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Bing Liu, Maoxi Yuan, Yi Sun, Ziming Cheng, Zaiyong Zhang, Shizheng Hou, Xiangdong Wang, Jingfeng Liu
Background: Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials. Materials and Methods: The databases of PubMed, Web of Science and abstracts presented at oncology conferences' proceedings were searched for relevant studies from January 2000 to January 2017...
February 6, 2018: Oncotarget
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
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
March 5, 2018: Nature Medicine
Hang Cao, Anja T Umbach, Rosi Bissinger, Meinrad Gawaz, Florian Lang
BACKGROUND/AIMS: The anaplastic lymphoma (tyrosine) kinase (ALK) inhibitor ceritinib triggers apoptosis of tumor cells and eryptosis of erythrocytes. Blood platelets may similarly enter a state resembling apoptosis, which could be triggered by activation with collagen related peptide (CRP). CRP-induced platelet apoptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the platelet surface and cell shrinkage, preceded by externalization of Ca2+ channel Orai1, increase of cytosolic Ca2+-activity ([Ca2+]i), formation of reactive oxygen species (ROS), and caspase activation...
February 23, 2018: Cellular Physiology and Biochemistry
Miyako Satouchi, Makoto Nishio, Toyoaki Hida, Kazuhiko Nakagawa
The advent of anaplastic lymphoma kinase(ALK)inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer(NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib(Zykadia® capsules)is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life...
February 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Katsuyuki Kiura, Fumio Imamura, Hiroshi Kagamu, Shingo Matsumoto, Toyoaki Hida, Kazuhiko Nakagawa, Miyako Satouchi, Isamu Okamoto, Mitsuhiro Takenoyama, Yasuhito Fujisaka, Takayasu Kurata, Masayuki Ito, Kota Tokushige, Ben Hatano, Makoto Nishio
Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days)...
February 21, 2018: Japanese Journal of Clinical Oncology
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
Zheng-Yi Zhou, Alex Mutebi, Simeng Han, Arielle G Bensimon, Marie Louise Ricculli, Jipan Xie, Anand Dalal, Ken Culver
AIMS: To assess the cost-effectiveness of first-line ceritinib vs crizotinib and platinum doublet chemotherapy for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) from a US third-party payer's perspective. MATERIALS AND METHODS: A partitioned survival model with three health states (stable disease, progressive disease, death) was developed over a 20-year time horizon. Ceritinib's efficacy inputs (progression-free and overall survival) were estimated from ASCEND-4; parametric survival models extrapolated data beyond the trial period...
March 12, 2018: Journal of Medical Economics
Mengting Han, Jiwei Shen, Lijing Wang, Yu Wang, Xin Zhai, Yao Li, Meiqiao Liu, Zengqiang Li, Daiying Zuo, Yingliang Wu
Anaplastic lymphoma kinase (ALK)-positive cancers have rising morbidity and mortality in recent years, and novel chemotherapeutic drugs with no drug resistance and high activity for treating ALK-positive cancers are needed urgently. In this study, we investigated the anti-cancer effect of 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-((4-methylpiperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-2,4-diamine (WY-135), a novel ALK inhibitor, on nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) positive cancer cell line Karpas299 and echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) positive cancer cell line H2228...
February 16, 2018: Chemico-biological Interactions
Brandon Golding, Anita Luu, Robert Jones, Alicia M Viloria-Petit
Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization...
February 19, 2018: Molecular Cancer
Carminia Maria Della Corte, Giuseppe Viscardi, Raimondo Di Liello, Morena Fasano, Erika Martinelli, Teresa Troiani, Fortunato Ciardiello, Floriana Morgillo
Anaplastic lymphoma kinase (ALK) gene activation is involved in the carcinogenesis process of several human cancers such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma, as a consequence of fusion with other oncogenes (NPM, EML4, TIM, etc) or gene amplification, mutation or protein overexpression. ALK is a transmembrane tyrosine kinase receptor that, upon ligand binding to its extracellular domain, undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain...
February 19, 2018: Molecular Cancer
Idoroenyi Amanam, Rohan Gupta, Isa Mambetsariev, Ravi Salgia
Lung cancer remains the leading cause of cancer deaths in the world with 1.69 million deaths in 2015. A total of 85% of lung cancer cases are non-small-cell lung cancers (NSCLCs). Driver mutations associated with anaplastic lymphoma kinase (ALK) have been identified in a variety of malignancies, including NSCLC. An ALK inhibitor (crizotinib, ceritinib and alectinib) is the preferred therapeutic approach to those advanced ALK fusion variant-positive NSCLC patients. Brigatinib, a next-generation ALK inhibitor, shows promising activity in ALK-rearranged NSCLC that have previously received crizotinib with response rates in ALTA ranging from 42-50%, intracranial response 42-67% and median progression-free survival 9...
February 16, 2018: Future Oncology
Jacques Cadranel, Alexis B Cortot, Hervé Lena, Bertrand Mennecier, Pascal Do, Eric Dansin, Julien Mazieres, Christos Chouaid, Maurice Perol, Fabrice Barlesi, Gilles Robinet, Sylvie Friard, Luc Thiberville, Clarisse Audigier-Valette, Alain Vergnenegre, Virginie Westeel, Khemaies Slimane, Alexandru Buturuga, Denis Moro-Sibilot, Benjamin Besse
Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase ( ALK ) positive ( ALK + ) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK + or ROS proto-oncogene 1 positive ( ROS1 + ) tumours. Patients received oral ceritinib (750 mg·day -1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months...
January 2018: ERJ Open Research
M C Mengoli, F Bertolini, M Maur, F Barbieri, L Longo, P Gasparri, M Tiseo, G Rossi
We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement...
December 2017: Pathologica
Francesco Facchinetti, Paola Bordi, Paola Bini, Livia Bidin, Roberta Camisa, Marcello Tiseo
INTRODUCTION: Several reports attest the feasibility and the favorable outcomes of kinase inhibitors administration through feeding tubes or percutaneous endoscopic gastrostomies (PEG), mainly in non-small cell lung cancer (NSCLC) patients exposed to first-generation compounds. Here we present the case of an ALK-positive NSCLC patient who achieved cerebral and extra-cranial disease response with ceritinib (a novel ALK inhibitor) administered through a nasogastric tube (NGT). We moreover provide a review gathering clinical successes obtained with targeted agents intake through NGT or PEG...
February 12, 2018: Current Drug Targets
Mart Schiefer, Lizza E L Hendriks, Trang Dinh, Ulrich Lalji, Anne-Marie C Dingemans
An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment...
March 2018: European Journal of Cancer
Jing Guo, Lihong Guo, Li Sun, Zhenzhen Wu, Junyi Ye, Jing Liu, Qiang Zuo
BACKGROUND: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance. METHODS: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors...
February 5, 2018: Cancer Biology & Therapy
Susanna M Wallerstedt, Martin Henriksson
AIMS: To review clinical and cost-effectiveness evidence underlying reimbursement decisions relating to drugs whose authorization mainly is based on evidence from prospective case series. METHODS: A systematic review of all new drugs evaluated in 2011-2016 within a health care profession-driven resource prioritization process, with a market approval based on prospective case series, and a reimbursement decision by the Swedish Dental and Pharmaceutical Benefits Board (TLV)...
January 30, 2018: British Journal of Clinical Pharmacology
Jason N Rosenbaum, Ryan Bloom, Jason T Forys, Jeff Hiken, Jon R Armstrong, Julie Branson, Samantha McNulty, Priya D Velu, Kymberlie Pepin, Haley Abel, Catherine E Cottrell, John D Pfeifer, Shashikant Kulkarni, Ramaswamy Govindan, Eric Q Konnick, Christina M Lockwood, Eric J Duncavage
In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Junhong Jiang, Xue Wu, Xiaoling Tong, Wangzhi Wei, Anan Chen, Xiaonan Wang, Yang W Shao, Jianan Huang
OBJECTIVES: ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential...
January 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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