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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 《Clinical lung cancer》2017,18(1):50-59
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. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics.Results
Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%).Conclusion
Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC. 相似文献2.
BACKGROUND: Shorter leg length is associated with an adverse environment in early childhood and has been found to be associated with a variety of disorders occurring in mid- to late-life, including dementia in a Korean population. In a community population of African-Caribbean elders, in whom leg length had been measured, we sought to compare associations with cognitive impairment at baseline and cognitive decline over a three-year follow-up period. METHODS: Of 290 African-Caribbean residents in south London recruited at baseline, 216 (74%) were re-interviewed after a three-year period and 203 had sufficient data for this analysis. Cognitive impairment was derived as a binary category from a battery of cognitive tests administered at baseline and cognitive decline was derived from change in performance on a subset of these tests. Leg length (iliac crest to lateral malleolus) was also measured. RESULTS: Shorter leg length was associated with female sex, lower occupational social class and reported hypertension and diabetes. Shorter leg length (lowest quartile) was significantly associated with cognitive impairment but there were no apparent associations with cognitive decline. The association with cognitive impairment was independent of age, sex and education. Social class appeared to be an important mediating factor. CONCLUSIONS: Shorter leg length may be a marker of early life stressors which result in reduced cognitive reserve. Interestingly this association was mediated more strongly by social class (previous occupational status) than by education in this population. 相似文献
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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 《Clinical lung cancer》2017,18(1):43-49
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). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC+ populations.Results
The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC+ populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety-evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm.Conclusion
Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further. 相似文献
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