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https://www.readbyqxmd.com/read/29228521/intercalated-treatment-following-rebiopsy-is-associated-with-a-shorter-progression-free-survival-of-osimertinib-treatment
#1
Jeng-Sen Tseng, Tsung-Ying Yang, Kun-Chieh Chen, Kuo-Hsuan Hsu, Yen-Hsiang Huang, Kang-Yi Su, Sung-Liang Yu, Gee-Chen Chang
Purpose: Epidermal growth factor receptor (EGFR) T790M mutation serves as an important predictor of osimertinib efficacy. However, little is known about how it works among patients with various timings of T790M emergence and treatment. Materials and Methods: Advanced EGFR-mutant lung adenocarcinoma patients with positive T790M mutation in tumor were retrospectively enrolled and observed to determine the outcomes of osimertinib treatment. We evaluated the association between patients' characteristics and the efficacy of osimertinib treatment, particularly with respect to the timing of T790M emergence and osimertinib prescription...
December 11, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/29217691/first-line-osimertinib-beneficial-in-advanced-nsclc
#2
(no author information available yet)
Osimertinib is more effective as first-line therapy than other EGFR inhibitors for patients with advanced EGFR-mutated non-small cell lung cancer-notably Asians, who have a higher incidence of the disease compared with Western populations. The conclusion is based on data from a subgroup analysis of the phase III FLAURA trial.
December 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29212784/an-oligoclonal-antibody-durably-overcomes-resistance-of-lung-cancer-to-third-generation-egfr-inhibitors
#3
Maicol Mancini, Hilah Gal, Nadège Gaborit, Luigi Mazzeo, Donatella Romaniello, Tomer Meir Salame, Moshit Lindzen, Georg Mahlknecht, Yehoshua Enuka, Dominick Ga Burton, Lee Roth, Ashish Noronha, Ilaria Marrocco, Dan Adreka, Raya Eilam Altstadter, Emilie Bousquet, Julian Downward, Antonio Maraver, Valery Krizhanovsky, Yosef Yarden
Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors...
December 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29203836/lung-cancer-osimertinib-strengthens-the-frontline
#4
David Killock
No abstract text is available yet for this article.
December 5, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29202823/trastuzumab-emtansine-delays-and-overcomes-resistance-to-the-third-generation-egfr-tki-osimertinib-in-nsclc-egfr-mutated-cell-lines
#5
Silvia La Monica, Daniele Cretella, Mara Bonelli, Claudia Fumarola, Andrea Cavazzoni, Graziana Digiacomo, Lisa Flammini, Elisabetta Barocelli, Roberta Minari, Nadia Naldi, Pier Giorgio Petronini, Marcello Tiseo, Roberta Alfieri
BACKGROUND: Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overexpression is a mechanism of resistance to osimertinib, this study was addressed to investigate the potential of combining osimertinib with trastuzumab emtansine (T-DM1) in order to improve the efficacy of osimertinib and delay or overcome resistance in NSCLC cell lines with EGFR activating mutation and with T790M mutation or HER-2 amplification...
December 4, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29190637/standard-dose-osimertinib-for-refractory-leptomeningeal-metastases-in-t790m-positive-egfr-mutant-non-small-cell-lung-cancer
#6
Shigeki Nanjo, Akito Hata, Chiyuki Okuda, Reiko Kaji, Hideaki Okada, Daisuke Tamura, Kei Irie, Hiroshi Okada, Shoji Fukushima, Nobuyuki Katakami
BACKGROUND: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. METHODS: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. RESULTS: We investigated 13 patients (5 definitive and 8 possible LM cases)...
November 30, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29180936/osimertinib-effective-treatment-of-nsclc-with-activating-egfr-mutations-after-progression-on-egfr-tyrosine-kinase-inhibitors
#7
Marcin Skrzypski, Amelia Szymanowska-Narloch, Rafał Dziadziuszko
Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib...
2017: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/29178442/the-effect-of-food-or-omeprazole-on-the-pharmacokinetics-of-osimertinib-in-patients-with-non-small-cell-lung-cancer-and-in-healthy-volunteers
#8
Karthick Vishwanathan, Paul A Dickinson, Khanh Bui, Philippe A Cassier, Alastair Greystoke, Eleanor Lisbon, Victor Moreno, Karen So, Karen Thomas, Doris Weilert, Timothy A Yap, Ruth Plummer
Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers...
November 26, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29175151/osimertinib-improves-progression-free-survival-in-nsclc
#9
Robert Stirrups
No abstract text is available yet for this article.
November 23, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29173769/durable-response-to-osimertinib-in-egfr-mutated-t790m-wildtype-non-small-cell-lung-cancer-with-leptomeningeal-metastases-a-case-report
#10
Anna Chalmers, Leif Jensen, Wallace Akerley
In patients with non-small cell lung cancer (NSCLC) progression with leptomeningeal (LM) metastases is a catastrophic event with limited treatment options. We report a patient who developed leptomeningeal disease while on front-line erlotinib. High-dose tyrosine kinase inhibitor was started but ineffective. She was transitioned to third-generation TKI osimertinib, despite lacking a T790M mutation, and responded with complete resolution of symptoms and malignant cytology in the cerebrospinal fluid (CSF). Recent phase one data and our case indicate osimertinib should be viewed as a best practice for treatment of LM disease in epidermal growth factor receptor (EGFR) mutated NSCLC regardless of T790M status...
December 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29160717/reprogramming-tumor-associated-macrophages-to-reverse-egfr-t790m-resistance-by-dual-targeting-codelivery-of-gefitinib-vorinostat
#11
Huige Peng, Binfan Chen, Wei Huang, Yubo Tang, Yifan Jiang, Wenyuan Zhang, Yongzhuo Huang
Gefitinib is a first-line therapy in the EGFR-mutated nonsmall cell lung cancer (NSCLC). However, the development of drug resistance is almost unavoidable, thus leading to an unsustainable regimen. EGFR(T790M) mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFR(T790M)-positive NSCLC, the osimertinib-resistant EGFR mutation is rapidly developed, too. In this study, we proposed a tumor-associated macrophage (TAM) reprogramming strategy for overcoming the EGFR(T790M)-associated drug resistance via a dual-targeting codelivery system of gefitinib/vorinostat that acted on both TAM with overexpression of mannose receptors and the HER-2 positive NSCLC cells...
November 21, 2017: Nano Letters
https://www.readbyqxmd.com/read/29156777/patients-with-nsclc-may-display-a-low-ratio-of-p-t790m-vs-activating-egfr-mutations-in-plasma-at-disease-progression-implications-for-personalised-treatment
#12
Marzia Del Re, Paola Bordi, Iacopo Petrini, Eleonora Rofi, Francesca Mazzoni, Lorenzo Belluomini, Enrico Vasile, Giuliana Restante, Francesco Di Costanzo, Alfredo Falcone, Antonio Frassoldati, Ron H N van Schaik, Christi M J Steendam, Antonio Chella, Marcello Tiseo, Riccardo Morganti, Romano Danesi
Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29151359/osimertinib-in-untreated-egfr-mutated-advanced-non-small-cell-lung-cancer
#13
Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, Thanyanan Reungwetwattana, Busyamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Byoung Chul Cho, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, David Planchard, Wu-Chou Su, Jhanelle E Gray, Siow-Ming Lee, Rachel Hodge, Marcelo Marotti, Yuri Rukazenkov, Suresh S Ramalingam
Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily)...
November 18, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29138581/puma-mediates-the-anti-cancer-effect-of-osimertinib-in-colon-cancer-cells
#14
Lingchuan Guo, Shan Huang, Xinwei Wang
Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73-mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29136465/recent-progress-of-small-molecule-epidermal-growth-factor-receptor-egfr-inhibitors-against-c797s-resistance-in-non-small-cell-lung-cancer
#15
Lingfeng Chen, Weitao Fu, Lulu Zheng, Zhiguo Liu, Guang Liang
The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein797 to serine790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs...
November 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29128427/osimertinib-and-cabozantinib-combinatorial-therapy-in-an-egfr-mutant-lung-adenocarcinoma-patient-with-multiple-met-secondary-site-mutations-after-resistance-to-crizotinib
#16
Jin Kang, Hua-Jun Chen, Zheng Wang, Jing Liu, Bing Li, Tengfei Zhang, Zhenfan Yang, Yi-Long Wu, Jin-Ji Yang
No abstract text is available yet for this article.
November 8, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29125233/in-vivo-imaging-xenograft-models-for-the-evaluation-of-anti-brain-tumor-efficacy-of-targeted-drugs
#17
Kenji Kita, Sachiko Arai, Akihiro Nishiyama, Hirokazu Taniguchi, Koji Fukuda, Rong Wang, Tadaaki Yamada, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Mitsutoshi Nakada, Kazuo Yasumoto, Yoshiharu Motoo, Takashi Murakami, Seiji Yano
Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion...
November 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29113230/squamous-cell-transformation-and-egfr-t790m-mutation-as-acquired-resistance-mechanisms-in-a-patient-with-lung-adenocarcinoma-treated-with-a-tyrosine-kinase-inhibitor-a-case-report
#18
Rossella Bruno, Agnese Proietti, Greta Alì, Gianfranco Puppo, Alessandro Ribechini, Antonio Chella, Gabriella Fontanini
The present case report describes the infrequent coexistence of squamous cell transformation and the epidermal growth factor receptor (EGFR) T790M mutation as resistance mechanisms to first line treatment with tyrosine kinase inhibitors. The patient was a 44-year-old female, diagnosed with a primitive advanced lung adenocarcinoma with bone metastases. The tumor was positive for the EGFR exon 19 deletion, therefore the patient was treated with afatinib (40 mg/day, orally) and radiotherapy for bone lesions. After 16 months, the patient developed resistance...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29101057/cost-effectiveness-of-osimertinib-for-egfr-mutation-positive-non-small-cell-lung-cancer-after-progression-of-first-line-egfr-tki-therapy
#19
Bin Wu, Xiaohua Gu, Qiang Zhang
INTRODUCTION: To investigate the cost-effectiveness of osimertinib for the treatment of advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) T790M mutation after the failure of first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS: A mathematical model was established by combining a decision tree and the Markov approach to project the cost-effectiveness of osimertinib for the treatment of patients who harbor an EGFR T790M mutation compared to that of standard chemotherapy, who had disease progression after first-line EGFR-TKI therapy with or without metastases to the central nervous system...
October 31, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29100434/oncogenic-driver-mutations-treatment-and-egfr-tki-resistance-in-a-caucasian-population-with-non-small-cell-lung-cancer-survival-in-clinical-practice
#20
Martin Faehling, Birgit Schwenk, Sebastian Kramberg, Robert Eckert, Anna-Lena Volckmar, Albrecht Stenzinger, Jörn Sträter
Introduction: Oncogenic driver mutations activating EGFR, ALK, or BRAF in NSCLC predict sensitivity to specific tyrosine-kinase inhibitors (TKIs). We provide data on prevalence, treatment and survival of driver-mutation positive NSCLC in a predominantly Caucasian population in routine clinical practice. Patients and Methods: NSCLC patients diagnosed from 2006-2015 with an EGFR-test result were included (n=265). Testing for EGFR, ALK, or BRAF was performed if specific TKI therapy was considered...
September 29, 2017: Oncotarget
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