Bayesian hierarchical model-based network meta-analysis to overcome survival extrapolation challenges caused by data immaturity

Aim: This research evaluated standard Weibull mixture cure (WMC) network meta-analysis (NMA) with Bayesian hierarchical (BH)WMCNMAto inform long-term survival of therapies. Materials & methods: Four trials in previously treated metastatic non-small-cell lung cancer with PD-L1 >1% were used comparing docetaxel with nivolumab, pembrolizumab and atezolizumab. Cure parameters related to a certain treatment class were assumed to share a common distribution. Results: Standard WMC NMA predicted cure rates were 0.03 (0.01; 0.07), 0.18 (0.12; 0.24), 0.07 (0.02; 0.15) and 0.03 (0.00; 0.09) for docetaxel, nivolumab, pembrolizumab and atezolizumab, respectively,with corresponding incremental life years (LY) of 3.11 (1.65; 4.66), 1.06 (0.41; 2.37) and 0.42 (-0.57; 1.68). The Bayesian hierarchical-WMC-NMA rates were 0.06 (0.03; 0.10), 0.17 (0.11; 0.23), 0.12 (0.05; 0.20) and 0.12 (0.03; 0.23), respectively, with incremental LY of 2.35 (1.04; 3.93), 1.67 (0.68; 2.96) and 1.36 (-0.05; 3.64). Conclusion: BH-WMC-NMA impacts incremental mean LYs and cost–effectiveness ratios, potentially affecting reimbursement decisions

Assessing the prognostic utility of hematologic response for overall survival in patients with newly diagnosed AL amyloidosis: results of a meta-analysis

ABSTRACTObjectives: Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and death. Recent studies suggest that hematologic response may be an important prognostic indicator of overall survival (OS) in AL amyloidosis. The aim of this study was to evaluate the trial-level association between hematologic complete response (CR) or very good partial response or better (≥ VGPR) and OS in newly diagnosed patients.Methods: Studies were identified via systematic literature review. Pooled effect estimates were generated by a random-effects model.Results: Nine observational studies reporting hematologic CR or ≥VGPR and OS hazard ratios (HRs) were included in the meta-analysis. Achieving hematologic CR was associated with improved OS (HR, 0.21; 95% confidence interval [CI] 0.13–0.34). Achieving ≥ VGPR was also associated with improved OS (HR 0.21; 95% CI 0.17–0.26). Results of a sensitivity analysis excluding one outlier study revealed no heterogeneity and a better overall HR estimate. Potential limitations of this meta-analysis include the small number of eligible studies (consistent with the rarity of the disease) and inconsistencies in reporting of results.Conclusions: Overall, our findings support the use of deep hematologic response (CR or ≥VGPR) as a clinical trial endpoint in newly diagnosed AL amyloidosis. This study provides evidence that early hematologic response is a strong patient-level surrogate for long-term OS in patients with AL amyloidosis receiving frontline therapy. Structured data collection of depth of response in future trials will further strengthen these observations

Novel and existing flexible survival methods for network meta-analyses

Aim: Technical Support Document 21 discusses trial-based, flexible relative survival models. The authors generalized flexible relative survival models to the network meta-analysis (NMA) setting while accounting for different treatment-effect specifications. Methods: The authors compared the standard parametric model with mixture, mixture cure and nonmixture cure, piecewise, splines and fractional polynomial models. The optimal treatment-effect parametrization was defined in two steps. First, all models were run with treatment effects on all parameters and subsequently the optimal model was defined by removing uncertain treatment effects, for which the parameter was smaller than its standard deviation. The authors used a network in previously treated advanced non-small-cell lung cancer. Results: Flexible model-based NMAs impact fit and incremental mean survival and they increase corresponding uncertainty. Treatment-effect specification impacts incremental survival, reduces uncertainty and improves the fit statistic. Conclusion: Extrapolation techniques already available for individual trials can now be used for NMAs to ensure that the most plausible extrapolations are being used for health technology assessment submissions

Supplementary materials: Bayesian hierarchical model-based network meta-analysis to overcome survival extrapolation challenges caused by data immaturity

These are peer-reviewed supplementary materials for the article 'Bayesian hierarchical model-based network meta-analysis to overcome survival extrapolation challenges caused by data immaturity' published in the Journal of Comparative Effectiveness Research.Figure S1: Network of evidenceFigure S2: Observed survival by reference trial vs predicted survival with standard Weibull mixture-cure model network meta-analysisFigure S3: Observed survival by reference trial vs predicted survival with BH WCM NMA with τ' = σ’ = 0.01Table S1: Overview of parameters, confidence intervals, effective sample size and Rhat by approach testedFigure S4: Density plots with the numbers corresponding to the parameter numbers in supplementary Table S1Figure S5: Autocorrelation plots on the cure parametersAim: This research evaluated standard Weibull mixture cure (WMC) network meta-analysis (NMA) with Bayesian hierarchical (BH)WMCNMAto inform long-term survival of therapies. Materials & methods: Four trials in previously treated metastatic non-small-cell lung cancer with PD-L1 >1% were used comparing docetaxel with nivolumab, pembrolizumab and atezolizumab. Cure parameters related to a certain treatment class were assumed to share a common distribution. Results: Standard WMC NMA predicted cure rates were 0.03 (0.01; 0.07), 0.18 (0.12; 0.24), 0.07 (0.02; 0.15) and 0.03 (0.00; 0.09) for docetaxel, nivolumab, pembrolizumab and atezolizumab, respectively,with corresponding incremental life years (LY) of 3.11 (1.65; 4.66), 1.06 (0.41; 2.37) and 0.42 (-0.57; 1.68). The Bayesian hierarchical-WMC-NMA rates were 0.06 (0.03; 0.10), 0.17 (0.11; 0.23), 0.12 (0.05; 0.20) and 0.12 (0.03; 0.23), respectively, with incremental LY of 2.35 (1.04; 3.93), 1.67 (0.68; 2.96) and 1.36 (-0.05; 3.64). Conclusion: BH-WMC-NMA impacts incremental mean LYs and cost–effectiveness ratios, potentially affecting reimbursement decisions.</p

Supplementary materials: Novel and existing flexible survival methods for network meta-analyses

These are peer-reviewed supplementary materials for the article 'Novel and existing flexible survival methods for network meta-analyses' published in the Journal of Comparative Effectiveness Research.Supplementary dataFigure 1: Overall survival hazard plots in evidence network for the pooled Checkmate 017-057 trials comparing nivolumab with docetaxelFigure 2: Network of evidenceFigure 3: Log cumulative hazard plots and Schoenfeld plotsFigure 4: Predicted survival best fitting reduced models and corresponding 95% credible interval on therapy with longest predicted survivalTable 1: Overview of the percentiles related to placements of knots and the corresponding uncensored survival times in the considered NMA datasetAim: Technical Support Document 21 discusses trial-based, flexible relative survival models. The authors generalized flexible relative survival models to the network meta-analysis (NMA) setting while accounting for different treatment-effect specifications. Methods: The authors compared the standard parametric model with mixture, mixture cure and nonmixture cure, piecewise, splines and fractional polynomial models. The optimal treatment-effect parametrization was defined in two steps. First, all models were run with treatment effects on all parameters and subsequently the optimal model was defined by removing uncertain treatment effects, for which the parameter was smaller than its standard deviation. The authors used a network in previously treated advanced non-small-cell lung cancer. Results: Flexible model based NMAs impact fit and incremental mean survival and they increase corresponding uncertainty. Treatment-effect specification impacts incremental survival, reduces uncertainty and improves the fit statistic. Conclusion: Extrapolation techniques already available for individual trials can now be used for NMAs to ensure that the most plausible extrapolations are being used for health technology assessment submissions.</p

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1

Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1

Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r