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TKI in ALK+ NSCLC

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https://www.readbyqxmd.com/read/28285695/optimal-management-of-alk-positive-nsclc-progressing-on-crizotinib
#1
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
#2
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/28185914/therapeutic-strategies-and-mechanisms-of-drug-resistance-in-anaplastic-lymphoma-kinase-alk-rearranged-lung-cancer
#3
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 different ALK fusion proteins that are constitutively expressed 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/28183697/safety-and-antitumor-activity-of-the-multi-targeted-pan-trk-ros1-and-alk-inhibitor-entrectinib-rxdx-101-combined-results-from-two-phase-1-trials-alka-372-001-and-startrk-1
#4
Alexander Drilon, Salvatore Siena, Sai-Hong Ignatius Ou, Manish Patel, Myung Ju Ahn, Jeeyun Lee, Todd M Bauer, Anna F Farago, Jennifer J Wheler, Stephen V Liu, Robert Doebele, Laura Giannetta, Giulio Cerea, Giovanna Marrapese, Michele Schirru, Alessio Amatu, Katia Bencardino, Laura Palmeri, Andrea Sartore-Bianchi, Angelo Vanzulli, Sara Cresta, Silvia Damian, Matteo Duca, Elena Ardini, Gang Li, Jason Christiansen, Karey Kowalski, Ann Johnson, Rupal Patel, David Luo, Edna Chow-Maneval, Zachary Hornby, Pratik S Multani, Alice T Shaw, Filippo G De Braud
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D...
February 9, 2017: Cancer Discovery
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-tkis
#5
Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Martin Früh
INTRODUCTION: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. METHODS: Outcomes of patients with metastatic NSCLC de novo co-alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. RESULTS: A total of 14 patients with adenocarcinoma were identified...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27835868/clinical-data-from-the-real-world-efficacy-of-crizotinib-in-chinese-patients-with-advanced-alk-rearranged-non-small-cell-lung-cancer-and-brain-metastases
#6
Puyuan Xing, Shouzheng Wang, Xuezhi Hao, Tongtong Zhang, Junling Li
Brain metastasis in non small cell lung cancer (NSCLC) patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein, we conducted a retrospective study to explore how Crizotinib affects the control of brain metastases and the overall prognosis in advanced ALK-rearranged NSCLC patients with brain metastases in Chinese population. A total of 34 patients were enrolled, of whom 20 (58.8%) patients had baseline brain metastases before Crizotinib treatment...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27821131/frequency-of-egfr-t790m-mutation-and-multimutational-profiles-of-rebiopsy-samples-from-non-small-cell-lung-cancer-developing-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-japanese-patients
#7
Ryo Ko, Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Mitsuhiro Isaka, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto, Kazuhisa Takahashi, Toshiaki Takahashi
BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs...
November 8, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27799783/personalized-treatment-in-advanced-alk-positive-non-small-cell-lung-cancer-from-bench-to-clinical-practice
#8
REVIEW
Antonio Passaro, Chiara Lazzari, Niki Karachaliou, Gianluca Spitaleri, Alessia Pochesci, Chiara Catania, Rafael Rosell, Filippo de Marinis
The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27780853/the-potent-alk-inhibitor-brigatinib-ap26113-overcomes-mechanisms-of-resistance-to-first-and-second-generation-alk-inhibitors-in-preclinical-models
#9
Sen Zhang, Rana Anjum, Rachel Squillace, Sara Nadworny, Tianjun Zhou, Jeff Keats, Yaoyu Ning, Scott D Wardwell, David Miller, Youngchul Song, Lindsey Eichinger, Lauren Moran, Wei-Sheng Huang, Shuangying Liu, Dong Zou, Yihan Wang, Qurish Mohemmad, Hyun Gyung Jang, Emily Ye, Narayana Narasimhan, Frank Wang, Juan Miret, Xiaotian Zhu, Tim Clackson, David Dalgarno, William C Shakespeare, Victor M Rivera
PURPOSE: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK(+)) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27760592/-driven-gene-in-patients-with-lung-squamous-cell-carcinoma-%C3%A2-analysis-of-clinicopathologic-characteristics-and-prognosis
#10
Tongtong Zhang, Junling Li
BACKGROUND: It has been proven that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS are common driver genes in non-small cell lung cancer (NSCLC). Molecular targeted therapy increases the overall response rate and progression-free survival (PFS) of patients with EGFR-sensitive mutation or echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. However, target and targeted drugs for lung squamous cell carcinoma to indicate clinical therapy remain to be confirmed...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/27753543/stat3-targeted-treatment-with-silibinin-overcomes-the-acquired-resistance-to-crizotinib-in-alk-rearranged-lung-cancer
#11
Elisabet Cuyàs, Almudena Pérez-Sánchez, Vicente Micol, Javier A Menendez, Joaquim Bosch-Barrera
The signal transducer and activator of transcription 3 (STAT3) has been suggested to play a prominent role in mediating non-small-cell lung cancer (NSCLC) resistance to some tyrosine kinase inhibitor (TKI)-mediated therapies. Using a model of anaplastic lymphoma kinase gene (ALK)-translocated NSCLC with acquired resistance to the ALK TKI crizotinib, but lacking amplifications or mutations in the kinase domain of ALK, we herein present evidence that STAT3 activation is a novel mechanism of crizotinib resistance that involves the upregulation of immune escape and epithelial to mesenchymal transition (EMT) signaling pathways...
December 16, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27668568/biopsy-procedures-and-molecular-testing-utilization-and-related-costs-in-patients-with-metastatic-lung-cancer
#12
Reshma Shinde, Xiting Cao, Smita Kothari
BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements are key therapeutic targets for biomarker-driven treatment with an EGFR or ALK tyrosine kinase inhibitor (TKI) in patients with metastatic non-small cell lung cancer (NSCLC). To appropriately guide treatment decisions, since 2011, the National Comprehensive Cancer Network and the American Society of Clinical Oncology therefore recommend EGFR and ALK analysis in tumor samples obtained at the time of diagnosis in patients with non-squamous NSCLC...
October 2016: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/27562868/adding-checkpoint-inhibitors-to-tyrosine-kinase-inhibitors-targeting-egfr-alk-in-non-small-cell-lung-cancer-a-new-therapeutic-strategy
#13
Samer Tabchi, Hampig Raphael Kourie, Joseph Kattan
After the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement...
August 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27544060/clinical-activity-of-alectinib-in-advanced-ret-rearranged-non-small-cell-lung-cancer
#14
Jessica J Lin, Elizabeth Kennedy, Lecia V Sequist, Priscilla K Brastianos, Kelly E Goodwin, Sara Stevens, Alexandra C Wanat, Lisa L Stober, Subba R Digumarthy, Jeffrey A Engelman, Alice T Shaw, Justin F Gainor
INTRODUCTION: Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported. METHODS: We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug...
August 17, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27535394/targeted-therapies-for-lung-cancer
#15
Thomas E Stinchcombe
Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting...
2016: Cancer Treatment and Research
https://www.readbyqxmd.com/read/27533086/clinical-outcomes-of-advanced-non-small-cell-lung-cancer-patients-with-egfr-mutation-alk-rearrangement-and-egfr-alk-co-alterations
#16
Na-Na Lou, Xu-Chao Zhang, Hua-Jun Chen, Qing Zhou, Li-Xu Yan, Zhi Xie, Jian Su, Zhi-Hong Chen, Hai-Yan Tu, Hong-Hong Yan, Zhen Wang, Chong-Rui Xu, Ben-Yuan Jiang, Bin-Chao Wang, Xiao-Yan Bai, Wen-Zhao Zhong, Yi-Long Wu, Jin-Ji Yang
The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27455248/non-invasive-methods-to-monitor-mechanisms-of-resistance-to-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-where-do-we-stand
#17
REVIEW
Paola Ulivi
The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment...
July 22, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27418132/responses-to-crizotinib-in-patients-with-alk-positive-lung-adenocarcinoma-who-tested-immunohistochemistry-ihc-positive-and-fluorescence-in-situ-hybridization-fish-negative
#18
Di Ma, Zheng Wang, Lin Yang, Xinlin Mu, Yan Wang, Xinming Zhao, Junling Li, Dongmei Lin
Although the Ventana immunohistochemistry (IHC) platform for detecting anaplastic lymphoma kinase gene (ALK) (D5F3) expression was recently approved by the US Food and Drugs Administration (FDA), fluorescence in situ hybridization (FISH) is still the "gold-standard" method recommended by the US National Comprehensive Cancer Network (NCCN) guideline for NSCLC. We evaluated 6 ALK-positive lung adenocarcinoma patients who tested Ventana IHC-positive and FISH-negative and assessed their clinical responses to the ALK tyrosine kinase inhibitor (TKI) crizotinib...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27401242/crizotinib-resistant-ros1-mutations-reveal-a-predictive-kinase-inhibitor-sensitivity-model-for-ros1-and-alk-rearranged-lung-cancers
#19
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Françoise Farace, Nathalie Auger, Jordi Remon, Jean-Yves Scoazec, Fabrice André, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far. METHODS: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27378174/neoadjuvant-oncogene-targeted-therapy-in-early-stage-non-small-cell-lung-cancer-as-a-strategy-to-improve-clinical-outcome-and-identify-early-mechanisms-of-resistance
#20
Caroline E McCoach, Trever G Bivona, Collin M Blakely, Robert C Doebele
Evaluations of resistance mechanisms to targeted treatments in non-small-cell lung cancer (NSCLC) are necessary for development of improved treatment after disease progression and to help delay progression of disease. Populations of cells that survive after initial treatment form the basis of resistance via outgrowth of resistant clones or activation of alternative signaling pathways. In this report we describe a clinical trial approach in which patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), C-ros-1 proto-oncogene (ROS1), and hepatocyte growth factor receptor (MET) exon 14 alterations and early stage (IA-IIIA) NSCLC will be treated with induction EGFR tyrosine kinase inhibitor (TKI) or crizotinib, a TKI that inhibits ALK, ROS1, and MET...
June 8, 2016: Clinical Lung Cancer
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