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In patients with coronary artery disease, treated with durable polymer-coated drug-eluting stents, the life-long presence of the polymer might delay arterial healing. Novel very thin strut biodegradable polymer stents, which leave only a bare metal stent after polymer resorption, might improve long-term outcome. We investigated in allcomers the safety and efficacy of three stents eluting either everolimus, sirolimus, or zotarolimus, often clinically used but never compared, of which the biodegradable polymer everolimus-eluting stent was never before assessed in allcomers. The large-scale, investigator-initiated, multicentre, assessor and patient blinded, three-arm, randomised, BIO-RESORT non-inferiority trial was done at four clinical sites in the Netherlands. All-comer patients were aged 18 years or older, capable of providing informed consent, and required a percutaneous coronary intervention with drug-eluting stent implantation according to clinical guidelines or the operators' judgment. Exclusion criteria were: participation in another randomised drug or device study before reaching the primary endpoint of that study; planned surgery necessitating interruption of dual antiplatelet therapy within the first 6 months; known intolerance to components of the investigational product or medication required; uncertainty about the adherence to follow-up procedures or an assumed life expectancy of less than 1 year; or known pregnancy. Web-based computer-generated allocation sequences randomly assigned patients (1:1:1) to treatment with very thin strut biodegradable polymer everolimus-eluting or sirolimus-eluting stents (which differ substantially in type, amount, distribution, and resorption speed of their respective coating), or thin strut durable polymer zotarolimus-eluting stents. The primary endpoint was a composite of safety (cardiac death or target vessel-related myocardial infarction) and efficacy (target vessel revascularisation) at 12 months of follow up with a very thin strut biodegradable polymer of either everolimus-eluting or sirolimus-eluting stents, compared with durable polymer zotarolimus-eluting stents, analysed by intention to treat (non-inferiority margin 3·5%). This trial was registered with ClinicalTrials.gov, number NCT01674803. From Dec 21, 2012, to Aug 24, 2015, 3514 patients were enrolled and analysed, of whom 2449 (70%) had acute coronary syndromes, which included 1073 (31%) ST-elevation myocardial infarctions. 12 month follow-up of 3490 (99%) patients (three lost to follow-up; 21 withdrawals) was available. The primary endpoint was met by 55 (5%) of 1172 patients assigned to everolimus-eluting stents, 55 (5%) of 1169 assigned to sirolimus-eluting stents and 63 (5%) of 1173 assigned to zotarolimus-eluting stents. Non-inferiority of the everolimus-eluting stents and sirolimus-eluting stents compared with zotarolimus-eluting stents was confirmed (both −0·7% absolute risk difference, 95% CI −2·4 to 1·1; upper limit of one sided 95% CI 0·8%, pnon-inferiority<0·0001). Definite stent thrombosis (defined by the Academic Research Consortium) occurred in four (0·3%) of 1172 patients who were allocated to everolimus-eluting stents, four (0·3%) of 1169 patients who were allocated to sirolimus-eluting stents, and three (0·3%) of 1173 patients who were allocated to zotarolimus-eluting stents (log-rank p=0·70 for both comparisons with zotarolimus-eluting stents). At 12 month follow-up, both very thin strut drug-eluting stents with dissimilar biodegradable polymer coatings (eluting either everolimus or sirolimus) were non-inferior to the durable polymer stent (eluting zotarolimus) in treating allcomers with a high proportion of patients with acute coronary syndromes. The absence of a loss of 1 year safety and efficacy with the use of these two biodegradable polymer-coated stents is a prerequisite before assessing their potential longer-term benefits. Biotronik, Boston Scientific, and Medtronic.

In a randomized trial involving patients with advanced previously treated renal-cell carcinoma, nivolumab produced higher response rates than everolimus (25% vs. 5%) and median overall survival was longer (by 5.4 months), to more than 2 years. Each year, an estimated 338,000 new cases of renal-cell carcinoma are diagnosed worldwide, 1 and approximately 30% of patients present with metastatic disease at the time of diagnosis. 2 A number of targeted therapies have been approved for the treatment of advanced or metastatic renal-cell carcinoma. These agents include vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) inhibitors. 3 , 4 Everolimus is an mTOR inhibitor that is recommended for the treatment of advanced renal-cell carcinoma after treatment with sorafenib or sunitinib has failed. 3 – 6 Although everolimus and other agents have changed the therapeutic landscape for this disease, these . . .

Resistance to hormone therapy through activation of cellular pathways involving mTOR can develop in postmenopausal hormone-receptor–positive breast cancer. Adding an mTOR inhibitor to an aromatase inhibitor improved outcomes in patients who had disease progression during hormone therapy. Endocrine therapy is the cornerstone of treatment for patients with hormone-receptor (HR)–positive advanced breast cancer. In postmenopausal patients, aromatase inhibitors (e.g., letrozole and anastrozole) have become the treatment of choice in first-line therapy. 1 – 5 Unfortunately, not all patients have a response to first-line endocrine therapy (primary or de novo resistance), and even patients who have a response will eventually relapse (acquired resistance). On disease progression, second-line treatment options include other classes of aromatase inhibitors (steroidal or nonsteroidal) and the estrogen-receptor (ER) antagonists fulvestrant and tamoxifen. 6 , 7 The study of resistance to endocrine therapies in HR-positive breast cancer has aimed at . . .

In a randomized trial involving patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes.

In a phase 3 clinical trial involving previously treated patients with advanced renal-cell carcinoma, progression-free survival was significantly longer with the VEGF receptor inhibitor cabozantinib than with everolimus (7.4 months vs. 3.8 months). Renal-cell carcinoma is the most common form of kidney cancer, with more than 330,000 cases diagnosed and more than 140,000 deaths attributed to it worldwide every year. 1 Approximately one third of patients present with metastatic disease at diagnosis, 2 and in about one third of treated patients with localized disease, the disease will relapse. 3 – 5 Inactivation of the von Hippel–Lindau (VHL) tumor-suppressor protein characterizes clear-cell tumors, the predominant histologic subtype in patients with renal-cell carcinoma, and results in the up-regulation of vascular endothelial growth factor (VEGF) production. 6 , 7 Antiangiogenic drugs that target VEGF (bevacizumab) and its receptors (sunitinib, sorafenib, pazopanib, and . . .

In this 2-year, double-blind trial, patients with ADPKD were randomly assigned to receive either placebo or the mTOR inhibitor everolimus, since the mTOR pathway is important in cyst growth. Although everolimus slowed the increase in kidney volume, as assessed by means of magnetic resonance imaging, it did not slow the progression of renal impairment. Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1 of every 1000 persons in the general population 1 and develops, by means of slowly progressive renal-cyst growth, to end-stage renal disease in over 50% of patients. Hepatic and pancreatic cysts, as well as cerebral and abdominal aneurysms, contribute to ADPKD-associated morbidity and mortality. Arterial hypertension, recurrent urinary tract infection, nephrolithiasis, and abdominal pain are frequently the presenting symptoms. 2 Approximately 85% of patients with ADPKD have mutations in the polycystic kidney disease 1 gene ( PKD1 ), whereas most of the remaining 15% have polycystic kidney disease 2 gene ( PKD2 ) . . .

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32–0·58]; median progression-free survival 14·6 months [95% CI 10·4–not estimable] vs 6·2 months [4·2–7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit–risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. Janssen Research & Development, LLC.

Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy. In the ZEUS multicentre, open-label study, 503 patients (aged 18–65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6–10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310. 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m2vs 61·9 mL/min per 1·73 m2, respectively; mean difference 9·8 mL/min per 1·73 m2, 95% CI −12·2 to −7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p=0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin. Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients. Novartis Pharma.

This trial showed that in patients with lymphangioleiomyomatosis (LAM), a progressive, cystic lung disease in women, sirolimus therapy was associated with stabilization of lung function, reduction in symptoms, and improvement in qualityof-life measures. Lymphangioleiomyomatosis (LAM) is an uncommon systemic disease that is associated with cystic destruction of the lung, chylous pleural effusions, and abdominal tumors such as renal angiomyolipomas. 1 , 2 LAM affects women almost exclusively and occurs sporadically, developing in about 5 persons per 1 million; it also affects 30 to 40% of women with tuberous sclerosis complex (TSC). Lung function, measured as the forced expiratory volume in 1 second (FEV 1 ), declines at the rate of 75 to 118 ml per year 3 – 5 ; clinically important respiratory impairment, recurrent pneumothoraxes, and hypoxemia develop in most patients within a decade after the . . .

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms—eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0–65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m2 per day (titrated to achieve blood trough concentrations of 5–15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response—ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15–52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. Novartis Pharmaceuticals.