First-Line Treatment of Advanced Breast Cancer With Sunitinib in Combination With Docetaxel Versus Docetaxel Alone: Results of a Prospective, Randomized Phase III Study

Bergh, Jonas; Bondarenko, Igor; Lichinitser, Mikhail; Liljegren, Annelie; Greil, Richard; Voytko, Nataliya L.; Махсон, А. Н.; Cortés, Javier; Lortholary, Alain; Bischoff, Joachim; Chan, Arlene; Delaloge, Suzette; Huang, Xin; Kern, Kenneth A.; Giorgetti, C.

doi:10.1200/jco.2011.35.7376

Cited by 241 publications

(137 citation statements)

References 23 publications

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“…Figure 1 outlined the selection process in detail. These trials represented three studies with sorafenib, 21,31,32 three with sunitinib, 20,33,34 three with vandetanib [35][36][37] and five with pazopanib. 2,[38][39][40][41] The characteristics of each included trial were presented in Table 2.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 4,430 patients were available for the meta-analysis; for calculation of the RRs, nine trials were pooled; 2,140 of these patients were assigned to treatment arms and 1,896 to placebo or control arms. Underlying metastatic malignancies included MBC, 20 …”

Section: Resultsmentioning

confidence: 99%

“…Recently, a systematic review and meta-analysis of RCTs with two VEGFR-TKIs (sunitinib and sorafenib) demonstrates a significant increase in the risk of ATEs with these agents, 18 and the anti-vascular endothelial growth factor agent bevacizumab has also been associated with an increase risk of VTEs in previous research. 19 In addition, VEGFR-TKIs associated VTEs have been sporadically reported in severally trials in advanced solid tumors with incidence ranging from 0.3% to 15.4%, 20,21 but the contribution of VEGFR-TKIs to VTEs remains poorly defined due to a limited number of patients included in the trials. The mechanism of angiogenesis induced-VTEs may be directly related to inhibitory effect on VEGF signaling pathway: angiogenesis inhibitors can disrupt the regenerative capacity of endothelial cells (ECs) and cause vascular wall defects, exposing prothrombotic phospholipids on the luminal plasma membrane and the underlying matrix, thus leading to thrombosis.…”

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confidence: 99%

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Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Min

Shen

et al. 2012

Intl Journal of Cancer

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Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p 5 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFRTKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Min

Shen

et al. 2012

Intl Journal of Cancer

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“…Monotherapy with any of these drugs is effective against some carcinomas [e.g., gastrointestinal stromal tumor (GIST), renal cell carcinoma, hepatocellular carcinoma, and pancreatic neuroendocrine tumors), suggesting that the inhibition of the VEGF/VEGFR pathway is a valid strategy for the treatment of cancer. Nevertheless, these VEGFR-targeted inhibitor monotherapies for various other carcinomas, except for the abovementioned carcinomas, have only marginal effects, and none of these agents have adequate efficacy when used in combination with chemotherapeutic agents (9)(10)(11)(12)(13). One reason for this issue may be the unfavorable tolerability profile associated with these drugs, resulting in a high percentage of cases requiring dose reduction and/or treatment interruption.…”

Section: Introductionmentioning

confidence: 95%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

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“…However, VEGFR-targeted inhibitor monotherapies showed limited effects on various carcinomas, and even combination therapies with chemotherapeutic agents are unsatisfactory (1,2). The tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and HGF-MET signaling is also involved in tumor progression, metastasis, angiogenesis, and resistance to chemotherapy in various cancers, indicating that MET kinase inhibitors could have major therapeutic potential.…”

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confidence: 99%

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Watanabe¹,

Hirata²,

Tominari

et al. 2016

Journal of Biological Chemistry

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The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-B ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.VEGF signaling through the tyrosine kinase receptor VEGF receptor (VEGFR) 3 is a pivotal factor for tumor angiogenesis that regulates tumor progression. However, VEGFR-targeted inhibitor monotherapies showed limited effects on various carcinomas, and even combination therapies with chemotherapeutic agents are unsatisfactory (1, 2). The tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and HGF-MET signaling is also involved in tumor progression, metastasis, angiogenesis, and resistance to chemotherapy in various cancers, indicating that MET kinase inhibitors could have major therapeutic potential. Inhibition of both VEGFR and MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically (3), suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, Fujita et al. (4) developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in MET-amplified human cancer-bearing mice. In this study, we have investigated the effect of TAS-115 on prostate cancer cell metastasis to bone and a process associated with osteoclast activation.Bone remodeling is regulated by osteoclastic bone resorption and new bone formation. Osteoclasts, which are the primary bone-resorbing cells, are differentiated from macrophages b...

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First-Line Treatment of Advanced Breast Cancer With Sunitinib in Combination With Docetaxel Versus Docetaxel Alone: Results of a Prospective, Randomized Phase III Study

Cited by 241 publications

References 23 publications

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

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