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Efficacy of Evolocumab vs low-density lipoprotein cholesterol apheresis in patients with familial hypercholesterolemia and high cardiovascular risk (EVOLAFER01).
Torres, E, Goicoechea, M, Hernández, A, Rodríguez Ferrero, ML, García, A, Macías, N, Anaya, F
Journal of clinical apheresis. 2020;(1):9-17
Abstract
UNLABELLED Low-density lipoprotein (LDL) apheresis has been considered the last option to treat refractory hyperlipidemia in patients with familiar hypercholesterolemia (FH). Evolocumab is a monoclonal antibody which has shown significant reduction of low-density lipoprotein cholesterol (LDL-C) serum levels and cardiovascular events. The aim of the study was to examine the comparative impact of LDL-apheresis vs Evolocumab vs the combination of both LDL-apheresis and Evolocumab on lipid and lipoprotein parameters, and other metabolic/inflammatory measures. DESIGN OF THE STUDY Non-randomized open case series study of 10 adult patients diagnosed with FH already on long-term LDL-apheresis therapy. The study was developed in three consecutive phases to compare LDL-apheresis, Evolocumab treatment and the combination of both. Laboratory parameters were collected pre and post LDL-apheresis and before Evolocumab administration. The primary endpoint was the reduction of LDL-C during the three phases. RESULTS Reduction of LDL-C levels with Evolocumab were 31.4% vs LDL-apheresis from 153 ± 35 mg/dL to 105 ± 56 mg/dL (P < .001). Reduction of Lp(a) was also significantly higher with Evolocumab (45.5%) than LDL-apheresis from 36 (6-119) to 20 (3-41) mg/dL, P = .027. In addition, HDL-C and apo-A increased after Evolocumab treatment, from 41 ± 6 to 46 ± 8 mg/dL (P = .003) and from 124 ± 13 to 144 ± 25 mg/dL (P = .001), respectively. No changes in immunological or inflammatory parameters were observed and no serious adverse events were recorded. CONCLUSION Evolocumab reduces LDL-C and Lp(a) more effectively than LDL-apheresis and combination of Evolocumab plus LDL-apheresis could be a therapeutic alternative to get lower LDL-C and Lp(a) levels in patients with very high cardiovascular risk.
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Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies.
Necchi, A, Raggi, D, Gallina, A, Madison, R, Colecchia, M, Lucianò, R, Montironi, R, Giannatempo, P, Farè, E, Pederzoli, F, et al
European urology. 2020;(4):439-446
Abstract
BACKGROUND Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. OBJECTIVE To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). DESIGN, SETTING, AND PARTICIPANTS In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH. INTERVENTION Neoadjuvant pembrolizumab and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response. RESULTS AND LIMITATIONS From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology. CONCLUSIONS The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes. PATIENT SUMMARY In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.
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Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial.
Giles, JT, Sattar, N, Gabriel, S, Ridker, PM, Gay, S, Warne, C, Musselman, D, Brockwell, L, Shittu, E, Klearman, M, et al
Arthritis & rheumatology (Hoboken, N.J.). 2020;(1):31-40
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OBJECTIVE To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. METHODS This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. RESULTS By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. CONCLUSION The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.
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Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Zhou, T, Zhang, Z, Luo, F, Zhao, Y, Hou, X, Liu, T, Wang, K, Zhao, H, Huang, Y, Zhang, L
JAMA network open. 2020;(10):e2015748
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IMPORTANCE Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is. OBJECTIVE To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019. STUDY SELECTION Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included. DATA EXTRACTION AND SYNTHESIS Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5. RESULTS A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97). CONCLUSIONS AND RELEVANCE The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
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Comparison of the Efficacy of Brolucizumab with Natural Disease Progression in Wet AMD Using Clinical Data from the Phase III HAWK and HARRIER Trials and Modelled Placebo Data.
Agostini, H, Mulyukov, Z, Tsilimbaris, M, Calvo, P, Bucher, F, Gaucher, D, Pigeolet, E, Colafrancesco, V, Clemens, A
Current eye research. 2020;(10):1298-1301
Abstract
Aim: To compare the treatment effect of brolucizumab, a novel anti-vascular endothelial growth factor therapeutic, with a putative placebo in patients with wet age-related macular degeneration. Materials and Methods: Clinical treatment-effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER studies were compared with modelled placebo data using a previously developed and validated indirect response, non-linear, mixed effects model describing the natural visual acuity decline in wet age-related macular degeneration. The placebo model incorporated patient-level data from the sham injection arms of the MARINA and PIER studies, corrected for baseline best corrected visual acuity and age difference between these studies and the HAWK and HARRIER studies. Results: Compared with a modelled placebo, brolucizumab treatment was associated with an overall best corrected visual acuity gain of approximately 22 Early Treatment Diabetic Retinopathy Study letters at Week 48 and 28 letters at Week 96. Conclusions: As anti-vascular endothelial growth factor therapy is now a standard of care for wet age-related macular degeneration, it is not feasible to conduct placebo-controlled trials for new wet age-related macular degeneration treatments. By allowing comparison with the natural decline in visual acuity without treatment, this analysis conveys the clinical importance of brolucizumab for the treatment of wet age-related macular degeneration.
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Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial.
Murphy, SA, Pedersen, TR, Gaciong, ZA, Ceska, R, Ezhov, MV, Connolly, DL, Jukema, JW, Toth, K, Tikkanen, MJ, Im, K, et al
JAMA cardiology. 2019;(7):613-619
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IMPORTANCE The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. OBJECTIVE To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. DESIGN, SETTING, AND PARTICIPANTS Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. MAIN OUTCOMES AND MEASURES The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. RESULTS The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001). CONCLUSIONS AND RELEVANCE The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01764633.
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Efficacy and safety profile of intravenous tocilizumab versus intravenous abatacept in treating female Saudi Arabian patients with active moderate-to-severe rheumatoid arthritis.
Elmedany, SH, Mohamed, AE, Galil, SMA
Clinical rheumatology. 2019;(8):2109-2117
Abstract
OBJECTIVES To compare the efficacy and safety of tocilizumab with those of abatacept in patients with active rheumatoid arthritis not responding to anti-tumor necrosis factor therapy. METHODS A prospective, open-label study was carried out on adult females with moderate-to-severe rheumatoid arthritis. Patients were randomly assigned to receive either intravenous tocilizumab or abatacept treatment. History taking, clinical examination, and laboratory evaluation were done at baseline and during a 24-week period of follow-up. Disease activity was calculated using the DAS28-ESR score. The incidence of accompanying adverse events was evaluated and all statistical analyses were performed by InStat. RESULTS One hundred thirty-two patients were enrolled and classified randomly into the tocilizumab (n = 68) and abatacept (n = 64) groups. By week 24, the mean DAS28-ESR was significantly reduced in both groups (P < 0.0001) in association with significant reductions in CRP, ESR, and HAQ scores. No significant difference in the incidence rate of adverse effects appeared between both study groups. However, there were marked declines in the hemoglobin levels (P = 0.003) and neutrophil count (P = 0.002) together with significant elevations in systolic blood pressure (P = 0.002), liver enzymes (P = 0.001), total cholesterol (P = 0.001), and high-density lipoproteins (P = 0.002) in the tocilizumab group compared with the abatacept group. CONCLUSION Both intravenous abatacept and tocilizumab significantly decreased the disease activity and improved the physical function in rheumatoid arthritis patients who failed to respond to anti-tumor necrosis factor therapy. Although the efficacy of both drugs was similar, abatacept showed a more promising short-term safety profile since it was associated with less adverse effects and better laboratory outcomes.
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Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3.
Egeberg, A, Wu, JJ, Korman, N, Solomon, JA, Goldblum, O, Zhao, F, Mallbris, L
Journal of the American Academy of Dermatology. 2018;(1):104-109.e8
Abstract
BACKGROUND The impact of ixekizumab treatment for psoriasis on cardiovascular-related parameters in patients is unknown. OBJECTIVE To investigate cardiovascular-related parameters in patients with psoriasis treated with ixekizumab. METHODS In phase 3 trials, patients with moderate-to-severe psoriasis were randomized and treated with placebo, ixekizumab, or etanercept during the induction period (weeks 0-12; UNCOVER-1, UNCOVER-2, and UNCOVER-3). At week 12, responders were rerandomized to receive placebo or ixekizumab through the maintenance period (weeks 12-60; UNCOVER-1 and UNCOVER-2). Laboratory measures (fasting lipid profiles, glucose level, or high-sensitivity C-reactive protein [hsCRP] level), weight, blood pressure, and electrocardiograms were obtained through 60 weeks. RESULTS Baseline parameters were within normal ranges with the exception of elevated triglyceride and hsCRP levels. After maintenance dosing, no significant changes were observed versus placebo for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, triglyceride, apolipoprotein A1, apolipoprotein B, or fasting glucose levels or for systolic/diastolic blood pressure at 60 weeks. Importantly, low-density lipoprotein-to-high-density lipoprotein ratios remained stable during the induction and maintenance periods. HsCRP concentrations were significantly reduced versus placebo at 12 weeks and remained reduced at 60 weeks, although not significantly. Although transient changes were observed for some parameters during the induction period, these changes did not persist into the maintenance period. LIMITATIONS A lack of echocardiogram evaluations. CONCLUSIONS Ixekizumab had a neutral impact on cardiovascular-related parameters in patients with psoriasis.
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FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
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Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.
Gabay, C, McInnes, IB, Kavanaugh, A, Tuckwell, K, Klearman, M, Pulley, J, Sattar, N
Annals of the rheumatic diseases. 2016;(10):1806-12
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OBJECTIVE Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab. METHODS Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8. RESULTS The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46 mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07 mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67 mmol/L (0.47 to 0.86)), triglycerides (0.24 mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8 weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were -3.2 and -1.1 mg/L (p=0.0077) for HDL-SAA and -4.1 and -1.3 ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was -7.12 mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria. CONCLUSION LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study. TRIAL REGISTRATION NUMBER NCT01119859.; post-results.