Motzer RJ, Escudier B, Oudard S, et al.RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
The Lancet (Impact Factor: 45.22). 08/2008; 372(9637):449-56. DOI: 10.1016/S0140-6736(08)61039-9
Source: PubMed


Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.
Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with, number NCT00410124.
All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.
Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

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    • "Hyperglycaemia is well established as an important mechanismbased toxicity associated with mTORi, which has led to development of guidelines for its effective management (Busaidy et al, 2012). In patients treated with everolimus and temsirolimus in large phase III clinical trials, incidence of all-grade hyperglycaemia ranged between 12 and 50% with 4–22% of high-grade (G3–G4; Hudes et al, 2007; Motzer et al, 2008; Verges et al, 2014). A recent meta-analysis studying toxicities of allosteric mTORi showed an increased risk of hyperglycaemia, all-grade by 2.95-fold (95% CI, 2.14, 4.05) and high-grade by 5.25-fold (95% CI, 3.07, 9.00) (Sivendran et al, 2014). "
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    ABSTRACT: Background: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.British Journal of Cancer advance online publication, 10 November 2015; doi:10.1038/bjc.2015.373
    British Journal of Cancer 11/2015; DOI:10.1038/bjc.2015.373 · 4.84 Impact Factor
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    • "Sunitinib [3], sorafenib [4], axitinib [5], pazopanib [6] and bevacizumab + interferon [7] have all been registered for the treatment of advanced RCC. Additionally, the mTOR inhibitors Temsirolimus and Everolimus have been registered for poor risk RCC patients [8] [9]. Implementation of these new treatment modalities has lead to an impressive increase in progression-free survival [10]. "
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    ABSTRACT: Anti-angiogenic treatment with tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined sunitinib, targeting the endothelial cells with Girentuximab (monoclonal antibody cG250, recognizing carbonic anhydrase IX (CAIX) targeting the tumor cells to study the effect of sunitinib on the biodistribution of Girentuximab because combination of modalities targeting tumor vasculature and tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day sunitinib, or vehicle for 7 to 14 days. Three days before start or cessation of treatment mice were injected i.v. with 0.4 MBq/5 μg (111)In-Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the tumor vasculature and CAIX expression and to confirm Girentuximab uptake. NU12 appeared to represent a sunitinib sensitive tumor: sunitinib treatment resulted in extensive necrosis and decreased microvessel density (MVD). Accumulation of Girentuximab was significantly decreased when sunitinib treatment preceded the antibody injection but remained unchanged when sunitinib followed Girentuximab injection. Cessation of therapy led to a rapid neovascularization, reminiscent of a tumor flare. SK-RC-52 appeared to represent a sunitinib-resistant tumor: (central) tumor necrosis was minimal and MVD was not affected. Sunitinib treatment resulted in increased Girentuximab uptake, regardless of the sequence of treatment. These data indicate that sunitinib can be combined with Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 02/2015; 49(2). DOI:10.1016/j.neo.2014.12.011 · 4.25 Impact Factor
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    • "Additionally, temsirolimus and everolimus, derivatives of rapamycin, are approved to treat advanced RCC [5]. While significant tumor responses are seen in the setting of VEGFR inhibition they are much less common upon mTOR inhibition suggesting potential compensatory survival and proliferative mechanisms that can be co-targeted [11], [12]. "
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    ABSTRACT: Rapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalytic mTOR inhibition, evaluate the crosstalk between the mTOR and MEK/ERK pathways, as well as the therapeutic potential of dual mTOR and MEK inhibition in RCC. Pharmacologic (rapamycin and BEZ235) and genetic manipulation of the mTOR pathway were evaluated by in vitro assays as monotherapy as well as in combination with MEK inhibition (GSK1120212). Catalytic mTOR inhibition with BEZ235 decreased proliferation and increased apoptosis better than allosteric mTOR inhibition with rapamycin. While mTOR inhibition upregulated MEK/ERK signaling, concurrent inhibition of both pathways had enhanced therapeutic efficacy. Finally, primary RCC tumors could be classified into subgroups [(I) MEK activated, (II) Dual MEK and mTOR activated, (III) Not activated, and (IV) mTOR activated] based on their relative activation of the PI3K/mTOR and MEK pathways. Patients with mTOR only activated tumors had the worst prognosis. In summary, dual targeting of the mTOR and MEK pathways in RCC can enhance therapeutic efficacy and primary RCC can be subclassified based on their relative levels of mTOR and MEK activation with potential therapeutic implications.
    PLoS ONE 09/2014; 9(9):e104413. DOI:10.1371/journal.pone.0104413 · 3.23 Impact Factor
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