Everolimus Patients Research Articles

Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell carcinoma (RCC).

5067 Background: In the primary analysis of Study 205 phase II trial (NCT01136733), lenvatinib+everolimus (vs everolimus) significantly prolonged progression-free survival (median PFS; 14.6 vs 5.5 months, HR = 0.40, 95% CI [0.24, 0.68]) in advanced RCC patients who received one prior anti-angiogenic therapy. Overall treatment differences were evaluated in a post hoc analysis using a quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) methodology. Methods: Patients’ survival time was partitioned into three mutually exclusive health states: time spent with grade 3/4 toxicity (TOX), time prior to disease progression and without grade 3/4 toxicity (TWiST) and time post disease progression (REL). Mean time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. Non-parametric bootstrapping method was used to generate 95% CI, which evaluates the between-treatment differences. At base case, utility for TWiST, TOX and REL were assigned as 1.0, 0.5 and 0.5, respectively. A sensitivity analysis was used, applying utilities across the range of 0 (similar to death) to 1.0 (perfect health). A relative gain in Q-TWiST of ≥10% and ≥15% has been established in previous literature as clinically important and clearly clinically important, respectively. Results: Patients receiving lenvatinib+everolimus (n = 51) vs everolimus (n = 50) had significantly longer mean time in TWiST (10.9 vs 6.4 months; difference 4.5 [95% CI: 1.4, 7.8]) and numerically longer in TOX (1.9 vs 0.7 months; difference 1.2 [95% CI: -0.3, 3.1]) but shorter in REL (5.8 vs 8.5 months; difference -2.8 [95% CI: -6.2, 0.6]). At base case, lenvatinib+everolimus patients had a significant mean Q-TWiST gain of 3.7 months (14.7 vs 11.0; 95% CI of difference [1.3, 6.3]), with a relative gain of 24% vs everolimus. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 - 0.9) with utility of TOX and REL both set as 0.5, absolute mean Q-TWiST gain ranged from 1.7 to 3.3 months, with a relative gain ranging from 11.0% to 21.2% (all significant). With TWiST utility set as 1.0 and utility of TOX and REL varying from 0 to 1.0, Q-TWiST gain ranged from 1.7 to 5.8 months (mostly significant and became non-significant as the REL utility gets closer to 1.0 and TOX utility gets closer to 0). Conclusions: Within Study 205, lenvatinib+everolimus resulted in a statistically significant and clinically important gain in Q-TWiST vs everolimus alone. Clinical trial information: NCT01136733 .

Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients.

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.

Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial.

The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)ml/min with everolimus versus -7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

BackgroundEverolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)–refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). ObjectiveThe purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. Design, setting, and participantsPatients with measurable mRCC and VEGF-refractory disease were eligible for this trial. InterventionStarting in February 2013, patients were randomised (1:1) to AZD2014 (50mg twice daily) or everolimus (10mg once daily) until progression of disease at 10 centres across the United Kingdom. Outcome measurements and statistical analysisProgression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. Results and limitationsRecruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2–6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3–4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1–8.4; p<0.02). ConclusionsThe PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. Patient summaryThere is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73m(2) ) with cyclosporine, a difference of 10.5ml/min/1.73m(2) in favour of everolimus (P<0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73m(2) ) (P<0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310).

First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium

Introduction/BackgroundApproval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. Patients and MethodsWe performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS). ResultsWe identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients. ConclusionPoor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.

Virtual Histology and the Morphologic Assessment of Cardiac Allograft Vasculopathy

To the Editor: We read with great interest the paper by Arora et al. reporting the results of a12-month multicenter Scandinavian study on the qualitative evaluation of the influence of everolimus on cardiac allograft vasculopathy (CAV) morphology among heart transplant (HTx) recipients with a long follow up of >5 years post-HTx. (1Arora S Erikstad I Ueland T et al.Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus—Results of a multicenter trial.Am J Transplant. 2012; 12: 2700-2709Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). With the use of virtual histology (VH) (2Prasad A Cipher DJ Mohandas A Roesle M Brilakis ES Banerjee S Reproducibility of intravascular ultrasound virtual histology analysis.Cardiovasc Revasc Med. 2008; 9: 71-77Crossref PubMed Scopus (27) Google Scholar,3Hernandez JM de Prada JA Burgos V et al.Virtual histology intravascular ultrasound assessment of cardiac allograft vasculopathy from 1 to 20 years after heart transplantation.J Heart Lung Transplant. 2009; 28: 156-162Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the authors revealed a significant increase in calcified and necrotic tissue component in intimal lesions of the everolimus group of HTx patients compared to controls, while the overall plaque volume was not affected at all. Calcified and necrotic components of the plaques were considered by the authors as a result of the inflammatory tissue component of the plaque, and their findings on VH were indeed accompanied by a parallel rise in plasma levels of the markers for endothelial cell activation vWF and VCAM. Intriguing in this study is that the increase in calcified and necrotic components was more prominent in those patients who had a longer time since HTx (>5 years). As recognized also by the authors, CAV lesions are pathologically heterogeneous and can be characterized by a prevalence of fibrous/ fibrocellular pattern or a more atheroma-like pattern. Studies on native atherosclerotic plaques have shown that the cellular microenvironment differs significantly in these two type of lesions and that they can also be affected differently by everolimus (4Li X de Winter RJ van der Wal AC The iatrogenic pathology of percutaneous interventions in coronary arteries.Minerva Medica. 2012; 103: 487-502PubMed Google Scholar). Here, the question comes up whether the results of this study could have been influenced by the specific morphological types of CAV lesions. These were not classified by the authors, but proliferation signal inhibitors (PSIs) could influence one type of lesion more than the other. We have recently evaluated pathologically 70 coronary plaques from heart transplanted pts who died because of CAV (5Castellani C Angelini A de Boer O et al.Intraplaque haemorrhage as a trigger of lesion progression in cardiac allograft vasculopathy.J Heart Lung Transplant. 2012; 31: 5275Abstract Full Text Full Text PDF Google Scholar). With the use of conventional histology and immunohistochemistry, we could identify intraplaque hemorrhages in 60% of CAV lesions, which was even more than the 30.4% of plaque hemorrhages that we observed in the coronary plaques of the same patients in their explanted native heart (p = 0.01). Such intraplaque hemorrhages can be responsible for necrotic core enlargement as was detected in the everolimus treated patients, and this process favors deposition of calcification on the long term. We believe that the lack of reduction of plaque volume in everolimus patients represents not just the inability of the PSI to inhibit the myofibroproliferative response, but can be also attributed to another mechanism of CAV evolution, namely intraplaque hemorrages. Today, we still need pathological evaluation of plaque morphology in patients with CAV. It will be a challenge for in vivo imaging techniques including IVUS to visualize plaque components like inflammation, angiogenesis and hemorrhages, to further unravel the pathophysiological mechanism of PSI in CAV development. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

1638 ARTERIAL EMBOLIZATION VERSUS MTOR MEDICAL THERAPY FOR TREATMENT OF RENAL ANGIOMYOLIPOMA

You have accessJournal of UrologyKidney Cancer: Localized (IV)1 Apr 20131638 ARTERIAL EMBOLIZATION VERSUS MTOR MEDICAL THERAPY FOR TREATMENT OF RENAL ANGIOMYOLIPOMA Rachel Edlin, Herman Bagga, Thomas Chi, Joe Miller, Jacqueline Villalta, Andrew Taylor, and Marshall Stoller Rachel EdlinRachel Edlin San Francisco, CA More articles by this author , Herman BaggaHerman Bagga San Francisco, CA More articles by this author , Thomas ChiThomas Chi San Francisco, CA More articles by this author , Joe MillerJoe Miller San Francisco, CA More articles by this author , Jacqueline VillaltaJacqueline Villalta San Francisco, CA More articles by this author , Andrew TaylorAndrew Taylor San Francisco, CA More articles by this author , and Marshall StollerMarshall Stoller San Francisco, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.3104AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Standard treatment for concerning renal angiomyolipomas (AML) is selective arterial embolization (SAE). Everolimus, which directly inhibits the mammalian target of rapamycin (mTOR) protein, is being investigated as an alternative systemic therapy for AML. We sought to compare these treatment options. METHODS Retrospective review of AML SAEs from 1999-2012 at our institution was undertaken. Demographics, response rates, and complications were evaluated. This data was compared to data from the EXIST-2 trial, a prospective, randomized-control study evaluating daily everolimus therapy for patients with AML lesions ≥ 3cm. RESULTS 35 AML patients underwent first-time SAE versus 79 who received everolimus therapy. SAE patients were older (47 versus 32 years), more commonly female (73% versus 56%), and fewer had tuberous sclerosis (27% versus 98%). 63% of everolimus patients had undergone previous AML treatment, either with SAE (24%) or surgical therapy (39%). Median pretreatment AML lesion volume treated with everolimus was 85 cm3 compared to 70 cm3 among SAE patients. Table 1 summarizes response rates of the two therapies. Both treatments were equally likely to result in any response to treatment, however, those patients treated with everolimus were more likely to experience a reduction of AML size of ≥ 30% (OR 7.8, CI 3.1-19.4, p < 0.05) or ≥ 50% (OR 9.4, CI 3-29.6, p <0.05). SAE complications were uncommon and generally minor, most often mild pain (11%). Most complications associated with everolimus treatment were also mild, and included stomatitis (78.5%), hypercholesteremia (20.3%), anemia (10%), vomiting (10%), and amenorrhea (15% of female patients). CONCLUSIONS AML lesions are equally likely to respond to SAE and everolimus treatment, however, everolimus is associated with a greater magnitude of response. Everolimus may be a promising alternative AML therapy for those patients that can tolerate the associated side effects. In particular, it may be a good choice for large, multifocal, and bilateral lesions for which SAE is difficult to administer effectively, or in patients where SAE has failed. Long-term data and head-to-head randomized control trials are necessary to better evaluate the long-term durability and efficacy of everolimus therapy in comparison to SAE. Change in Volume of Target AML Lesions After Treatment Everolimus (n=71, followup 24 weeks) Embolization (n=35, mean followup 149 weeks) P value Reduction from baseline, n (%) ≥ 50% 39 (54.9) 4 (11.4) < 0.05 ≥ 30% 57 (80.3) 12 (34.3) < 0.05 > 0% 68 (95.8) 31 (88.6) 0.18 Increase from baseline, n (%) > 0% 3 (4.2) 1 (2.9) 0.73 ≥ 10% 3 (4.2) 0 0.4 ≥ 25% 0 0 - No change from baseline, n (%) 0 3 (8.6) 0.07 © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e673-e674 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rachel Edlin San Francisco, CA More articles by this author Herman Bagga San Francisco, CA More articles by this author Thomas Chi San Francisco, CA More articles by this author Joe Miller San Francisco, CA More articles by this author Jacqueline Villalta San Francisco, CA More articles by this author Andrew Taylor San Francisco, CA More articles by this author Marshall Stoller San Francisco, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Relationship between biomarkers and everolimus efficacy in the phase III RECORD-1 trial of patients with metastatic renal cell carcinoma (mRCC).

352 Background: Compared with placebo, everolimus provided significant improvement in median PFS in the RECORD-1 study of VEGFr-TKI-refractory mRCC. To investigate the role of angiogenesis pathway molecules as potential biomarkers of everolimus efficacy in RECORD-1, plasma levels of sVEGFR-2, VEGF-A, and bFGF were estimated. Methods: In addition to best supportive care, patients received everolimus 10 mg/day (n = 277) or placebo (n = 139). Placebo patients who progressed were offered everolimus. Predose blood samples were collected on day 1 of the first four 28-day treatment cycles. Plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed by ELISA. Effect of treatment over time on each biomarker was assessed by a mixed effects model. Hazard ratios (HR) for prognostic effects were obtained using log baseline biomarker values as continuous variables in a stratified Cox proportional hazards model. Results: Plasma levels of sVEGFR-2, VEGF-A, and bFGF were available for 45%, 45%, and 39% of everolimus patients and 50%, 50%, and 45% of placebo patients. Patients with biomarker data had baseline characteristics similar to those of the overall population. Mean baseline levels (pg/mL) of sVEGFR-2, VEGF-A, and bFGF were similar for everolimus (8945, 245, and 8, respectively) and placebo (8985, 253, and 13, respectively). Everolimus significantly improved median PFS over placebo irrespective of baseline levels of the analyzed biomarkers (p &lt; 0.001), indicating they are not predictive of everolimus efficacy. Prolonged PFS in the biomarker population was associated with lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57; p = 0.028), suggesting VEGF-A may be prognostic for mRCC. Compared with placebo, everolimus significantly reduced bFGF (p = 0.0095) and sVEGFR-2 (p&lt; 0.001) levels over the time course of the study; no effect on VEGF-A levels was observed. Conclusions: Everolimus significantly improved PFS compared with placebo, regardless of baseline biomarker levels. Lower VEGF-A levels may be a potential prognostic factor for longer PFS. Everolimus treatment significantly downregulated plasma levels of bFGF and sVEGFR-2 from baseline. Clinical trial information: NCT00410124.

The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24months posttransplant. eGFR and graft loss was compared by proteinuria status at 3months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5mg/day), higher exposure EVR (3.0mg/day) and MPA-treated patients had proteinuria≥ 300mg/g Cr at 3months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p= 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels>8ng/mL were significantly associated with proteinuria compared to 3-8ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2years was not evident.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. 118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. Novartis Pharmaceuticals.

Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial

In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

842P - Biomarkers of Everolimus Efficacy in Patients with Metastatic Renal Cell Carcinoma (MRCC): Analysis of the Phase III Record-1 Trial

ABSTRACT Background In RECORD-1, everolimus significantly increased median PFS (primary end point) over placebo in VEGFr-TKI-refractory patients with mRCC. We investigated angiogenesis pathway molecules, sVEGFR-2, VEGF-A, and bFGF, in plasma as potential biomarkers of everolimus efficacy in RECORD-1. Material and methods Patients received everolimus 10 mg daily (n = 277) or placebo (n = 139), both with BSC; placebo patients could cross over to everolimus at disease progression. Pre-dose blood samples were collected on day 1 of the first four 28-day treatment cycles; plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed using ELISA. A mixed effects model was used to assess treatment effect over time on each biomarker. Hazard ratios (HR) for prognostic effects were obtained using log baseline biomarker values as continuous variables in a stratified Cox proportional hazards model. Results Plasma values for sVEGFR-2, VEGF-A, and bFGF were available for 45/45/39% of everolimus patients and 50/50/45% of placebo patients. Baseline characteristics of patients with biomarker data were similar to the overall population. Mean log baseline values for sVEGFR-2, VEGF-A, and bFGF were similar for both arms; 9.1/5.1/1.6 for everolimus and 9.1/5.2/1.8 for placebo, respectively. Median PFS was significantly improved with everolimus vs placebo, regardless of baseline levels of any of the biomarkers analyzed (P Conclusions Everolimus provided significant clinical benefit over placebo, regardless of baseline biomarker levels. However, lower VEGF-A level was seen as a potential prognostic factor for longer PFS. Plasma levels of bFGF and sVEGFR-2 were significantly down-regulated from baseline by everolimus treatment. Disclosure S. Oudard: Stephane Oudard received honoraria from Bayer, Novartis, Pfizer, Roche, and Sanofi-Aventis. B. Escudier: Bernard Escudier has received honorarium from Novartis, Pfizer, GSK, Aveo, and Bayer. J. Thompson: John Thompson received clinical study support from Novartis. V. Grunwald: Viktor Grunwald served as consultant to Roche, Bayer, Novartis, Pfizer, GlaxoSmithKline, and Aveo/Astellas, received honoraria from GlaxoSmithKline, Novartis, and Pfizer, and received research funding from Pfizer and GlaxoSmithKline. S. Bracarda: Sergio Bracarda has served as advisor for Pfizer, Bayer-Schering, GlaxoSmithKline, Novartis, Aveo/Astellas, Boheringer-Ingelheim, Johnson & Johnson, and Sanofi-Aventis and has received speaker fees from Pfizer, Novartis, and Sanofi-Aventis. A. Panneerselvam: Ashok Panneerselvam is an employee of Novartis Pharmaceuticals Corporation. S. Gogov: Sven Gogov is an employee of Novartis Pharma AG. D. Chen: David Chen is an employee of Novartis Pharmaceuticals Corporation. R.J. Motzer: Robert Motzer has received research funding from Novartis. All other authors have declared no conflicts of interest.

Conversion From Cyclosporine to Everolimus at 4.5 Months Posttransplant: 3-Year Results From the Randomized ZEUS Study

The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m(2) , 95%CI 4.3, 11.0 mL/min/1.73 m(2) ; p < 0.001) and month 36 (7.5 mL/min/1.73 m(2) , 95%CI 3.6, 11.4 mL/min/1.73 m(2) ; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

Updated safety results from EXIST-2: Everolimus therapy for angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM).

4632 Background: EXIST-2 (NCT00790400) is a randomized, double-blind, placebo-controlled, phase 3 trial assessing the efficacy and safety of everolimus, an oral mTOR inhibitor, for treating AML in patients with TSC or sLAM. We have previously reported that everolimus resulted in a significantly higher AML response rate vs placebo (41.8% vs 0%; 95% CI: 23.5–58.4; p&lt;0.0001) with a consistent safety profile (Bissler et al. J Am Soc Nephrol. 22, 2011, Abstract LB-PO3159). Here we present a 90-day safety update. Methods: 118 eligible patients were randomized 2:1 to receive everolimus 10 mg daily (n=79) or placebo (n=39). The primary efficacy endpoint was AML response rate (proportion of patients with best overall AML response status of “response”). Original cut-off date for data analysis was 30 Jun 2011. An updated analysis of the safety data for the safety set (all patients receiving ≥1 dose of double-blind study drug with a valid post-baseline assessment) to 14 Oct 2011 are presented here. Results: As of 14 Oct 2011, median treatment duration was 48.1 and 45.0 weeks for everolimus and placebo arms, respectively. Discontinuations in the double-blind period were the same in the everolimus arm as the initial analysis, but had increased by 4 patients in the placebo arm since initial analysis (3 due to disease progression, 1 withdrew consent). The majority of adverse events (AEs) continued to be grade 1 or 2; the incidence of serious AEs was slightly higher than initially reported, particularly in the placebo arm (everolimus 20.3%, placebo 23.1%). AE incidence leading to discontinuation was the same as initially reported (everolimus 3.8%, placebo 10.3%). In the updated data, 3 additional everolimus patients required dose interruption or reduction due to AEs; dose reduction/interruption remained more common in the everolimus arm (51.9% vs. 20.5%). Conclusions: Overall, the 90-day updated safety data analysis from the EXIST-2 trial has not revealed any additional safety concerns. No other patients receiving everolimus withdrew for any reason, whereas 3 more patients receiving placebo withdrew due to disease progression.

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: The significance of baseline glomerular filtration rate

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure. This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance. In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period. Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.