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Onartuzumab

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https://www.readbyqxmd.com/read/27918764/effect-of-fluorouracil-leucovorin-and-oxaliplatin-with-or-without-onartuzumab-in-her2-negative-met-positive-gastroesophageal-adenocarcinoma-the-metgastric-randomized-clinical-trial
#1
Manish A Shah, Yung-Jue Bang, Florian Lordick, Maria Alsina, Meng Chen, Stephen P Hack, Jean Marie Bruey, Dustin Smith, Ian McCaffery, David S Shames, See Phan, David Cunningham
Importance: Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. Objective: To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC...
December 1, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27918718/randomized-double-blind-placebo-controlled-multicenter-phase-ii-study-of-onartuzumab-plus-bevacizumab-versus-placebo-plus-bevacizumab-in-patients-with-recurrent-glioblastoma-efficacy-safety-and-hepatocyte-growth-factor-and-o-6-methylguanine-dna-methyltransferase
#2
Timothy Cloughesy, Gaetano Finocchiaro, Cristóbal Belda-Iniesta, Lawrence Recht, Alba A Brandes, Estela Pineda, Tom Mikkelsen, Olivier L Chinot, Carmen Balana, David R Macdonald, Manfred Westphal, Kirsten Hopkins, Michael Weller, Carlos Bais, Thomas Sandmann, Jean-Marie Bruey, Hartmut Koeppen, Bo Liu, Wendy Verret, See-Chun Phan, David S Shames
Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression...
December 5, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27856142/efficacy-and-safety-of-onartuzumab-in-combination-with-first-line-bevacizumab-or-pemetrexed-based-chemotherapy-regimens-in-advanced-non-squamous-non-small-cell-lung-cancer
#3
Heather Wakelee, Zanete Zvirbule, Filippo De Braud, C Daniel Kingsley, Tarek Mekhail, Thomas Lowe, Wolfgang Schütte, Hervé Lena, William Lawler, Fadi Braiteh, Thomas Cosgriff, Diego Kaen, Michelle Boyer, Jessie Hsu, See Phan, Silvia Novello
BACKGROUND: Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. METHODS: Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate...
October 19, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27461773/efficacy-and-safety-results-from-a-phase-ii-placebo-controlled-study-of-onartuzumab-plus-first-line-platinum-doublet-chemotherapy-for-advanced-squamous-cell-non-small-cell-lung-cancer
#4
Fred R Hirsch, Ramaswamy Govindan, Zanete Zvirbule, Fadi Braiteh, Achim Rittmeyer, Cristóbal Belda-Iniesta, Dolores Isla, Thomas Cosgriff, Michelle Boyer, Masamichi Ueda, See Phan, David R Gandara
INTRODUCTION: The treatment options for squamous cell non-small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC. PATIENTS AND METHODS: The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0)...
June 4, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27401892/a-randomized-phase-ii-study-of-folfox-with-or-without-the-met-inhibitor-onartuzumab-in-advanced-adenocarcinoma-of-the-stomach-and-gastroesophageal-junction
#5
Manish A Shah, Jae-Yong Cho, Iain B Tan, Niall C Tebbutt, Chia-Jui Yen, Alice Kang, David S Shames, Lilian Bu, Yoon-Koo Kang
BACKGROUND: The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined. PATIENTS AND METHODS: Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression...
September 2016: Oncologist
https://www.readbyqxmd.com/read/27349303/validation-of-an-electronic-program-for-pathologist-training-in-the-interpretation-of-a-complex-companion-diagnostic-immunohistochemical-assay
#6
Eslie Dennis, Peter Banks, Lauren B Murata, Stephanie A Sanchez, Christie Pennington, Linda Hockersmith, Rachel Miller, Jess Lambe, Janine Feng, Monesh Kapadia, June Clements, Isabell Loftin, Shalini Singh, Ashis Das-Gupta, William Lloyd, Kenneth Bloom
Companion diagnostics assay interpretation can select patients with the greatest targeted therapy benefits. We present the results from a prospective study demonstrating that pathologists can effectively learn immunohistochemical assay-interpretation skills from digital image-based electronic training (e-training). In this study, e-training was used to train board-certified pathologists to evaluate non-small cell lung carcinoma for eligibility for treatment with onartuzumab, a MET-inhibiting agent. The training program mimicked the live training that was previously validated in clinical trials for onartuzumab...
October 2016: Human Pathology
https://www.readbyqxmd.com/read/26651519/antibodies-to-watch-in-2016
#7
Janice M Reichert
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) granted first approvals as of mid-November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016...
2016: MAbs
https://www.readbyqxmd.com/read/26445503/safety-of-onartuzumab-in-patients-with-solid-tumors-experience-to-date-from-the-onartuzumab-clinical-trial-program
#8
Roland Morley, Alison Cardenas, Peter Hawkins, Yasuyo Suzuki, Virginia Paton, See-Chun Phan, Mark Merchant, Jessie Hsu, Wei Yu, Qi Xia, Daniel Koralek, Patricia Luhn, Wassim Aldairy
BACKGROUND: Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program. METHODS: Adverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards...
2015: PloS One
https://www.readbyqxmd.com/read/26202594/randomized-phase-ii-placebo-controlled-trial-of-onartuzumab-and-or-bevacizumab-in-combination-with-weekly-paclitaxel-in-patients-with-metastatic-triple-negative-breast-cancer
#9
RANDOMIZED CONTROLLED TRIAL
V Diéras, M Campone, D A Yardley, G Romieu, V Valero, S J Isakoff, H Koeppen, T R Wilson, Y Xiao, D S Shames, S Mocci, M Chen, P Schmid
BACKGROUND: Increased hepatocyte growth factor/MET signaling is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer (TNBC). We evaluated the benefit of adding onartuzumab, a monoclonal anti-MET antibody, to paclitaxel with/without bevacizumab in patients with TNBC. PATIENTS AND METHODS: Women with metastatic TNBC were randomized to receive onartuzumab plus placebo plus weekly paclitaxel (OP; n = 60) or onartuzumab plus bevacizumab plus paclitaxel (OBP; n = 63) or placebo plus bevacizumab plus paclitaxel (BP; n = 62)...
September 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25902737/analysis-of-kras-and-braf-genes-mutation-in-the-central-nervous-system-metastases-of-non-small-cell-lung-cancer
#10
Marcin Nicoś, Paweł Krawczyk, Bożena Jarosz, Marek Sawicki, Justyna Szumiłło, Tomasz Trojanowski, Janusz Milanowski
KRAS mutations are associated with tumor resistance to EGFR TKIs (erlotinib, gefitinib) and to monoclonal antibody against EGFR (cetuximab). Targeted treatment of mutated RAS patients is still considered as a challenge. Inhibitors of c-Met (onartuzumab or tiwantinib) and MEK (selumetinib-a dual inhibitor of MEK1 and MEK2) signaling pathways showed activity in patients with mutations in KRAS that can became an effective approach in carriers of such disorders. BRAF mutation is very rare in patients with NSCLC, and its presence is associated with sensitivity of tumor cells to BRAF inhibitors (vemurafenib, dabrafenib)...
May 2016: Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/25818471/onartuzumab-in-lung-cancer-the-fall-of-icarus
#11
EDITORIAL
Christian Rolfo, Nele Van Der Steen, Patrick Pauwels, Federico Cappuzzo
The development of targeted therapies has led to a revolution in non-small-cell lung cancer, and opened up possibilities for improved personalized medicine. With the constant findings of new targets, a lot of inhibitors are being developed. However, reliable biomarkers are urgently needed. The design of clinical trials needs to become more flexible in order to obtain the best results and gain the US FDA/EMEA approval for the new drugs. A recent example of a failed trial is the Phase III MetLung trial that compared the effects of the c-MET monovalent antibody onartuzumab with erlotinib versus erlotinib alone in late-stage non-small-cell lung cancer...
May 2015: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/25806331/targeting-met-and-egfr-in-nsclc-what-can-we-learn-from-the-recently-reported-phase-iii-trial-of-onartuzumab-in-combination-with-erlotinib-in-advanced-non-small-cell-lung-cancer
#12
Michail Charakidis, Michael Boyer
No abstract text is available yet for this article.
December 2014: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/25806328/a-critical-question-for-cancer-therapy-what-new-targets-exist
#13
Rafael Rosell, Niki Karachaliou, Jordi Codony, Cristina Teixido, Silvia Garcia-Roman, Daniela Morales, María González Cao, Santiago Viteri, Ignacio Veliz, Yong Loo, Omar Castillo
Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti-EGFR therapies...
December 2014: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/25777467/phase-i-study-of-the-anti-met-antibody-onartuzumab-in-patients-with-solid-tumors-and-met-positive-lung-cancer
#14
MULTICENTER STUDY
Makoto Nishio, Atsushi Horiike, Hiroshi Nokihara, Hidehito Horinouchi, Shinji Nakamichi, Hiroshi Wakui, Fumiyoshi Ohyanagi, Keita Kudo, Noriko Yanagitani, Shunji Takahashi, Yasutoshi Kuboki, Noboru Yamamoto, Yasuhide Yamada, Masaichi Abe, Takashi Tahata, Tomohide Tamura
Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC...
June 2015: Investigational New Drugs
https://www.readbyqxmd.com/read/25542267/onartuzumab-with-or-without-bevacizumab-in-combination-with-weekly-paclitaxel-does-not-prolong-qtc-or-adversely-affect-other-ecg-parameters-in-patients-with-locally-recurrent-or-metastatic-triple-negative-breast-cancer
#15
RANDOMIZED CONTROLLED TRIAL
Marie T Borin, Meng Chen, Simonetta Mocci, Igor Rubets, Jason Chittenden, Wassim Aldairy, Mark Stroh
PURPOSE: The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer. METHODS: Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV)...
February 2015: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/25522765/combining-onartuzumab-with-erlotinib-inhibits-growth-of-non-small-cell-lung-cancer-with-activating-egfr-mutations-and-hgf-overexpression
#16
Yuji Sano, Eri Hashimoto, Noriaki Nakatani, Masaichi Abe, Yasuko Satoh, Kiyoaki Sakata, Toshihiko Fujii, Kaori Fujimoto-Ouchi, Masamichi Sugimoto, Shigehisa Nagahashi, Masahiro Aoki, Hiroshi Motegi, Eiichi Sasaki, Yasushi Yatabe
Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models...
February 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/25266653/c-met-inhibitors-in-the-treatment-of-lung-cancer
#17
REVIEW
Joanna Goździk-Spychalska, Katarzyna Szyszka-Barth, Lukasz Spychalski, Katarzyna Ramlau, Jerzy Wójtowicz, Halina Batura-Gabryel, Rodryg Ramlau
Lung cancer is the most common malignant neoplasm and constitutes the most common neoplastic cause of death globally. The results of therapies employing standard chemotherapy are unsatisfactory. Currently, efforts are being made to personalize the therapy; numerous clinical studies are being conducted around the world to assess the efficacy and safety of agents directed at molecular targets. One of these molecular targets is the c-MET proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF). C-MET hyperactivity has been observed in numerous neoplasms, including non-small-cell lung carcinoma...
December 2014: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/25074413/pak1-mediates-pancreatic-cancer-cell-migration-and-resistance-to-met-inhibition
#18
Wei Zhou, Adrian M Jubb, Karen Lyle, Qian Xiao, Christy C Ong, Rupal Desai, Ling Fu, Florian Gnad, Qinghua Song, Peter M Haverty, Daniela Aust, Robert Grützmann, Mally Romero, Klara Totpal, Richard M Neve, Yibing Yan, William F Forrest, Yulei Wang, Rajiv Raja, Christian Pilarsky, Ana de Jesus-Acosta, Marcia Belvin, Lori S Friedman, Mark Merchant, Elizabeth M Jaffee, Lei Zheng, Hartmut Koeppen, Klaus P Hoeflich
Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development...
December 2014: Journal of Pathology
https://www.readbyqxmd.com/read/24959087/emerging-molecular-targets-in-oncology-clinical-potential-of-met-hepatocyte-growth-factor-inhibitors
#19
REVIEW
Elizabeth C Smyth, Francesco Sclafani, David Cunningham
The MET/hepatocyte growth-factor (HGF) signaling pathway plays a key role in the processes of embryogenesis, wound healing, and organ regeneration. Aberrant activation of MET/HGF occurs through multiple mechanisms including gene amplification, mutation, protein overexpression, and abnormal gene splicing interrupting autocrine and paracrine regulatory feedback mechanisms. In many cancers including non-small-cell lung cancer, colorectal, gastric, renal, and hepatocellular cancer, dysregulation of MET may lead to a more aggressive cancer phenotype and may be a negative prognostic indicator...
2014: OncoTargets and Therapy
https://www.readbyqxmd.com/read/24687921/biomarker-analyses-from-a-placebo-controlled-phase-ii-study-evaluating-erlotinib%C3%A2-onartuzumab-in-advanced-non-small-cell-lung-cancer-met-expression-levels-are-predictive-of-patient-benefit
#20
RANDOMIZED CONTROLLED TRIAL
Hartmut Koeppen, Wei Yu, Jiping Zha, Ajay Pandita, Elicia Penuel, Linda Rangell, Rajiv Raja, Sankar Mohan, Rajesh Patel, Rupal Desai, Ling Fu, An Do, Vaishali Parab, Xiaoling Xia, Tom Januario, Sharianne G Louie, Ellen Filvaroff, David S Shames, Ignacio Wistuba, Marina Lipkind, Jenny Huang, Mirella Lazarov, Vanitha Ramakrishnan, Lukas Amler, See-Chun Phan, Premal Patel, Amy Peterson, Robert L Yauch
PURPOSE: In a recent phase II study of onartuzumab (MetMAb), patients whose non-small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. EXPERIMENTAL DESIGN: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA...
September 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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