Safety Of Everolimus Research Articles

1326P - Evaluation of the efficacy and safety of everolimus as a first-line treatment in newly diagnosed patients with advanced gastroenteropancreatic neuroendocrine tumors

1326P - Evaluation of the efficacy and safety of everolimus as a first-line treatment in newly diagnosed patients with advanced gastroenteropancreatic neuroendocrine tumors

Everolimus plus endocrine vs endocrine therapy in treatment advanced ER+, HER2− breast cancer patients: A meta-analysis

The purpose of this review was to compare the efficacy and safety of everolimus plus endocrine therapy with endocrine therapy for hormone receptor-positive, human epidermal growth factor 2 negative advanced breast cancer patients. We comprehensively searched the PubMed, the Cochrane Library, EMBASE, Web of Science, Chinese biomedicine literature database, WanFang Data, CNKI, and VIP database for relevant articles. The retrieval time limit is from building the database to July 2018. The computer search was supplemented with a manual search of reference lists for all available review articles. We scanned references of all included studies for additional studies. We included 7 randomized trials involving 1527 patients. Meta-analysis results are as follows: Everolimus plus endocrine therapy group is significantly better than endocrine therapy group in progression-free survival and clinical benefit rate, (hazard ratio [HR] = 0.48, 95% confidence interval [CI 0.42-0.55], P < 0.00001) and (risk ratio = 1.9, 95% CI [1.60-2.26], P < 0.00001). But there was no significant difference between the 2 groups in overall response rate and time to definitive deterioration (risk ratio = 4.37, 95% CI [0.79-24.27], P = 0.21) and (HR = 0.74, 95% CI [0.49-1.11], P = 0.15). In terms of safety, the incidence rate in everolimus plus endocrine therapy was higher than that in endocrine therapy group. Most frequently reported adverse events associated with everolimus treatment were stomatitis, rash, fatigue, diarrhea, decreased appetite, cough, dyspnea, and pneumonitis. The incidences of grade 3-4 adverse events were stomatitis, fatigue, diarrhea, pneumonitis, and hyperglycemia. Everolimus increased the efficacy of endocrine therapy in treatment advanced endocrine receptor-positive, human epidermal growth factor 2 negative breast cancer patients, and the safety profile of the combination is acceptable.

Efficacy and Safety of Everolimus with Reduced-Dose Calcineurin Inhibitor in De Novo Kidney Transplant Recipients

Efficacy and Safety of Everolimus with Reduced-Dose Calcineurin Inhibitor in De Novo Kidney Transplant Recipients

The Athena Study

Athena Study Group. Background The ATHENA study was set up to compare efficacy and safety of everolimus [EVR] combined with tacrolimus [TAC] or cyclosporine A [CyA] vs. a mycophenolic acid [MPA] with TAC standard regimen in de novo kidney transplant [KTx] recipients. Methods In this 12 months [M] prospective, open-label, multi-center study 612 patients [pts] were randomized 1:1:1 at time of Tx to either EVR (target trough: 3-8ng/ml M1-M12) + TAC (target trough: 4-8ng/ml M1-M3; and 3-5ng/ml M3-M12), or EVR (3-8ng/ml M1-M12) + CyA (target trough: 75-125ng/ml M1-M3; and 50-100ng/ml M3-M12) or TAC (target trough: 4-8ng/ml M1-M3; and 3-5ng/ml M3-M12) + MPA, all with steroids. Here we report M12 efficacy and safety data from 208 EVR+TAC, 199 EVR+CyA and 205 TAC+MPA treated pts. Results Treated BPAR events occurred in 6.7% of EVR+TAC pts vs 17.6% of EVR+CyA and 3.9% of TAC+MPA pts. Most of these events were graded mild, classified as BANFF IA: 1.9% vs 9% vs 1.5%, respectively; only few BANFF IIB/III occurred with 1.5% vs 2% vs 0.5% per group, respectively. Only few patients died during study period: 5 pts in EVR+TAC, 5 in EVR+CyA and 6 in TAC+MPA group. Incidence of graft loss was overall small: 4.8% (10 pts) in EVR+TAC vs 6.5% (13pts) in EVR+CyA and 2.9% (6pts) in TAC+MPA group - including 5 primary non-functioning grafts in each EVR-group and 1 in TAC+MPA group. Safety profiles of the three regimen were comparable: the incidence of AEs or infections leading to study drug discontinuation or dose adjustment/interruption were 56.7% in EVR+TAC, 55.5% in EVR+CyA vs 61.3% in TAC+MPA arm. These discontinuations or pausing [d/p] of study drug application were driven mainly by infections (as reasons for d/p: 15.2%EVR+TAC, 10.1%EVR+CyA, 31.3%TAC+MPA) and leukopenia (as reasons for d/p: 1.9%EVR+TAC, 3.0%EVR+CyA vs.10.8%TAC+MPA; p<0.01). Total incidence of leukopenia under treatment was 8.6% in EVR+TAC, 6.6% in EVR+CyA vs 19.1% for TAC+MPA (p<0.01). There were no differences on wound healing seen from incidences of AEs on wound complications, such as wound dehiscence, wound complications or impaired healing, with summed up incidences as follows: 41.9% EVR+TAC, 38.9% EVR+CyA, 43.2% TAC+MPA. No difference in proteinuria was seen, incidence of nephrotic proteinuria was 1.3% in EVR+TAC vs 0.7% in EVR+CyA and 3.7% in TAC+MPA treated patients. Conclusion ATHENA as to date largest prospective randomized European KTx study confirmed good efficacy and event rates within international standards for all 3 groups. There were no unexpected safety events for the patient population studied herein. Of note, there were no differences in reported AEs on wound healing, no differences in proteinuria but less leukopenia and fewer infections with EVR-based regimens.

Efficacy and safety of everolimus plus low-dose calcineurin inhibitor vs. mycophenolate mofetil plus standard-dose calcineurin inhibitor in renal transplant recipients: A systematic review and meta-analysis .

To seek an optimized immunotherapy which can preserve renal function while maintaining low acute rejection rates, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of everolimus (EVR) plus low-dose calcineurin inhibitor (CNI) vs. mycophenolate mofetil (MMF) plus standard-dose CNI regimen after kidney transplantation (KT). We searched for RCTs comparing the outcomes of EVR plus low-dose CNI and MMF plus standard-dose CNI regimen after KT and identified eligible RCTs according to strict inclusion and exclusion criteria. Two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Eleven RCTs with 850 renal transplant recipients were included. This meta-analysis showed that EVR plus low-dose CNI regimen was associated with comparable renal function (standardized mean difference (SMD) 0.16, 95% CI (-0.03, 0.35), p=0.09) and a similar rate of acute rejection (risk ratio (RR) 1.16, 95% CI (0.96, 1.42), p=0.13), graft loss (RR 0.89, 95% CI (0.63, 1.24), p=0.49) and mortality (RR 1.19, 95% CI (0.69, 2.08), p=0.53) compared to MMF plus standard-dose CNI regimen. In addition, EVR plus low-dose CNI regimen could reduce the rate of cytomegalovirus and infection, whereas a lower rate of other adverse events were noted in MMF plus standard-dose CNI regimen. EVR plus low-dose CNI regimen was similar in efficacy and safety to MMF plus standard-dose CNI regimen after KT. However, this should be confirmed by further studies. .

PCN10 - Efficacy and Safety of Everolimus in the Treatment of Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

PCN10 - Efficacy and Safety of Everolimus in the Treatment of Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

A national, multicenter, non-interventional, observational study on treatment patterns in patients with metastatic renal cell carcinoma in Turkey - NOTES study.

IntroductionThe introduction of targeted therapies in renal cell carcinoma has significantly improved its prognosis and treatment outcomes in recent years. Such treatment options are targeted therapies of the vascular endothelial growth factor (VEGF) pathway and the mammalian target of the rapamycin pathway. With the use of tyrosine kinase inhibitors (TKIs) and mammalian target of the rapamycin inhibitors, overall survival has increased up to 2 years. In Turkey, due to applicable reimbursement conditions for patients with metastatic renal cell carcinoma (mRCC), interferon use is mandated as a first-line treatment, thus providing information on the use of everolimus only after initial interferon and second-line VEGF-targeted treatments such as VEGF-TKI.Patients and methodsTo provide a first real-life data set in Turkey, we conducted a prospective, non-interventional, observational study and assessed the efficacy and safety of everolimus after two lines of treatment including interferon. A total of 100 patients with histologically confirmed mRCC were enrolled in the study from 11 centers between June 2012 and March 2014 (70 males and 30 females). Efficacy was assessed on the basis of progression-free survival and overall survival; safety of everolimus was assessed on the basis of adverse event occurrence.ResultsThe study results showed that the median progression-free survival with everolimus treatment was 8.1 months (95% CI: 5.1–11.1) and the median overall survival was 17.6 months (95% CI: 10.1–25.1), thus indicating a better overall response based on survival durations than those from the randomized Phase III REnal Cell cancer treatment with Oral RAD001 given Daily study results (4.9 and 14.8 months, respectively).ConclusionThe study showed that everolimus treatment is a safe and effective treatment option in the treatment of mRCC after VEGF-TKI, with an acceptable safety and tolerability profile in real-life settings.

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

Malignancy is one of the leading causes of death in recipients with a kidney grafts. The use of proliferative signal inhibitors (PSI) is one of the approaches to solve this problem.Aim: to evaluate the effi cacy and safety of everolimus in combination with reduced dose of calcineurin inhibitors (CNI) in patients with posttransplant malignancy.Materials and methods.62 kidney graft recipients (KGR) with neoplasia were converted from mycophenolate mofetil to everolimus in combination with reduced dose of CNI at 83.5 ± 69.3 months after transplantation. The duration follow-up was 35.5 ± 26.9 month. The effectiveness of management was assessed by patient survival, type of immunosuppression therapy, renal function and proteinuria. The patient survival in PSI group was compared with the survival in the patients in control group (n = 145), who did not receive everolimus.Results.10-year and 15-year patient survival was 92% and 85,7% in patients treated with PSi versus 61.1% and 52.8% in control group (p &lt; 0.0003). Patients survival with everolimus-therapy after 1 year was 86.5%, after 3 year it was 64.2%, and by the end of 5 years the possibility of treatment with everolimus decreased to 50.8%, mainly due to the proteinuria and other adverse events. The recurrence rate of tumors among patients, who was treated with everolimus for 35 (26; 60) months was 13.2%. Creatinine level in serum increased from 0.13 ± 0.04 to 0.15 ± 0.09 mmol during the treatment (p &lt; 0.031), and the daily proteinuria increased from 0.18 ± 0.25 g/day to 0.75 ± 1.63 g/day, p &lt; 0.011.Conclusion.The usage of PSi improves long-term survival of KTR with posttransplant malignancy and demonstrates a relatively low tumors recurrence rate (13.2%) over a period of 35 months. However this treatment is not suitable for many patients and it was stopped in almost half of them due to increasing proteinuria or serious adverse events.

Efficacy and Safety of Everolimus plus Somatostatin Analogues in Patients with Neuroendocrine Tumors.

Everolimus, an oral mammalian target of rapamycin(mTOR) inhibitor, which acts upstream of the phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signaling pathway to downregulate cellular metabolism, growth, proliferation, and angiogenesis, has been shown to significantly prolong the progression-free survival of patients with advanced neuroendocrine tumors. Somatostatin analogues (SSAs) such as octreotide, lanreotide, and pasireotide, have been widely used for symptom control and antiproliferative effects in metastatic or unresectable neuroendocrine tumors. Both everolimus and SSAs have demonstrated antitumor effects in randomized controlled trials (RCTs) involving selected patients with neuroendocrine tumors, but the efficacy and safety of their combined use require further investigation. In this systematic review, we summarize the published studies that have investigated the use of everolimus and SSAs to provide a comprehensive understanding of their combined effects and better guidance for the treatment of neuroendocrine tumors.

Efficacy and safety of everolimus in hormone receptor positive breast cancer in a developing country: Real-life single institutional experience.

Breast cancer is the second leading cause of cancer-related mortality despite the staggering improvement in cancer therapeutics. So far, published data illustrate endocrine therapy as the cornerstone treatment for patients with hormone receptor-positive metastatic breast cancer. Unfortunately, most patients eventually develop resistance to this treatment. The purpose of this study is to evaluate the efficacy of mammalian target of rapamycin inhibition in reversing hormone resistance in the Lebanese breast cancer patients. Efficacy of the intervention according to the independent factors and notable side effects encountered were the primary points of the evaluation. In total, fifty patients received the combination of everolimus and exemestane. The mean age of the study population was 61 ± 11 years. Sensitivity to hormonal therapy before the start of the combination treatment was estimated at 64%. Response rate was 14%, and all patients were partial responders. After regular interval evaluation, the median progression-free survival was 5.2 months since the initiation of therapy. The main toxicities associated with the combination were stomatitis (22%), myalgia (22%), skin toxicity (8%), and hyperglycemia (4%), all Grades 1 and 2. Everolimus has been shown to be effective in overcoming hormonal resistance in Lebanese breast cancer patients with results inferior to those reported in the BOLERO-2 population. The particular differences in molecular and pathological aspects of breast cancer in our region should stimulate the extensive research for a better understanding of the particular pattern of the disease.

Assessment of the Role of Everolimus Therapy in Patients with Renal Cell Carcinoma Based on Daily Routine and Recent Research Results

Everolimus is indicated for adults with metastatic renal cell carcinoma (mRCC) after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (TKI). Currently, the therapeutic applicability of EVE has been changing. Multicenter evaluation of efficacy and safety of everolimus in daily routine and definition of patient characteristics with favorable outcome. Data of 165 patients from 9 oncology institutes in Hungary were analyzed retrospectively. Everolimus therapy was used after one TKI in 10mg starting dose. Physical and laboratory examinations and imaging tests were performed monthly and every 3months, respectively. Median progression-free survival (PFS) was 5.4months. Median overall survival (OS) was 16.2months. PFS and OS results were more favorable in patients with ECOG 0-1 (pPFS=0.033, pOS=0.008) and after >9months of TKI therapy (pPFS=0.019, pOS=0.045). Survival was longer in nonanemic patients with ECOG 0-1 than in anemic patients with ECOG 2-3, 30.9 and 7.7months, respectively (p=0.029). Dose reduction and treatment delay was required in 6.2% and 8.9% of patients, respectively. Common adverse events were exanthema, edema, stomatitis, anemia, and abnormal kidney functions and glucose levels. Results of this study show that everolimus is safe and efficacious in a real-world setting. Everyday practice showed that nonanemic patients with good performance status receiving TKI therapy for >9months are favorable candidates for this treatment. Despite the efficiency of novel, registered drugs, everolimus still plays an important role during and after second-line therapy for mRCC when availability of modern remedies is limited.

Efficacy and safety of everolimus and exemestane for metastatic breast cancer patients: a real-life experience of three Oncology Departments

Efficacy and safety of everolimus and exemestane for metastatic breast cancer patients: a real-life experience of three Oncology Departments

Clinical outcomes of everolimus in patients with advanced, nonfunctioning pancreatic neuroendocrine tumors: a multicenter study in Korea.

Everolimus is a standard treatment option for advanced pancreatic neuroendocrine tumors (pNETs). This multicenter study evaluated the efficacy and safety of everolimus in low and intermediate grade advanced pNETs. Tumors were graded according to the World Health Organization 2010 classification system. Patients with low or intermediate grade pNETs who received everolimus as first- or second-line chemotherapy between 2002 and 2014 were included. A total of 40 patients with metastatic or recurrent pNETs were included in this study. The median age was 54.5years (range 19-83years). Twelve patients (30%) experienced recurrence. There were 11 patients (27.5%) with low grade pNETs and 29 (72.5%) with intermediate. Everolimus was administered as first-line therapy in 30 patients (75%) and as second-line therapy in 10 patients (25%). The median progression-free survival (PFS) of patients with low and intermediate grade pNETs was significantly different (median not reached vs. 11months, P=0.015). On multivariate analysis, tumor grade (intermediate grade; HR 6.52, 95% CI 1.31-32.27, P=0.022) was the only independent prognostic factor for PFS in pNETs. The most common adverse events were stomatitis, skin rash, and anemia. World Health Organization 2010 grade is the most important determinant for PFS in patients undergoing everolimus treatment for pNETs with an acceptable incidence of adverse events.

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial

Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. EudraCT number 2010-022273-34, NCT01317615.

Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2−) advanced breast cancer patients: New insights beyond clinical trials. The EVA study

BackgroundThe BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. Patients and methodsThis study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. ResultsFrom July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33–83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1–7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4–58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). ConclusionsThe EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

P-198 - Clinical outcomes of everolimus in patients with advanced pancreatic neuroendocrine tumor: A multicenter study in Korea

Introduction: Everolimus is a standard treatment option for advanced pancreatic neuroendocrine tumor. This multicenter study evaluated the efficacy and safety of everolimus in low grade- and intermediate grade advanced pancreatic neuroendocrine tumors (pNETs). Methods: Tumors were graded according to the World Health Organization 2010 classification system. Patients who received everolimus as first line or second line chemotherapy with low grade- and intermediate grade pNETs were included between 2002 and 2014. Results: A total of 40 patients with pNETs were included in this study. The median age was 54.5 years (range; 19-83 years). Twelve patients (30%) underwent recurrence. There were 11 patients (27.5%) with low grade pNETs and 29 (72.5%) with intermediate. Everolimus was administered in 30 patients (75%) as first-line and 10 patients (25%) as second. The median progression free survival (PFS) with low and intermediate grade pNETs was significantly different (median not reached vs. 11 months, P = 0.015). In multivariate analysis, tumor grade (intermediate grade; Hazard ratio = 5.46, 95% CI 1.32-22.51, P = 0.026) was the only independent prognostic factor for PFS in pNETs. The most common adverse events were stomatitis, skin rash and anemia. Conclusion: In the everolimus treatment for pNETs, WHO 2010 grade acts as an important determinant for PFS. However, the incidence of adverse events was acceptable.

Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1

BackgroundThe current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial.MethodsPostmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR–) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety.ResultsIn the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61–1.11)). In the HR– subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29–0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm.ConclusionsThe efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population.Trial registrationClinicalTrials.gov, NCT00876395. Registered on 2 April 2009.

Efficacy and safety of everolimus in Chinese metastatic HR positive, HER2 negative breast cancer patients: a real-world retrospective study.

BackgroundEverolimus combined with endocrine therapy has been proved to be effective among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). We aimed to evaluate the efficacy and safety of everolimus plus endocrine therapy in Chinese real-world practice for the first time, and investigate factors associated with efficacy.MethodsSeventy-five HR+/HER2- MBC patients were included in this retrospective study who received everolimus plus endocrine therapy after progression on prior endocrine therapy in Fudan University Shanghai Cancer Center (FUSCC) between June 2013 and February 2016. Main outcome measures are progression free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety profile.ResultsAfter a median follow up of 10.3 (range: 2.1-32.2) months, median PFS was 5.9 months (95%CI 4.6-7.2), and median OS was not reached. The CBR was 38.8% (95%CI, 26.8-50.8) and ORR was 9.0% (95%CI, 2.0-16.0). Most common all-grade adverse events were stomatitis (57.1%), fatigue (25.7%), infection (24.3%) and hyperglycemia (21.4%). The most common ≥3 grade adverse events were stomatitis (9.3 %) and thrombocytopenia (5.7%). No treatment-related death was documented during and one month after the drug administration.ConclusionsThe combination of everolimus and endocrine therapy proved to be effective in Chinese population. The safety profiles were similar to previous studies but incidences were lower. In conclusion, everolimus combined with endocrine therapy provides a reasonable option for Chinese HR+/HER2- metastatic breast cancer patients.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n=93) or to tacrolimus-based therapy (n=95), both with basiliximab induction and enteric-coated mycophenolate sodiumwith or withoutsteroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1vs. -13.3mL/min per 1.73m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p<0.001). Mean eGFR at week 24 was 95.8versus 76.0mL/min per 1.73m2 for everolimus versus tacrolimus (p<0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p=0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p=0.026); the rate of treated BPAR was 8.9% versus 2.2% (p=0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

The SUNPAZ study: Results of an open label, single arm trial to evaluate patients with mRCC treated with everolimus after failure of first line therapy with sunitinib or pazopanib.

473 Background: The VEGFR-TKIs Sunitinib and Pazopanib are the currently recommended 1st line agents for the treatment of renal cell carcinoma (RCC). Everolimus is a well-established treatment option after failure of a prior VEGFR-TKI. However, few prospective clinical data exist on the efficacy and safety of Everolimus after failure of a single line of VEGFR-TKI therapy and no clinical data exists on the efficacy and safety of Everolimus following Pazopanib treatment. Methods: This phase IV clinical trial investigated Everolimus 10 mg daily in patients who have progressed on or after 1st line treatment with Sunitinib or Pazopanib. Adult patients with advanced clear cell RCC and an ECOG 0-1 were included. The primary endpoint was the rate of patients progression-free after 6 months of treatment. Results: 16 and 13 patients who received prior Sunitinib and Pazopanib, respectively, have been enrolled at 13 German sites. The median age was 65 years in the Sunitinib (SUN) group and 74 years in the Pazopanib (PAZ) group. After 6 months of Everolimus treatment, 11/12 (92%) patients in the SUN group showed disease progression, whereas 6/13 (46%) patients in the PAZ group remained progression-free (FAS population). The median OS was 14.8 months in the SUN group (95% CI 9.4 – not reached (NR)) and 20.4 months in the PAZ group (95% CI 11.7 – NR). The most common adverse events (AE) regardless of any relation to study drug included anemia (31.1% (SUN group) vs. 53.8% (PAZ group)), nausea (25.0 vs. 46.2%), stomatitis (12.5 vs. 61.5%), peripheral edema (12.5 vs. 53.8%), and dyspnea (12.5 vs. 46.2%). Conclusions: Patients in the PAZ group showed a lower rate of tumor progression within 6 months and a longer PFS as compared to the SUN group. The results confirm Everolimus as an effective 2nd line treatment option with a favorable safety profile, especially following Pazopanib, and the sequence Pazopanib - Everolimus as effective treatment option for mRCC patients. However, due to the small number of patients enrolled in the study, results have to be interpreted with caution. The types of observed AE are consistent with the well-known toxicity profile of Everolimus. Clinical trial information: NCT01514448.