Varella-Garcia, Tami J Bang, Dara L Aisner, D Ross Camidge
No abstract text is available yet for this article.
March 6, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28271729/egfr-tki-combination-with-immunotherapy-in-non-small-cell-lung-cancer
#11
Myung-Ju Ahn, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation. Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy...
March 8, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28237877/osimertinib-induces-autophagy-and-apoptosis-via-reactive-oxygen-species-generation-in-non-small-cell-lung-cancer-cells
#12
Zheng-Hai Tang, Wen-Xiang Cao, Min-Xia Su, Xiuping Chen, Jin-Jian Lu
Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells...
February 22, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28235855/osimertinib-is-more-effective-than-standard-therapy-in-egfr-t790m-tumors
#13
(no author information available yet)
Osimertinib achieved better responses than platinum-pemetrexed in patients with EGFR(T790M) lung cancer.
February 24, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28221867/osimertinib-in-pretreated-t790m-positive-advanced-non-small-cell-lung-cancer-aura-study-phase-ii-extension-component
#14
James Chih-Hsin Yang, Myung-Ju Ahn, Dong-Wan Kim, Suresh S Ramalingam, Lecia V Sequist, Wu-Chou Su, Sang-We Kim, Joo-Hang Kim, David Planchard, Enriqueta Felip, Fiona Blackhall, Daniel Haggstrom, Kiyotaka Yoh, Silvia Novello, Kathryn Gold, Tomonori Hirashima, Chia-Chi Lin, Helen Mann, Mireille Cantarini, Serban Ghiorghiu, Pasi A Jänne
Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg...
February 21, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28217439/egfr-targeted-therapy-in-lung-cancer-an-evolving-story
#15
C Bartholomew, L Eastlake, P Dunn, D Yiannakis
Specific oncogenes with driver mutations, such as the Epidermal Growth Factor Receptor (EGFR 1) gene can lead to non-small-cell lung cancer formation. Identification of these oncogenes, their driver mutations and downstream effects allow the targeting of these pathways by drugs. Such personalised therapy has become an important strategy in combating lung cancer and highlights the need to test for these mutations. Tyrosine Kinase Inhibitors (TKIs) against EGFR, such as Erlotinib, are able to halt these tumour promoting properties in non-small-cell lung cancers...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28213007/effect-of-dasatinib-on-emt-mediated-mechanism-of-resistance-against-egfr-inhibitors-in-lung-cancer-cells
#16
Yuichi Sesumi, Kenichi Suda, Hiroshi Mizuuchi, Yoshihisa Kobayashi, Katsuaki Sato, Masato Chiba, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
OBJECTIVE: The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells (Wilson et al...
February 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28199182/one-reporter-for-in-cell-activity-profiling-of-majority-of-protein-kinase-oncogenes
#17
Iva Gudernova, Silvie Foldynova-Trantirkova, Barbora El Ghannamova, Bohumil Fafilek, Miroslav Varecha, Lukas Balek, Eva Hruba, Lucie Jonatova, Iva Jelinkova, Michaela Kunova Bosakova, Lukas Trantirek, Jiri Mayer, Pavel Krejci
In-cell profiling enables the evaluation of receptor tyrosine activity in a complex environment of regulatory networks that affect signal initiation, propagation and feedback. We used FGF-receptor signaling to identify EGR1 as a locus that strongly responds to the activation of a majority of the recognized protein kinase oncogenes, including 30 receptor tyrosine kinases and 154 of their disease-associated mutants. The EGR1 promoter was engineered to enhance trans-activation capacity and optimized for simple screening assays with luciferase or fluorescent reporters...
February 15, 2017: ELife
https://www.readbyqxmd.com/read/28178168/rapid-intracranial-response-to-osimertinib-without-radiotherapy-in-nonsmall-cell-lung-cancer-patients-harboring-the-egfr-t790m-mutation-two-case-reports
#18
Taro Koba, Takashi Kijima, Takayuki Takimoto, Haruhiko Hirata, Yujiro Naito, Masanari Hamaguchi, Tomoyuki Otsuka, Muneyoshi Kuroyama, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh
RATIONALE: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases...
February 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28167215/treatments-for-egfr-mutant-non-small-cell-lung-cancer-nsclc-the-road-to-a-success-paved-with-failures
#19
REVIEW
Dae Ho Lee
The discovery of epidermal growth factor receptor (EGFR) activating mutations in non-small cell lung cancer (NSCLC) and the success story of EGFR tyrosine kinases inhibitors (TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. As a result, EGFR TKI therapy, including gefitinib, erlotinib and afatinib, has become the standard therapy for NSCLC patients with EGFR activating mutation as first-line therapy. However, most patients inevitably progress despite initial dramatic and rapid response to EGFR TKIs and therefore during the last decade, a lot of efforts have been made to identify and overcome various resistance mechanisms...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28149764/third-generation-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-in-t790m-positive-non-small-cell-lung-cancer-review-on-emerged-mechanisms-of-resistance
#20
REVIEW
Roberta Minari, Paola Bordi, Marcello Tiseo
Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months...
December 2016: Translational Lung Cancer Research
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