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      Pazopanib in the management of advanced soft tissue sarcomas

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          Abstract

          Therapy of soft tissue sarcomas represents an area of significant unmet need in oncology. Angiogenesis has been explored as a potential target both preclinically and clinically, with suggestions of activity. Pazopanib is a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects. In a Phase II study, pazopanib demonstrated activity in strata enrolling patients with leiomyosarcomas, synovial sarcomas, or other sarcomas but not those enrolling adipocytic sarcomas. PALETTE, the pivotal Phase III trial, demonstrated improved progression-free survival versus placebo in pazopanib-treated patients previously treated for advanced soft tissue sarcomas. No survival benefit was observed, and adipocytic sarcomas were excluded. Health-related quality-of-life assessments indicated significant decrements in several areas affected by pazopanib toxicities, but no global deterioration. Cost-effectiveness analyses indicate that pazopanib therapy may or may not be cost-effective in different geographic settings. Pazopanib provides important proof-of-concept for antiangiogenic therapy in soft tissue sarcomas. Its use can be improved by further biological studies of its activity profile in sarcomas, studies of biological rational combinations, and clinicopathologic/biological correlative studies of activity to allow better drug targeting.

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          Most cited references 95

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          Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.

          Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. Copyright 2004 Massachusetts Medical Society
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            Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.

            Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.) 2006 Massachusetts Medical Society
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              Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.

              PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2016
                09 June 2016
                : 12
                : 941-955
                Affiliations
                [1 ]Division of Medical Oncology, University of Washington, Seattle, WA, USA
                [2 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                Author notes
                Correspondence: Lee D Cranmer, Division of Medical Oncology, University of Washington, 825 Eastlake Avenue E, G3-630, Seattle, WA 98109, USA, Tel +1 206 288 7439, Email lcranmer@ 123456seattlecca.org
                Article
                tcrm-12-941
                10.2147/TCRM.S84792
                4907704
                27354810
                © 2016 Cranmer et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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