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Leora Horn, Jeffrey R Infante, Karen L Reckamp, George R Blumenshein, Ticiana A Leal, Saiama N Waqar, Barbara J Gitlitz, Rachel E Sanborn, Jennifer G Whisenant, Liping Du, Joel W Neal, Jon P Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J Gibbons, Allison Holzhausen, Christine M Lovly, Heather A Wakelee
PURPOSE: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: In dose escalation, ensartinib was administered at doses of 25-250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily...
March 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
You-Cai Zhu, Yue-Fen Zhou, Wen-Xian Wang, Chun-Wei Xu, Wu Zhuang, Kai-Qi Du, Gang Chen
ROS1 rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC) and represents a small subset (1-2%) of NSCLC. A total of 17 different fusion partner genes of ROS1 in NSCLC have been reported. The multi-targeted MET/ALK/ROS1 tyrosine kinase inhibitor (TKI) crizotinib has demonstrated remarkable efficacy in ROS1-rearranged NSCLC. Consequently, ROS1 detection assays include fluorescence in situ hybridization, immunohistochemistry, and real-time PCR. Next-generation sequencing (NGS) assay covers a range of fusion genes and approaches to discover novel receptor-kinase rearrangements in lung cancer...
March 8, 2018: Thoracic Cancer
Eric K Singhi, Leora Horn
Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib...
March 6, 2018: Future Oncology
Geeta Geeta Sharma, Ines Mota, Luca Mologni, Enrico Patrucco, Carlo Gambacorti-Passerini, Roberto Chiarle
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy...
February 28, 2018: Cancers
Alfredo Addeo, Fabrizio Tabbò, Tim Robinson, Lucio Buffoni, Silvia Novello
IMPORTANCE: The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of its oral tyrosine kinase inhibitor (TKI). Crizotinib was the first ALK inhibitor approved and utilised in the treatment of ALK+ NSCLC patients in the second line setting first and subsequently in the first line one. Since then many other ALK inhibitors have been developed (ceritinib, alectinib, brigatinib, lorlatinib,etc) and the treatment paradigm of these patients has considerably drifted...
February 2018: Critical Reviews in Oncology/hematology
Jessica J Lin, Viola W Zhu, Satoshi Yoda, Beow Y Yeap, Alexa B Schrock, Ibiayi Dagogo-Jack, Nicholas A Jessop, Ginger Y Jiang, Long P Le, Kyle Gowen, Philip J Stephens, Jeffrey S Ross, Siraj M Ali, Vincent A Miller, Melissa L Johnson, Christine M Lovly, Aaron N Hata, Justin F Gainor, Anthony J Iafrate, Alice T Shaw, Sai-Hong Ignatius Ou
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants...
January 26, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Petros Christopoulos, Volker Endris, Farastuk Bozorgmehr, Mei Elsayed, Martina Kirchner, Jonas Ristau, Ivo Buchhalter, Roland Penzel, Felix J Herth, Claus P Heussel, Martin Eichhorn, Thomas Muley, Michael Meister, Jürgen R Fischer, Stefan Rieken, Arne Warth, Helge Bischoff, Peter Schirmacher, Albrecht Stenzinger, Michael Thomas
In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require novel therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2, V3 as detected by next-generation sequencing (NGS) or RT-PCR (n=67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy...
January 24, 2018: International Journal of Cancer. Journal International du Cancer
Y S Li, B Y Jiang, J J Yang, X C Zhang, Z Zhang, J Y Ye, W Z Zhong, H Y Tu, H J Chen, Z Wang, C R Xu, B C Wang, H J Du, S Chuai, H Han-Zhang, J Su, Q Zhou, X N Yang, W B Guo, H H Yan, Y H Liu, L X Yan, B Huang, M M Zheng, Y L Wu
Background: Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM. Patients and methods: Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled...
January 15, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
N Guibert, Y Hu, N Feeney, Y Kuang, V Plagnol, G Jones, K Howarth, J F Beeler, C P Paweletz, G R Oxnard
Background: Genomic analysis of plasma cell-free DNA is transforming lung cancer care, however available assays are limited by cost, turnaround time, and imperfect accuracy. Here we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). Methods: Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1 and other rare genotypes) were collected while on therapy and analyzed, blinded to tumor genotype...
January 9, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Zhichao Liu, Youting Bao, Butuo Li, Xindong Sun, Linlin Wang
BACKGROUND: Advanced ALK-rearranged non-small cell lung cancer (NSCLC) patients will develop acquired resistance after anaplastic lymphoma kinase (ALK) inhibitors therapies. Vascular endothelial growth factor-A (VEGF-A) production and tumor vessel formation were found to be more significantly enriched in ALK-rearrangement NSCLC than that in epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene mutated NSCLC. However, the correlation between ALK rearrangement and the efficacy of bevacizumab (a recombinant humanized IgG1 monoclonal antibody targeting VEGF-A) was still elusive...
January 9, 2018: Clinical and Translational Medicine
Agnes Balla, Kenneth J Hampel, Farrah Khan, Dara L Aisner, Nikoletta Sidiropoulos
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). These rearrangements occur because of a chromosomal inversion within the short arm of chromosome 2, which results in the formation of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene. While NSCLC transformation to SCLC is a rare phenomenon described in EGFR mutant cancers primarily after treatment with targeted therapy, it is exceedingly rare in ALK rearranged adenocarcinomas (Toyokawa et al...
January 9, 2018: Cold Spring Harbor Molecular Case Studies
Qiqi Gao, Honghai Ma, Bo Wang, Yake Yao, Jianya Zhou, Jianying Zhou
Background: The anaplastic lymphoma kinase (ALK) protein has recently become a promising target in the treatment of non-small cell lung carcinomas(NSCLC) patients with ALK translocation because of the high response rates obtained with an ALK inhibitor. ALK translocations are present in approximately 3-5% of NSCLC patients. According to the literature, little information about the relationship of ALK status between the primary tumor and metastatic sites has been reported. We intended to determine whether the ALK translocations of primary lung cancers are consistent with those in corresponding metastatic lymph node tumors...
December 12, 2017: Oncotarget
Paolo Borghetti, Marco Lorenzo Bonù, Elisa Roca, Sara Pedretti, Emiliano Salah, Anna Baiguini, Diana Greco, Luca Triggiani, Marta Maddalo, Niccolò Giaj Levra, Filippo Alongi, Stefano Maria Magrini, Michela Buglione
AIM: To investigate the role of conventional radiotherapy (RT) and stereotactic body radiotherapy (SBRT) in patients with epidermal growth factor (EGFR)-mutant or anaplastic lymphoma kinase (ALK) rearrangement-positive metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty patients with EGFR-mutated or ALK rearrangement-positive NSCLC were treated at our Institution. Radiotherapy was delivered before, after or concomitantly with tyrosine kinase inhibitors (TKIs)...
January 2018: In Vivo
Enriqueta Felip, Fabrice Barlesi, Benjamin Besse, Quincy Chu, Leena Gandhi, Sang-We Kim, Enric Carcereny, Lecia V Sequist, Paal Brunsvig, Christos Chouaid, Egbert F Smit, Harry J M Groen, Dong-Wan Kim, Keunchil Park, Emin Avsar, Sebastian Szpakowski, Mikhail Akimov, Edward B Garon
INTRODUCTION: In this phase 2 study, we evaluated the activity of AUY922 in pretreated stage IV NSCLC patients. METHODS: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in EGFR, ALK, KRAS, or wild-type for all three. All patients must have received > 2 prior lines of therapy, except a fifth stratum for less pretreated EGFR cohort (EGFR < 2). In EGFR mutant and ALK-rearranged strata, prior platinum therapy was not required...
December 13, 2017: Journal of Thoracic Oncology
Zili Wang, Haitao Yang, Shuimei Luo, Bo Liu, Nianhai Zhang, Lina Li, Sijing Zhou, Ruifen Shen, Xianhe Xie
OBJECTIVE: For non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) mutations are predictive markers of the treatment benefit from selective tyrosine kinase inhibitors (TKI). However, their prognostic roles remained uncertain. Thus, we conducted this meta-analysis to evaluate the prognosis of ALK+ NSCLC patients in the treatment of surgery, chemotherapy, and/or EGFR-TKI. MATERIALS AND METHODS: PubMed, Embase and Cochrane databases were thoroughly searched to identify relevant studies...
October 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Amanda Tufman, Kathrin Kahnert, Thomas Duell, Diego Kauffmann-Guerrero, Katrin Milger, Christian Schneider, Julia Stump, Zulfiya Syunyaeva, Rudolf Maria Huber, Simone Reu
Background: Tyrosine kinase inhibitors (TKIs) have improved response rates in some patients with non-small cell lung cancer (NSCLC), and testing for EGFR mutation and ALK translocation is recommended for all patients with advanced lung adenocarcinoma. The frequency of driver mutations in elderly and very elderly patients has not been described. Patients and methods: We reviewed EGFR and ALK in patients over the age of 70 years diagnosed and treated at our center in 2015 (subgroups: 70-74, 75-79 and >80 years)...
2017: OncoTargets and Therapy
A Passaro, A Prelaj, A Pochesci, G Spitaleri, G Rossi, E Del Signore, C Catania, F de Marinis
Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease...
August 2017: Drugs of Today
Martin Faehling, Birgit Schwenk, Sebastian Kramberg, Robert Eckert, Anna-Lena Volckmar, Albrecht Stenzinger, Jörn Sträter
Introduction: Oncogenic driver mutations activating EGFR, ALK, or BRAF in NSCLC predict sensitivity to specific tyrosine-kinase inhibitors (TKIs). We provide data on prevalence, treatment and survival of driver-mutation positive NSCLC in a predominantly Caucasian population in routine clinical practice. Patients and Methods: NSCLC patients diagnosed from 2006-2015 with an EGFR-test result were included (n=265). Testing for EGFR, ALK, or BRAF was performed if specific TKI therapy was considered...
September 29, 2017: Oncotarget
Helei Hou, Xiaonan Yang, Jinping Zhang, Zhe Zhang, Xiaomei Xu, Xiaoping Zhang, Chuantao Zhang, Dong Liu, Weihua Yan, Na Zhou, Hongmei Zhu, Zhaoyang Qian, Zhuokun Li, Xiaochun Zhang
Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assays have provided a new method of identifying tumor-driving genes in patients with advanced non-small cell lung carcinoma (NSCLC), especially in those whose cancer tissues are unavailable or in those that have acquired treatment resistance. Here, we describe a total of 119 patients with advanced EGFR-TKI-naive NSCLC and 15 EGFR-TKI-resistant patients to identify somatic SNVs, small indels, CNVs and gene fusions in 508 tumor-related genes...
November 6, 2017: Scientific Reports
Alice T Shaw, Enriqueta Felip, Todd M Bauer, Benjamin Besse, Alejandro Navarro, Sophie Postel-Vinay, Justin F Gainor, Melissa Johnson, Jorg Dietrich, Leonard P James, Jill S Clancy, Joseph Chen, Jean-François Martini, Antonello Abbattista, Benjamin J Solomon
BACKGROUND: Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC...
December 2017: Lancet Oncology
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