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Dacomitinib

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https://www.readbyqxmd.com/read/29864379/improvement-in-overall-survival-in-a-randomized-study-that-compared-dacomitinib-with-gefitinib-in-patients-with-advanced-non-small-cell-lung-cancer-and-egfr-activating-mutations
#1
Tony S Mok, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Seiji Niho, Min Lee, Rolf Linke, Rafael Rosell, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Eric I Sbar, Tao Wang, Jane Liang White, Yi-Long Wu
Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225)...
June 4, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29780702/dacomitinib-in-egfr-positive-non-small-cell-lung-cancer-an-attractive-but-broken-option
#2
EDITORIAL
Antonio Passaro, Filippo de Marinis
No abstract text is available yet for this article.
April 2018: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29734047/efficacy-and-safety-of-single-agent-pan-human-epidermal-growth-factor-receptor-her-inhibitor-dacomitinib-in-locally-advanced-unresectable-or-metastatic-skin-squamous-cell-cancer
#3
S Cavalieri, F Perrone, R Miceli, P A Ascierto, L D Locati, C Bergamini, R Granata, S Alfieri, C Resteghini, D Galbiati, A Busico, N Paielli, R Patuzzo, A Maurichi, G Gallino, R Ruggeri, L Mariani, M Palla, L Licitra, P Bossi
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR)...
May 4, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29733883/distinct-apoptotic-blocks-mediate-resistance-to-panher-inhibitors-in-her2-breast-cancer-cells
#4
Bahriye Karakas, Yeliz Ozmay, Huveyda Basaga, Ozgur Gul, Ozgur Kutuk
Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells...
May 4, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29725456/application-of-molecular-targeted-therapies-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma
#5
REVIEW
Paulina Kozakiewicz, Ludmiła Grzybowska-Szatkowska
Despite the development of standard therapies, including surgery, radiotherapy and chemotherapy, survival rates for head and neck squamous cell carcinoma (HNSCC) have not changed significantly over the past three decades. Complete recovery is achieved in <50% of patients. The treatment of advanced HNSCC frequently requires multimodality therapy and involves significant toxicity. The promising, novel treatment option for patients with HNSCC is molecular-targeted therapies. The best known targeted therapies include: Epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab and nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatinib and dacomitinib), vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or vascular endothelial growth factor receptor (VEGFR) inhibitors (sorafenib, sunitinib and vandetanib) and inhibitors of phosphatidylinositol 3-kinase/serine/threonine-specific protein kinase/mammalian target of rapamycin...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29620166/antitumour-effects-and-mechanisms-of-action-of-the-panher-inhibitor-dacomitinib-alone-and-in-combination-with-the-stat3-inhibitor-s3i-201-in-human-sarcoma-cell-lines
#6
Xiaochun Wang, David Goldstein, Philip J Crowe, Jia-Lin Yang
The 5-year survival rate for metastatic sarcoma is 16%. Although the phosphorylated human epidermal growth factor receptor (pEGFR/HER1) has been shown to be an independent predictor of overall survival in patients with sarcoma, we have previously demonstrated that sarcoma cell lines exhibit resistance, despite gefitinib blocking p-EGFR and signal transducers in EGFR downstream pathways. Gefitinib failed to decrease the ratio of phosphorylated (p-)signal transducer and activator of transcription (STAT3)/p-STAT1, suggesting that relative STAT3 abundance and activation may be involved in drug resistance...
June 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29574250/a-pre-clinical-assessment-of-the-pan-erbb-inhibitor-dacomitinib-in-pediatric-and-adult-brain-tumors
#7
Raelene Endersby, Jacqueline Whitehouse, Hilary Hii, Sameer A Greenall, Terrance G Johns, Nicholas G Gottardo
Glioblastoma in adults, and medulloblastoma and pineoblastoma that mainly affect children, are aggressive brain tumors. The survival for patients with glioblastoma remains dismal. While the cure rate for medulloblastoma exceeds 70%, this figure has stagnated over the past few decades and survivors still contend with significant long-term debilitating side effects. The prognosis for pineoblastoma is age-dependent, with little chance of a cure for children younger than three years. More effective molecularly targeted strategies are urgently required to treat these cancers...
May 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29547491/prophylactic-probiotics-for-cancer-therapy-induced-diarrhoea-a-meta-analysis
#8
Hannah R Wardill, Ysabella Z A Van Sebille, Matthew A Ciorba, Joanne M Bowen
PURPOSE OF REVIEW: Strong preclinical data support prophylactic probiotics as an effective preventive strategy for diarrhoea secondary to anticancer therapies. To determine the composite evidence that this approach translates to the clinic, we performed a meta-analysis of randomized controlled trials (RCTs) of prophylactic probiotics for the prevention of cancer therapy-induced diarrhoea. RECENT FINDINGS: A three-step search strategy was used to identify relevant studies (1 June 2000-1 June 2017) investigating probiotic intervention for diarrhoea secondary to any cancer therapy (cytotoxic, targeted and immunotherapies)...
June 2018: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/29458405/dacomitinib-potentiates-the-efficacy-of-conventional-chemotherapeutic-agents-via-inhibiting-the-drug-efflux-function-of-abcg2-in-vitro-and-in-vivo
#9
Xiaoran Guo, Kenneth K W To, Zhen Chen, Xiaokun Wang, Jianye Zhang, Min Luo, Fang Wang, Shirong Yan, Liwu Fu
BACKGROUND: ATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily proteins, mediates multidrug resistance (MDR) by transporting substrate anticancer drugs out of cancer cells and decreasing their intracellular accumulation. MDR is a major hurdle to successful chemotherapy. A logical approach to overcome MDR is to inhibit the transporter. However, no safe and effective MDR inhibitor has been approved in the clinic. METHODS: The MTT assay was used to evaluate cell cytotoxicity and MDR reversal effect...
February 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29430509/molecular-correlates-of-in-vitro-responses-to-dacomitinib-and-afatinib-in-bladder-cancer
#10
Shuzo Tamura, Yin Wang, Brendan Veeneman, Daniel Hovelson, Armand Bankhead, Luke J Broses, Guadalupe Lorenzatti Hiles, Monica Liebert, John R Rubin, Kathleen C Day, Maha Hussain, Nouri Neamati, Scott Tomlins, Philip L Palmbos, Petros Grivas, Mark L Day
Background: The HER family of proteins (EGFR, HER2, HER3 and HER4) have long been thought to be therapeutic targets for bladder cancer, but previous clinical trials targeting these proteins have been disappointing. Second generation agents may be more effective. Objective: The aim of this study was to evaluate responses to two second-generation irreversible tyrosine kinase inhibitors, dacomitinib and afatinib, in bladder cancer cell lines. Methods: Cell lines were characterized by targeted next generation DNA sequencing, RNA sequencing, western blotting and flow cytometry...
January 20, 2018: Bladder Cancer
https://www.readbyqxmd.com/read/29410323/egfr-t790m-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-dacomitinib
#11
Yoshihisa Kobayashi, Toshio Fujino, Masaya Nishino, Takamasa Koga, Masato Chiba, Yuichi Sesumi, Shuta Ohara, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
INTRODUCTION: Dacomitinib was superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. METHODS: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib by using N-ethyl-N-nitrosourea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU...
May 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29331420/dacomitinib-antagonizes-multidrug-resistance-mdr-in-cancer-cells-by-inhibiting-the-efflux-activity-of-abcb1-and-abcg2-transporters
#12
Ying-Fang Fan, Wei Zhang, Leli Zeng, Zi-Ning Lei, Chao-Yun Cai, Pranav Gupta, Dong-Hua Yang, Qingbin Cui, Zuo-Dong Qin, Zhe-Sheng Chen, Louis D Trombetta
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR)...
May 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29300395/treating-epidermal-growth-factor-receptor-mutated-non-small-cell-lung-cancer-is-dacomitinib-the-winner
#13
EDITORIAL
Wolfram C M Dempke, Klaus Fenchel
No abstract text is available yet for this article.
December 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29191595/phase-2-study-of-intermittent-pulse-dacomitinib-in-patients-with-advanced-non-small-cell-lung-cancers
#14
Helena A Yu, Myung-Ju Ahn, Byoung Chul Cho, David E Gerber, Ronald B Natale, Mark A Socinski, Nagdeep Giri, Susan Quinn, Eric Sbar, Hui Zhang, Giuseppe Giaccone
BACKGROUND: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of dacomitinib may result in inhibition of EGFR T790M. METHODS: We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389)...
October 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29156674/novel-combinations-of-pi3k-mtor-inhibitors-with-dacomitinib-or-chemotherapy-in-pten-deficient-patient-derived-tumor-xenografts
#15
Irene Brana, Nhu-An Pham, Lucia Kim, Shingo Sakashita, Ming Li, Christine Ng, Yuhui Wang, Peter Loparco, Rafael Sierra, Lisa Wang, Blaise A Clarke, Benjamin G Neel, Lillian L Siu, Ming-Sound Tsao
PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K/AKT/ mTOR pathway. Activation of this pathway has been involved in resistance to chemotherapy or anti-EGFR/HER2 therapies. We evaluated the combination of PI3K-mTOR inhibitors with chemotherapy or the pan-HER inhibitor dacomitinib in PTEN-deficient patient-derived tumor xenografts (PDX). Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC)...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29103264/suppressors-for-human-epidermal-growth-factor-receptor-2-4-her2-4-a-new-family-of-anti-toxoplasmic-agents-in-arpe-19-cells
#16
Yeong Hoon Kim, Lokraj Bhatt, Hye-Jin Ahn, Zhaoshou Yang, Won-Kyu Lee, Ho-Woo Nam
The effects of tyrosine kinase inhibitors (TKIs) were evaluated on growth inhibition of intracellular Toxoplasma gondii in host ARPE-19 cells. The number of tachyzoites per parasitophorous vacuolar membrane (PVM) was counted after treatment with TKIs. T. gondii protein expression was assessed by western blot. Immunofluorescence assay was performed using Programmed Cell Death 4 (PDCD4) and T. gondii GRA3 antibodies. The TKIs were divided into 3 groups; non-epidermal growth factor receptor (non-EGFR), anti-human EGFR 2 (anti-HER2), and anti-HER2/4 TKIs, respectively...
October 2017: Korean Journal of Parasitology
https://www.readbyqxmd.com/read/29024815/identification-of-a-novel-autophagic-inhibitor-cepharanthine-to-enhance-the-anti-cancer-property-of-dacomitinib-in-non-small-cell-lung-cancer
#17
Zheng-Hai Tang, Wen-Xiang Cao, Xia Guo, Xiao-Yang Dai, Jia-Hong Lu, Xiuping Chen, Hong Zhu, Jin-Jian Lu
Inhibition of autophagy is a promising strategy for non-small cell lung cancer (NSCLC) treatment, which is in the clinical trials. However, only chloroquine is used in clinic as an autophagic inhibitor and the inhibitory effect of chloroquine on autophagy is finite. Therefore, the development of an alternative autophagic inhibitor for NSCLC therapy becomes necessary. In the present study, cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata, was identified as a novel autophagic inhibitor in NSCLC cells...
January 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/28994420/lung-cancer-dacomitinib-delays-disease-progression
#18
Peter Sidaway
No abstract text is available yet for this article.
December 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28969097/clinical-strategies-for-acquired-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-resistance-in-non-small-cell-lung-cancer-patients
#19
REVIEW
Lijun Dong, Dan Lei, Haijun Zhang
Epidermal growth factor receptor (EGFR) mutations (EGFRm+) occur in 10-35% of non-small-cell lung cancer (NSCLC) cases and confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs are standard treatments for NSCLC patients harboring EGFR exon 19 deletions or exon 21 L858R point mutations. Despite initial benefit, most patients develop drug resistance, posing a challenge to oncologists. The secondary T790M point mutation in EGFR exon 20 contributes to approximately 60% of resistance cases. Optimum strategies for overcoming acquired EGFR TKI resistance are not clearly defined, although current common practice is to switch to platinum-based chemotherapy following resistance onset...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28958502/dacomitinib-versus-gefitinib-as-first-line-treatment-for-patients-with-egfr-mutation-positive-non-small-cell-lung-cancer-archer-1050-a-randomised-open-label-phase-3-trial
#20
RANDOMIZED CONTROLLED TRIAL
Yi-Long Wu, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Seiji Niho, Fumito Tsuji, Rolf Linke, Rafael Rosell, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Eric I Sbar, Tao Wang, Jane Liang White, Sashi Nadanaciva, Rickard Sandin, Tony S Mok
BACKGROUND: Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). METHODS: In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions...
November 2017: Lancet Oncology
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