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TKIs in ALK+ NSCLC

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https://www.readbyqxmd.com/read/28915678/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
#1
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...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881856/strategies-targeting-angiogenesis-in-advanced-non-small-cell-lung-cancer
#2
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...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881815/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
#3
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...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28856564/the-current-landscape-of-anaplastic-lymphoma-kinase-alk-in-non-small-cell-lung-cancer-emerging-treatment-paradigms-and-future-directions
#4
Angel Qin, Shirish Gadgeel
Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3-7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors...
August 31, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28838400/emergence-of-fgfr3-tacc3-fusions-as-a-potential-by-pass-resistance-mechanism-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutated-nsclc-patients
#5
Sai-Hong Ignatius Ou, Leora Horn, Marcelo Cruz, Davood Vafai, Christine M Lovly, Allison Spradlin, Michael J Williamson, Ibiayi Dagogo-Jack, Adrienne Johnson, Vincent A Miller, Shirish Gadgeel, Siraj M Ali, Alexa B Schrock
Resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) with activating EGFR mutations generally involve development of acquired secondary or tertiary EGFR mutations, such as T790M or C797S. However, case reports have demonstrated that actionable receptor tyrosine kinase fusions such as EML4-ALK, CCDC6-RET, and FGFR3-TACC3 can potentially confer resistance to EGFR TKIs. We seeked to identify the prevalence of FGFR3-TACC3 fusion transcripts as resistance mechanism to EGFR TKIs...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28838271/an-update-on-biomarkers-for-kinase-inhibitor-response-in-non-small-cell-lung-cancer
#6
Bo Mi Ku, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
The discovery of activating genetic and their use as predictive biomarkers for targeted therapy, such as tyrosine kinase inhibitors (TKIs), has changed the treatment paradigm of non-small cell lung cancer (NSCLC). As a result, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs have become the standard first-line treatment. Since then, other kinds of targetable oncogenic alterations have been identified in NSCLC. Several novel, molecularly-targeted TKIs have now achieved regulatory approval, while many others are currently in early- or late-phase clinical trial testing...
August 30, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28818606/recent-advances-in-targeting-ros1-in-lung-cancer
#7
REVIEW
Jessica J Lin, Alice T Shaw
ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed...
August 14, 2017: Journal of Thoracic Oncology
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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 NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. METHODS: Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR tyrosine kinase inhibitors and underwent postprogression biopsy 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
Nagarajan Nagasundaram, 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
#20
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
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