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Lung cancer third line therapy

Kathleen M Aguilar, Katherine B Winfree, Catherine E Muehlenbein, Yajun Emily Zhu, Thomas Wilson, Stewart Wetmore, Eric S Nadler
INTRODUCTION: Targeted therapies, including tyrosine kinase inhibitors (TKIs) that target the sensitizing epidermal growth factor receptor (EGFR) gene are recommended for patients with non-small cell lung cancer (NSCLC). Most patients with NSCLC who test positive for the EGFR mutation and receive TKIs develop resistance to these drugs. Questions remain regarding which treatment sequence is optimal for patients with EGFR-mutant NSCLC, and few studies have evaluated patterns of TKI treatment use in NSCLC, irrespective of EGFR mutation status, in a real-world setting...
October 19, 2018: Advances in Therapy
Sara Redaelli, Monica Ceccon, Marina Zappa, Geeta G Sharma, Cristina Mastini, Mario Mauri, Marion Nigoghossian, Luca Massimino, Nicoletta Cordani, Francesca Farina, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni
Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F in vitro at high drug concentrations...
October 15, 2018: Cancer Research
Zhiwei Sun, Shixia Zhou, Junling Tang, Ting Ye, Jingyuan Li, Doudou Liu, Jian Zhou, Jianyu Wang, H Rosie Xing
BACKGROUND: Cancer treatment is based on tumor staging. Curative intent is only applied to localized tumors. Recent studies show that oligometastatic patients who have limited number of metastases may benefit from metastasis-directed local treatments to achieve long-term survival. However, mechanisms underlying oligometastatic to polymetastatic progression remains elusive. METHODS: The effects of miR-200c and Sec23a on tumor metastasis were verified both in vitro and in vivo...
October 6, 2018: EBioMedicine
Jessica Davies, Michael Martinec, Mathieu Coudert, Paul Delmar, Gracy Crane
BACKGROUND: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed. METHODS: This retrospective US cohort study used Flatiron Health's longitudinal electronic health record (EHR)-derived database. Patients (≥18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016...
October 8, 2018: Current Medical Research and Opinion
Akiko Takahashi, Masahiro Seike, Mika Chiba, Satoshi Takahashi, Shinji Nakamichi, Masaru Matsumoto, Susumu Takeuchi, Yuji Minegishi, Rintaro Noro, Shinobu Kunugi, Kaoru Kubota, Akihiko Gemma
Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs...
October 5, 2018: Scientific Reports
Jin-Min Xue, Manirakiza Astère, Mao-Xi Zhong, Han Lin, Jin Shen, Yu-Xi Zhu
Apatinib (Aitan® , brand name in China) is a new anti-antiangiogenic agent that has recently been approved for the treatment of advanced gastric cancer (GC) in China. Nevertheless, its therapeutic efficacy against other types of advanced solid tumors remains unclear. This meta-analysis examines the short-term efficacy and safety of apatinib or combination therapy for GC, hepatocellular carcinoma (HCC) and non-small-cell lung cancer (NSCLC); and provides a discussion of its anti-angiogenesis therapy applications...
2018: OncoTargets and Therapy
Jan A Stratmann, Sebastian Michels, Sofia Hornetz, Daniel C Christoph, Sandra Sackmann, Werner Spengler, Helge Bischoff, Monica Schäfer, Jürgen Alt, Annette Müller, Eckart Laack, Martin Kimmich, Frank Griesinger, Martin Sebastian
PURPOSE: Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials. METHODS: We performed a retrospective data analysis on patients who were included into the German osimertinib EAP...
September 22, 2018: Journal of Cancer Research and Clinical Oncology
Cesare Gridelli, Javier de Castro Carpeno, Anne-Marie C Dingemans, Frank Griesinger, Francesco Grossi, Corey Langer, Yuichiro Ohe, Konstantinos Syrigos, Nick Thatcher, Ashis Das-Gupta, Matt Truman, Margarita Donica, Vlatka Smoljanovic, Jaafar Bennouna
Importance: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non-small cell lung cancer (NSCLC). Objective: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide...
August 30, 2018: JAMA Oncology
Tao Jiang, Chunxia Su, Shengxiang Ren, Federico Cappuzzo, Gaetano Rocco, Joshua D Palmer, Nico van Zandwijk, Fiona Blackhall, Xiuning Le, Nathan A Pennell, Caicun Zhou
The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have brought substantial clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) and sensitizing EGFR mutation. However, acquired resistance is inevitable since the vast majority of patients experience disease relapse within ~1-2 years. Osimertinib is a novel irreversible, covalent third-generation EGFR-TKI and potent inhibitor of EGFR T790M mutation, the most common mechanism of acquired resistance to first-generation EGFR-TKIs...
July 2018: Journal of Thoracic Disease
Zachary A Yochum, Jessica Cades, Hailun Wang, Suman Chatterjee, Brian W Simons, James P O'Brien, Susheel K Khetarpal, Ghali Lemtiri-Chlieh, Kayla V Myers, Eric H-B Huang, Charles M Rudin, Phuoc T Tran, Timothy F Burns
Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting...
August 31, 2018: Oncogene
Lijia Xie, Seema Nagpal, Heather A Wakelee, Gordon Li, Scott G Soltys, Joel W Neal
INTRODUCTION: Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone...
August 20, 2018: Oncologist
Zui Liu, Wei Ou, Ning Li, Si-Yu Wang
BACKGROUND: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), has proven to be effective and safe for treating patients with advanced gastric cancer after second-line chemotherapy failure. As VEGFR-2 targeted therapy has made encouraging progress for the treatment of a broad range of malignancies, we explored the efficacy and safety of apatinib for the treatment of advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy...
October 2018: Thoracic Cancer
Baohui Han, Kai Li, Qiming Wang, Li Zhang, Jianhua Shi, Zhehai Wang, Ying Cheng, Jianxing He, Yuankai Shi, Yizhuo Zhao, Hao Yu, Yang Zhao, Weiqiang Chen, Yi Luo, Lin Wu, Xiuwen Wang, Robert Pirker, Kejun Nan, Faguang Jin, Jian Dong, Baolan Li, Yan Sun
Importance: Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC). Objective: To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment...
August 9, 2018: JAMA Oncology
Rachel Ryu, Kristina E Ward
Purpose: Atezolizumab is a programmed death ligand 1 (PDL-1) blocking antibody that was approved for metastatic non-small cell lung cancer (NSCLC) in patients with disease progression. Various studies have been initiated to explore the effectiveness of atezolizumab among different patient cohorts and disease statuses, including as first-line therapy. The purpose of this paper is to identify and summarize the trials that use atezolizumab as a first-line agent in chemotherapy-naïve patients with NSCLC. Methods: A database search was performed on Pubmed, Embase, and Wiley Cochrane Library-Central Register of Controlled Trials to identify clinical trials using atezolizumab as first-line therapy in NSCLC...
2018: Frontiers in Oncology
Xiaofen Li, Xia Li, Xuefeng Fang, Ying Yuan
To date, there is no standard third-line therapy for EGFR - and ALK -negative lung squamous cell carcinoma (SCC). Apatinib, an oral small-molecule VEGFR-2 inhibitor, has shown good therapeutic effect and safety in chemotherapy-refractory gastric cancer, but its efficacy in lung SCC is not determined. In this report, we present a 69-year-old Chinese man with locally advanced EGFR- and ALK-negative lung SCC, who received apatinib after failure of 2 treatment regimens. After 4 months of apatinib therapy, chest computed tomography scan showed a large cavity in the lung tumor, while there was minimal change in tumor size...
2018: OncoTargets and Therapy
Xiaoyan Si, Li Zhang, Hanping Wang, Xiaotong Zhang, Mengzhao Wang, Baohui Han, Kai Li, Qiming Wang, Jianhua Shi, Zhehai Wang, Yin Cheng, Jianxing He, Yuankai Shi, Weiqiang Chen, Xiuwen Wang, Yi Luo, Kejun Nan, Faguang Jin, Baolan Li, Yinlan Chen, Jianying Zhou, Donglin Wang
OBJECTIVES: Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients...
August 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Fengying Wu, Shijia Zhang, Anwen Xiong, Guanghui Gao, Wei Li, Weijing Cai, Chunxia Su, Xiaoxia Chen, Fei Zhou, Jing Zhao, Shengxiang Ren, Caicun Zhou
OBJECTIVES: Apatinib exhibits broad-spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor-2. This study evaluated the efficacy and safety of apatinib in patients with advanced non-squamous non-small-cell lung cancer who were heavily pretreated or not suitable to receive standard second-line chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm phase II clinical trial (ClinicalTrials.govNCT02515435). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death...
June 27, 2018: Clinical Lung Cancer
K Patatsos, T M Shekhar, C J Hawkins
Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective...
July 12, 2018: Veterinary and Comparative Oncology
Nobuko Matsuura, Genju Koh, Chihiro Konishi, Satoshi Minamino, Yoshinori Takahara, Hiromasa Harada, Ken Kodama, Masanori Emoto
Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody...
July 11, 2018: Cancer Immunology, Immunotherapy: CII
Cesare Gridelli, Paolo Antonio Ascierto, Francesco Grossi, Editta Baldini, Adolfo Favaretto, Maria Chiara Garassino, Alessandro Morabito, Maria Rita Migliorino, Antonio Rossi, Filippo de Marinis
BACKGROUND: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options...
July 11, 2018: Current Clinical Pharmacology
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