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https://www.readbyqxmd.com/read/28098949/identification-of-cellular-targets-involved-in-cardiac-failure-caused-by-pki-in-oncology-an-approach-combining-pharmacovigilance-and-pharmacodynamics
#1
E Patras de Campaigno, E Bondon-Guitton, G Laurent, F Montastruc, J L Montastruc, M Lapeyre-Mestre, F Despas
AIMS: To evaluate the risk of cardiac failure (CF) of 15 anticancer protein kinase inhibitors (PKIs) through a case/non-case analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS: To evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the WHO safety report database (VigiBase®). We realised a literature review to identify 21 PK possibly involved in CF caused by PKIs. Pearson's correlation coefficients (r) between aROR and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely involved in PKI-induced CF...
January 18, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28090532/afatinib-for-patients-with-epidermal-growth-factor-receptor-mutation-positive-non-small-cell-lung-cancer-clinical-implications-of-the-lux-lung-7-study
#2
COMMENT
Keunchil Park
No abstract text is available yet for this article.
December 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28089942/targeting-egfr-t790m-mutation-in-nsclc-from-biology-to-evaluation-and-treatment
#3
Antonio Passaro, Elena Guerini-Rocco, Alessia Pochesci, Davide Vacirca, Gianluca Spitaleri, Chiara Matilde Catania, Alessandra Rappa, Massimo Barberis, Filippo de Marinis
The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life...
January 12, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28088511/brief-report-egfr-l858m-l861q-cis-mutations-confer-selective-sensitivity-to-afatinib
#4
Jamie A Saxon, Lynette M Sholl, Pasi A Jänne
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with epidermal growth factor receptor (EGFR)-mutant lung cancers. However, the therapeutic efficacy of TKIs in patients with uncommon EGFR mutations remains unclear. METHODS: Next-generation sequencing was performed on a patient's lung adenocarcinoma tumor sample, revealing rare combined in cis (on the same allele) EGFR mutations. Stable Ba/F3 and NIH-3T3 cell lines harboring the mutations were established to investigate the effect of first, second, and third generation EGFR TKIs on cell proliferation by MTS assay and EGFR phosphorylation by Western blotting...
January 11, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28063177/comparable-clinical-outcomes-in-patients-with-her2-mutant-and-egfr-mutant-lung-adenocarcinomas
#5
Chien-Hung Gow, Hou-Tai Chang, Chor-Kuan Lim, Chao-Yu Liu, Jin-Shing Chen, Jin-Yuan Shih
HER2 is a major proliferative driver in lung cancer. HER2 gene aberrations impact the prognosis of lung adenocarcinoma (ADC). A one-step reverse transcription-polymerase chain reaction was performed using RNA samples from 888 Asian lung cancer patients to detect HER2, EGFR, KRAS, ALK, and ROS1 mutations. The demographic data and treatment outcomes of HER2 mutation-positive lung ADC patients were analyzed and compared to those with HER2 mutation-negative tumors. HER2 mutation was identified in 40 (4.5%) lung ADC patients...
January 7, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28031832/effectiveness-of-afatinib-in-lung-cancer-with-paralytic-ileus-due-to-peritoneal-carcinomatosis
#6
Haruki Kobayashi, Kazushige Wakuda, Toshiaki Takahashi
A 61-year-old never-smoking woman with stage IV lung adenocarcinoma with initially unknown epidermal growth factor receptor (EGFR) status, lung metastasis, pleural dissemination, and malignant pleural effusion in 2007 received 10 prior anti-cancer regimens including gefitinib as second- and ninth-line treatments, with minimal efficacy with gefitinib. EGFR mutation analysis performed in pleural effusion specimens during ninth-line gefitinib was negative. In 2015, she developed progressive disease with peritoneal dissemination...
November 2016: Respirology Case Reports
https://www.readbyqxmd.com/read/28031719/potential-role-of-immunotherapy-in-advanced-non-small-cell-lung-cancer
#7
REVIEW
Ramon Andrade de Mello, Ana Flávia Veloso, Paulo Esrom Catarina, Sara Nadine, Georgios Antoniou
Immuno checkpoint inhibitors have ushered in a new era with respect to the treatment of advanced non-small-cell lung cancer. Many patients are not suitable for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (eg, gefitinib, erlotinib, and afatinib) or with anaplastic lymphoma kinase inhibitors (eg, crizotinib and ceritinib). As a result, anti-PD-1/PD-L1 and CTLA-4 inhibitors may play a novel role in the improvement of outcomes in a metastatic setting. The regulation of immune surveillance, immunoediting, and immunoescape mechanisms may play an interesting role in this regard either alone or in combination with current drugs...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28030859/clinical-efficacy-of-afatinib-treatment-for-a-patient-with-leptomeningeal-carcinomatosis
#8
Yo Kawaguchi, Jun Hanaoka, Hideki Hayashi, Naoki Mizusaki, Hirotoshi Iihara, Yoshinori Itoh, Tadashi Sugiyama
Leptomeningeal metastases occur in 1% of patients with non-small-cell lung cancer. There have been several reports on the treatment of leptomeningeal metastases with afatinib. Our patient was a 41-year-old woman who had never smoked and was diagnosed with stage IV adenocarcinoma of the lung with an epidermal growth factor receptor (EGFR) mutation. She was treated with afatinib for the recurrence of leptomeningeal metastases. After the treatment with afatinib was initiated, the neurological symptoms dramatically regressed, and she achieved progression-free survival for 7 months...
December 29, 2016: Chemotherapy
https://www.readbyqxmd.com/read/28012496/an-autopsy-case-of-bronchiolitis-obliterans-as-a-previously-unrecognized-adverse-event-of-afatinib-treatment
#9
Nobuhiro Kanaji, Yoichi Chiba Md PhD, Akira Sato Md PhD, Masaki Ueno Md PhD, Akira Tadokoro Md PhD, Nobuyuki Kita Md, Tomoya Ishii Md PhD, Naoki Watanabe Md, Norimitsu Kadowaki Md PhD, Shuji Bandoh Md PhD
Interstitial lung disease is a well-known pulmonary adverse event that occurs during epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and results in restrictive ventilatory dysfunction. However, obstructive changes such as those associated with bronchiolitis obliterans (BO) have never been reported as adverse events resulting from the use of any approved EGFR-TKI. This report documents an autopsy case of BO that developed during afatinib treatment for adenocarcinoma of the lung...
January 2017: Respiratory Investigation
https://www.readbyqxmd.com/read/28007627/clinical-outcome-of-alk-positive-non-small-cell-lung-cancer-nsclc-patients-with-de-novo-egfr-or-kras-co-mutations-receiving-tyrosine-kinase-inhibitors-tki
#10
Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Früh Martin
BACKGROUND: Non-small cell lung cancer (NSCLC) with de novo anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients (pts) are poorly understood. METHODS: Outcomes of pts with metastatic NSCLC de novo co- alterations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and sequencing (EGFR/KRAS) from six Swiss centres were analysed...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28007626/risk-of-treatment-related-toxicities-from-egfr-tyrosine-kinase-inhibitors-a-meta-analysis-of-clinical-trials-of-gefitinib-erlotinib-and-afatinib-in-advanced-egfr-mutated-non-small-cell-lung-cancer
#11
Pei Ni Ding, Sarah J Lord, Val Gebski, Matthew Links, Victoria Bray, Richard J Gralla, James Chih-Hsin Yang, Chee Khoon Lee
BACKGROUND: Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced epidermal growth factor receptor (EGFR) mutated non-small-cell lung cancer (NSCLC). Estimating differences in toxicity between these EGFR-TKIs is important for personalizing treatment. METHODS: We performed a meta-analysis of randomized trials that compared EGFR-TKI against chemotherapy or placebo. We extracted data from the EGFR-TKI arm for indirect comparisons to estimate the relative risk of toxic death, grade 3-4 (G3/4) adverse events (AEs) and treatment discontinuation due to AE for each EGFR-TKI...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28006816/egfr-mutation-detection-in-circulating-cell-free-dna-of-lung-adenocarcinoma-patients-analysis-of-lux-lung-3-and-6
#12
Yi-Long Wu, Lecia V Sequist, Cheng-Ping Hu, Jifeng Feng, Shun Lu, Yunchao Huang, Wei Li, Mei Hou, Martin Schuler, Tony Mok, Nobuyuki Yamamoto, Kenneth O'Byrne, Vera Hirsh, Neil Gibson, Dan Massey, Miyoung Kim, James Chih-Hsin Yang
BACKGROUND: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). METHODS: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit...
January 17, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28004883/afatinib-successfully-treated-leptomeningeal-metastasis-during-erlotinib-treatment-in-a-patient-with-egfr-mutant-exon18-g719s-lung-adenocarcinoma-as-a-second-line-chemotherapy
#13
Motohiro Tamiya, Takayuki Shiroyama, Takashi Nishihara, Takuji Nishida, Manabu Hayama, Ayako Tanaka, Naoko Morishita, Hidekazu Suzuki, Norio Okamoto, Tomonori Hirashima
Exon18 mutations are detected in 3.6% of epidermal growth factor receptor mutations. Exon 18 mutations as driver mutations have higher sensitivities in vitro to second-generation (G)-tyrosine kinase inhibitors (TKIs) than to first G- and third G-TKIs at clinically relevant doses. In clinical trial, first G-TKIs have moderate but insufficient efficacy, and afatinib was more active in uncommon epidermal growth factor receptor mutations. Here, we present a case of a woman who was initially prescribed erlotinib for lung adenocarcinoma with an exon18 mutation...
December 22, 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27972557/cost-utility-analysis-of-first-line-gefitinib-erlotinib-and-afatinib-in-patients-with-non-small-cell-lung-cancer-harboring-egfr-mutations
#14
M S Holleman, R Zaim, C A Uyl-De Groot
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27972417/gefitinib-erlotinib-or-afatinib-for-egfr-mutated-nsclc-patients-a-meta-analysis-and-indirect-comparison-on-the-efficacy-of-first-line-tyrosine-kinase-inhibitors
#15
M S Holleman, R Zaim, C A Uyl-De Groot
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27935868/analysis-of-progression-free-survival-of-first-line-tyrosine-kinase-inhibitors-in-patients-with-non-small-cell-lung-cancer-harboring-leu858arg-or-exon-19-deletions
#16
Feng-Che Kuan, Shih-Hong Li, Chih-Liang Wang, Meng-Hung Lin, Ying-Huang Tsai, Cheng-Ta Yang
BACKGROUND: Gefitinib, erlotinib and afatinib provide remarkable response rates and progression-free survival compared to platinum-based chemotherapy in patients with non-small cell lung cancer harboring epidermal growth factor receptor-activating mutations, and are therefore standard first-line treatment in these patients. However, no study has compared these drugs regarding progression-free survival. MATERIALS AND METHODS: We conducted this retrospective study at a single medical center in Taiwan from February 16, 2011 to October 30, 2015...
December 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27934455/kinetics-and-thermodynamics-of-reversible-thiol-additions-to-mono-and-diactivated-michael-acceptors-implications-for-the-design-of-drugs-that-bind-covalently-to-cysteines
#17
Elizabeth H Krenske, Russell C Petter, K N Houk
Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct...
December 2, 2016: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27923043/clonal-evolutionary-analysis-during-her2-blockade-in-her2-positive-inflammatory-breast-cancer-a-phase-ii-open-label-clinical-trial-of-afatinib-vinorelbine
#18
Gerald Goh, Ramona Schmid, Kelly Guiver, Wichit Arpornwirat, Imjai Chitapanarux, Vinod Ganju, Seock-Ah Im, Sung-Bae Kim, Arunee Dechaphunkul, Jedzada Maneechavakajorn, Neil Spector, Thomas Yau, Mehdi Afrit, Slim Ben Ahmed, Stephen R Johnston, Neil Gibson, Martina Uttenreuther-Fischer, Javier Herrero, Charles Swanton
BACKGROUND: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27920501/three-generations-of-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-developed-to-revolutionize-the-therapy-of-lung-cancer
#19
REVIEW
Haijun Zhang
Lung cancer, ~80%-85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm(+)), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27913578/characterization-of-egfr-t790m-l792f-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-afatinib-in-lung-cancer
#20
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
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