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Chee-Seng Tan, Nesaretnam Barr Kumarakulasinghe, Yi-Qing Huang, Yvonne Li En Ang, Joan Rou-En Choo, Boon-Cher Goh, Ross A Soo
Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development...
February 19, 2018: Molecular Cancer
Shang-Gin Wu, Jin-Yuan Shih
Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs...
February 19, 2018: Molecular Cancer
(no author information available yet)
[This corrects the article on p. 5281 in vol. 10, PMID: 29138581.].
2018: OncoTargets and Therapy
A Kenneth MacLeod, De Lin, Jeffrey T-J Huang, Lesley A McLaughlin, Colin J Henderson, C Roland Wolf
PURPOSE: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy. EXPERIMENTAL DESIGN: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivo Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S Mok, Trever G Bivona, Mayumi Ono, Jean Cui, Santiago Ramón Y Cajal, Peng Cao, Rafael Rosell
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo...
February 5, 2018: EBioMedicine
Zheng-Hai Tang, Jin-Jian Lu
Given the successful identification of epidermal growth factor receptor EGFR T790M, the third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib (OSI, AZD9291), was developed to target EGFR T790M mutation. OSI was approved for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. However, the disease would progress after the patient received OSI treatment for approximately 10 months. Resistance mechanisms to OSI, such as additional mutation of EGFR and alternative kinase activation, were recently identified, and some novel therapeutic strategies were proposed to overcome OSI resistance...
February 6, 2018: Cancer Letters
Joan Rou-En Choo, Chee-Seng Tan, Ross A Soo
The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic mutations of the epidermal growth factor receptor (EGFR). Despite remarkable initial responses, patients eventually develop progressive disease, with the most common cause of resistance to first-line EGFR TKIs being the acquired T790M mutation. Various third-generation EGFR TKIs have been developed to specifically target this acquired mutation, of which osimertinib is currently the only approved agent...
February 8, 2018: Targeted Oncology
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
Yutao Liu, Xuezhi Hao, Xingsheng Hu, Junling Li, Yan Wang, Hongyu Wang, Puyuan Xing, Weihua Li, Jianming Ying, Xiaohong Han, Yuankai Shi
Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism...
February 7, 2018: Thoracic Cancer
Yoshihisa Kobayashi, Toshio Fujino, Masaya Nishino, Takamasa Koga, Masato Chiba, Yuichi Sesumi, Shuta Ohara, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
INTRODUCTION: Dacomitinib is superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. METHODS: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib using N-ethyl-N-nitrosurea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU...
February 1, 2018: Journal of Thoracic Oncology
Venkata Pradeep Babu Koyyala, Ullas Batra, Parveen Jain, Mansi Sharma, Pankaj Goyal, Kshitiz Domadia, Sneha Botra
No abstract text is available yet for this article.
October 2017: South Asian Journal of Cancer
Vanita Noronha, Swaratika Majumdar, Amit Joshi, Vijay Patil, Vaishakhi Trivedi, Anuradha Chougule, Kumar Prabhash
No abstract text is available yet for this article.
October 2017: South Asian Journal of Cancer
Seher Nazlı Kazaz, İlhan Öztop
Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies...
July 2017: Turkish thoracic journal
Qin Feng, Fei Gai, Yaxiong Sang, Jie Zhang, Ping Wang, Yue Wang, Bing Liu, Dongmei Lin, Yang Yu, Jian Fang
Background: The AURA3 clinical trial has shown that advanced non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations in circulating tumor DNA (ctDNA) could benefit from osimertinib. Purpose: The aim of this study was to assess the usefulness of QuantStudio™ 3D Digital PCR System platform for the detection of plasma EGFR T790M mutations in NSCLC patients, and compare the performances of 3D Digital PCR and ARMS-PCR. Patients and methods: A total of 119 Chinese patients were enrolled in this study...
2018: Cancer Management and Research
Yoichi Nishii, Osamu Hataji, Kentaro Ito, Fumiaki Watanabe, Tetsu Kobayashi, Corina D'Alessandro-Gabazza, Masaaki Toda, Osamu Taguchi, Nobuyuki Yamamoto, Esteban C Gabazza
Osimertinib, a third-generation epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated to be effective for treating patients with T790M-positive advanced non-small cell lung cancer (NSCLC) with a relatively good performance status (grade 0-1). Reports of therapeutic response to osimertinib in advanced NSCLC patients with poor performance status are infrequent. The present case report discusses a patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion and T790M mutation with central nervous system involvement and poor performance status...
February 2018: Molecular and Clinical Oncology
Chuangzhou Rao, Liangqin Nie, Xiaobo Miao, Yunbao Xu, Bing Li, Tengfei Zhang
Purpose: Circulating tumor DNA (ctDNA) is a noninvasive and real-time marker for tumor diagnosis, prognosis, and prediction. However, further investigations about ctDNA prognostic and predictive value are still needed, and conclusions from several studies were inconsistent. Experimental design: We performed capture-based targeted ultradeep sequencing on liquid biopsies from a cohort of 34 advanced Chinese non-small-cell lung cancer (NSCLC) patients and analyzed the clinical use of ctDNA in this study...
2018: OncoTargets and Therapy
Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M...
January 31, 2018: Scientific Reports
Fusao Komada
The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Vera Hirsh
Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first- (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles...
2018: Therapeutic Advances in Medical Oncology
Karthick Vishwanathan, Paul A Dickinson, Karen So, Karen Thomas, Yuh-Min Chen, Javier De Castro Carpeño, Anne-Marie C Dingemans, Hye Ryun Kim, Joo-Hang Kim, Matthew G Krebs, James Chih-Hsin Yang, Khanh Bui, Doris Weilert, R Donald Harvey
AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two phase I, open-label, two-part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6-18 orally...
January 30, 2018: British Journal of Clinical Pharmacology
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