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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...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
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...
October 18, 2016: Cell Cycle
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
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
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
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
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...
August 11, 2016: Oncotarget
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...
2016: International Journal of Molecular Sciences
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...
July 13, 2016: Oncotarget
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Cassin-Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Nathalie Auger, Françoise Farace, Jordi Remon, Jean-Yves Scoazec, Fabrice Andre, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to Tyrosine Kinase Inhibitor (TKIs) is a key-step to improve therapeutic results for patients with oncogene-addiction. Several alterations leading to Epidermal Growth Factor Receptor (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...
July 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
Giulio Metro, Gianluigi Lunardi, Chiara Bennati, Pietro Chiarini, Isabella Sperduti, Biagio Ricciuti, Luca Marcomigni, Cinzia Costa, Lucio Crinò, Piero Floridi, Stefania Gori, Rita Chiari
In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS...
September 2016: Journal of Neuro-oncology
Justin F Gainor, Alice T Shaw, Lecia V Sequist, Xiujun Fu, Christopher G Azzoli, Zofia Piotrowska, Tiffany G Huynh, Ling Zhao, Linnea Fulton, Katherine R Schultz, Emily Howe, Anna F Farago, Ryan J Sullivan, James R Stone, Subba Digumarthy, Teresa Moran, Aaron N Hata, Yukako Yagi, Beow Y Yeap, Jeffrey A Engelman, Mari Mino-Kenudson
PURPOSE: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. EXPERIMENTAL DESIGN: We identified 58 patients treated with PD-1/PD-L1 inhibitors...
September 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
L Sorber, K Zwaenepoel, V Deschoolmeester, P E Y Van Schil, J Van Meerbeeck, F Lardon, C Rolfo, P Pauwels
Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer...
May 4, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Francesca Casaluce, Assunta Sgambato, Paola Claudia Sacco, Giovanni Palazzolo, Paolo Maione, Antonio Rossi, Fortunato Ciardiello, Cesare Gridelli
Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance...
2016: Current Clinical Pharmacology
Lixia Ju, Mingquan Han, Chao Zhao, Xuefei Li
The c-ros oncogene 1 (ROS1) fusion is almost mutually exclusive to epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in non-small cell lung cancer (NSCLC), and it is not seen in the literature for patients to exhibit three mutations. The present study reported a case of a 53-year-old male diagnosed with adenocarcinoma, exhibiting combined EGFR, KRAS mutations and ROS1 rearrangement. At the first line therapy, the patient was treated with crizotinib because of the KRAS mutation that is a known resistant factor of EGFR-TKI resistance, but no responsive...
May 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Emei Gao, Jun Zhao, Minglei Zhuo, Zhijie Wang, Yuyan Wang, Tongtong An, Meina Wu, Xue Yang, Jia Zhong
BACKGROUND AND OBJECTIVE: Crizotinib was developed in recent years based on targets of anaplastic lymphoma kinase (ALK) fusion genes. The aim of this study is to explore the efficacy of crizotinib in treatment of non-small cell lung cancer (NSCLC) with ALK/ROS1 rearrangement. METHODS: Retrospective analysis of 40 patients with ALK/ROS1-positive NSCLC, who received treatment in Beijing Cancer Hospital during the period from Jun. 2013 to Dec. 2014. RESULTS: Among these cases, 39 were adenocarcinoma and adenosquamous carcinoma, with characters involving signet-ring cell carcinoma, polypoid adenocarcinoma, acini and papillary adenocarcinoma...
March 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Tatsuya Yoshida, Toyoaki Hida, Yasushi Yatabe
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear...
July 2016: Anti-cancer Drugs
Ryohei Katayama, Takuya Sakashita, Noriko Yanagitani, Hironori Ninomiya, Atsushi Horiike, Luc Friboulet, Justin F Gainor, Noriko Motoi, Akito Dobashi, Seiji Sakata, Yuichi Tambo, Satoru Kitazono, Shigeo Sato, Sumie Koike, A John Iafrate, Mari Mino-Kenudson, Yuichi Ishikawa, Alice T Shaw, Jeffrey A Engelman, Kengo Takeuchi, Makoto Nishio, Naoya Fujita
The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%-5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect...
January 2016: EBioMedicine
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