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TKIs in ALK+ NSCLC

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https://www.readbyqxmd.com/read/28673332/a-multicenter-survey-of-first-line-treatment-patterns-and-gene-aberration-test-status-of-patients-with-unresectable-stage-iiib-iv-nonsquamous-non-small-cell-lung-cancer-in-china-ctong-1506
#1
Qing Zhou, Yong Song, Xin Zhang, Gong-Yan Chen, Dian-Sheng Zhong, Zhuang Yu, Ping Yu, Yi-Ping Zhang, Jian-Hua Chen, Yi Hu, Guo-Sheng Feng, Xia Song, Qiang Shi, Lu Lu Yang, Ping Hai Zhang, Yi-Long Wu
BACKGROUND: In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China. METHODS: Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment...
July 3, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28637019/clinicopathological-characteristics-of-ros1-and-ret-rearranged-nsclc-in-caucasian-patients-data-from-a-cohort-of-713-non-squamous-nsclc-lacking-kras-egfr-her2-braf-pik3ca-alk-alterations
#2
Frédéric Dugay, Francisco Llamas-Gutierrez, Marjory Gournay, Sarah Medane, François Mazet, Dan Christian Chiforeanu, Emmanuelle Becker, Régine Lamy, Hervé Léna, Nathalie Rioux-Leclercq, Marc-Antoine Belaud-Rotureau, Florian Cabillic
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine.We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients...
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28625641/emergence-of-novel-and-dominant-acquired-egfr-solvent-front-mutations-at-gly796-g796s-r-together-with-c797s-r-and-l792f-h-mutations-in-one-egfr-l858r-t790m-nsclc-patient-who-progressed-on-osimertinib
#3
Sai-Hong Ignatius Ou, Jean Cui, Alexa B Schrock, Michael E Goldberg, Viola W Zhu, Lee Albacker, Philip J Stephens, Vincent A Miller, Siraj M Ali
Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28621260/meta-analysis-of-the-incidence-and-risks-of-interstitial-lung-disease-and-qtc-prolongation-in-non-small-cell-lung-cancer-patients-treated-with-alk-inhibitors
#4
Liping Lin, Juanjuan Zhao, Ning Kong, Yan He, Jiazhu Hu, Fuxi Huang, Jianjun Han, Xiaolong Cao
BACKGROUND: To conduct a systematic review and meta-analysis to assess the overall incidence and risk of interstitial lung disease (ILD) and QTc prolongation associated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) in non-small-cell lung cancer (NSCLC) patients. RESULTS: A total of 1,770 patients from 8 clinical trials were included. The incidences of high-grade ILD and QTc prolongation was 2.5% (95% CI 1.7-3.6%), and 2.8% (95% CI 1.8-4...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28606126/pooled-safety-analyses-of-alk-tki-inhibitor-in-alk-positive-nsclc
#5
Qian Zhu, Hao Hu, De-Sheng Weng, Xiao-Fei Zhang, Chang-Long Chen, Zi-Qi Zhou, Yan Tang, Jian-Chuan Xia
BACKGROUND: The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear. METHODS: We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials...
June 12, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28576746/a-higher-proportion-of-the-egfr-t790m-mutation-may-contribute-to-the-better-survival-of-patients-with-exon-19-deletions-compared-with-those-with-l858r
#6
E-E Ke, Qing Zhou, Qiu-Yi Zhang, Jian Su, Zhi-Hong Chen, Xu-Chao Zhang, Chong-Rui Xu, Jin-Ji Yang, Hai-Yan Tu, Hong-Hong Yan, Yi-Chen Zhang, Fei-Yu Niu, Yi-Long Wu
INTRODUCTION: Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in non-small-cell lung cancer (NSCLC). We aimed to investigate whether these 2 mutations produced differences in resistance mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). METHODS: Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR-TKIs and underwent post-progression biopsies were enrolled...
May 30, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28574849/strategies-targeting-angiogenesis-in-advanced-non-small-cell-lung-cancer
#7
REVIEW
Jun Wang, Jianpeng Chen, Yan Guo, Baocheng Wang, Huili Chu
Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28529640/lung-cancer-targeting-peptides-with-multi-subtype-indication-for-combinational-drug-delivery-and-molecular-imaging
#8
Yi-Hsuan Chi, Jong-Kai Hsiao, Ming-Huang Lin, Chen Chang, Chun-Hsin Lan, Han-Chung Wu
Lung cancer is the leading cause of cancer-related death worldwide. Most targeted drugs approved for lung cancer treatment are tyrosine kinase inhibitors (TKIs) directed against EGFR or ALK, and are used mainly for adenocarcinoma. At present, there is no effective or tailored targeting agent for large cell carcinoma (LCC) or small cell lung cancer (SCLC). Therefore, we aimed to identify targeting peptides with diagnostic and therapeutic utility that possess broad subtype specificity for SCLC and non-small cell lung cancer (NSCLC)...
2017: Theranostics
https://www.readbyqxmd.com/read/28463570/anaplastic-lymphoma-kinase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-non-small-cell-lung-cancer
#9
REVIEW
Niki Karachaliou, Mariacarmela Santarpia, Maria Gonzalez Cao, Cristina Teixido, Aaron E Sosa, Jordi Berenguer, Alejandra Rodriguez Capote, Giuseppe Altavilla, Rafael Rosell
Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development...
June 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28442019/-progress-of-c-met-signaling-pathway-and-tkis-in-non-small-cell-lung-cancer
#10
REVIEW
Xiaoqing Yu, Yanjun Xu, Yun Fan
c-MET is considered a promising oncogenic driver in non-small cell lung cancer (NSCLC) after the discovery of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). MET activation including gene mutation, amplification and protein overexpression, all of these are potential therapeutic targets and are associated with poor prognosis. Clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI)...
April 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28363487/treatment-options-for-patients-with-brain-metastases-from-egfr-alk-driven-lung-cancer
#11
Mark K Doherty, Grzegorz J Korpanty, Pascale Tomasini, Moein Alizadeh, Kevin Jao, Catherine Labbé, Celine M Mascaux, Petra Martin, Suzanne Kamel-Reid, Ming-Sound Tsao, Melania Pintilie, Geoffrey Liu, Penelope A Bradbury, Ronald Feld, Natasha B Leighl, Caroline Chung, Frances A Shepherd
INTRODUCTION: Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC. METHODS: This single center retrospective review included 184 patients with brain metastases from EGFR/ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS)...
May 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28332225/molecular-dynamics-validation-of-crizotinib-resistance-to-alk-mutations-l1196m-and-g1269a-and-identification-of-specific-inhibitors
#12
Nagasundaram Nagarajan, Carlton Ranjith Wilson Alphonse, Prakash Vincent Samuel Gnana, Rajesh Kannan Rajaretinam
Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are mostly treated with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first generation ALK inhibitor practiced as a primary chemo to combat cancer cells followed by second generation inhibitor ceritinib which are effective against crizotinib resistant ALK mutations. However, patients treated with these drugs invariably relapsed because of the development of new drug resistance mutations. In this study we explored the crizotinib resistance in the presence of ALK mutations L1196M and G1269A through molecular dynamics simulation studies...
March 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#13
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/28285695/optimal-management-of-alk-positive-nsclc-progressing-on-crizotinib
#14
REVIEW
Giulio Metro, Marco Tazza, Roberta Matocci, Rita Chiari, Lucio Crinò
Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285694/sbrt-for-oligoprogressive-oncogene-addicted-nsclc
#15
REVIEW
L Basler, S G C Kroeze, M Guckenberger
Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28228224/-clinical-advanced-in-early-stage-alk-positive-non-small-cell-lung-cancer-patients
#16
REVIEW
Qiongqiong Gao, Xiangli Jiang, Chun Huang
Lung cancer is the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, with the majority of the cases diagnosed at the advanced stage. Molecular targeted therapy is becoming the focus attention for advanced NSCLC. Echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene (EML4-ALK) is among the most common molecular targets of NSCLC; its specific small-molecule tyrosine kinase inhibitors (TKIs) are approved for use in advanced NSCLC cases of ALK-positive...
February 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28185914/therapeutic-strategies-and-mechanisms-of-drug-resistance-in-anaplastic-lymphoma-kinase-alk-rearranged-lung-cancer
#17
REVIEW
Ryohei Katayama
Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in constitutive ALK fusion proteins expression via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase...
February 7, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28149754/non-small-cell-lung-cancer-nsclc-and-central-nervous-system-cns-metastases-role-of-tyrosine-kinase-inhibitors-tkis-and-evidence-in-favor-or-against-their-use-with-concurrent-cranial-radiotherapy
#18
REVIEW
Panagiota Economopoulou, Giannis Mountzios
Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis...
December 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28149753/achievements-and-future-developments-of-alk-tkis-in-the-management-of-cns-metastases-from-alk-positive-nsclc
#19
REVIEW
Lorenza Landi, Federico Cappuzzo
Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the newest and most appealing. Presence of ALK fusions is associated with some particular clinical and pathological features, including a preferential seeding into the central nervous system (CNS). In addition, ALK rearrangements are recognized as the strongest predictor for benefit of anti-ALK therapy...
December 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28111120/real-world-eq5d-health-utility-scores-for-patients-with-metastatic-lung-cancer-by-molecular-alteration-and-response-to-therapy
#20
Catherine Labbé, Yvonne Leung, João Gabriel Silva Lemes, Erin Stewart, Catherine Brown, Andrea Perez Cosio, Mark Doherty, Grainne M O'Kane, Devalben Patel, Nicholas Cheng, Mindy Liang, Gursharan Gill, Alexandra Rett, Hiten Naik, Lawson Eng, Nicole Mittmann, Natasha B Leighl, Penelope A Bradbury, Frances A Shepherd, Wei Xu, Geoffrey Liu, Doris Howell
INTRODUCTION: Economic analyses of upcoming treatments for lung cancer benefit from real-world health utility scores (HUSs) in an era of targeted therapy. METHODS: A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUSs in 475 outpatients with metastatic lung cancer across various disease states. Patients with epidermal growth factor receptor (EGFR) (n = 183) and anaplastic lymphoma kinase (ALK) (n = 38) driver alterations were enriched through targeted enrolment; patients with wild-type non-small-cell lung cancer (WT NSCLC) (n = 224) and small-cell lung cancer (SCLC) (n = 30) were sampled randomly...
December 28, 2016: Clinical Lung Cancer
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