Comparative efficacy and safety of Gla-300 versus IDegAsp in insulin-naïve people with type 2 diabetes mellitus uncontrolled on oral anti-diabetics.

AIM: To compare the efficacy and safety of insulin glargine-300 once daily (Gla-300) with insulin degludec/aspart (IDegAsp) once daily in patients with type 2 diabetes (T2D) inadequately controlled on oral anti-diabetic drugs (OADs). MATERIALS AND METHODS: A systematic literature review of randomized controlled trials was followed by an indirect treatment comparison of studies involving insulin naïve adults, inadequately controlled [glycated haemoglobin (HbA1c) ≥7.0%] on OADs, who received Gla-300 or IDegAsp once daily. Outcomes of interest were change in HbA1c, blood glucose, weight and insulin dose, as well as incidence and event rate of hypoglycaemia and other adverse events. RESULTS: Four trials with broadly similar baseline patient characteristics were included in the meta-analyses and indirect treatment comparison. At 24-28 weeks, the indirect comparison of Gla-300 to IDegAsp once daily estimated no statistically significant difference for change in HbA1c (%) from baseline [mean difference of 0.10% (95% CI: -0.20, 0.39; p = .52)]; a statistically significant mean difference of -1.31 kg (95% CI: -1.97, -0.65; p < .05) for change in body weight from baseline; statistically significant odds ratios of 0.62 (95% CI: 0.41, 0.93; p < .05) for incidence of any hypoglycaemia; and 0.47 (95% CI: 0.25, 0.87; p < .05) for incidence of anytime confirmed hypoglycaemia (plasma glucose <3.0-3.1 mmol/L). No significant differences were observed for insulin dose and adverse events. CONCLUSION: In insulin-naïve patients with T2D inadequately controlled on OADs, commencing Gla-300 shows a comparable HbA1c reduction, but with significantly less weight gain and a lower incidence of any and confirmed hypoglycaemia compared with commencing IDegAsp.

Cost-Effectiveness of Cemiplimab Versus Standard of Care in the United States for First-Line Treatment of Advanced Non-small Cell Lung Cancer With Programmed Death-Ligand 1 Expression ≥50.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness, from a US commercial payer perspective, of cemiplimab versus other first-line treatments for advanced non-small cell lung cancer with programmed death-ligand 1 expression ≥50%. METHODS: A 30-year "partitioned survival" model was constructed. Overall survival and progression-free survival were estimated by applying time-varying hazard ratios from a network meta-analysis of randomized clinical trials. Overall survival and progression-free survival were estimated from EMPOWER-Lung 1 (cemiplimab monotherapy vs chemotherapy) and KEYNOTE-024 and KEYNOTE-042 (pembrolizumab monotherapy vs chemotherapy). Drug acquisition costs were based on published 2020 US list prices. A 3% discount rate was applied to life-years, quality-adjusted life-years (QALYs), and costs. A deterministic analysis was performed on the base case; 1-way sensitivity and probabilistic sensitivity analyses assessed model and parameter uncertainties. RESULTS: Cemiplimab was associated with increased time in the "preprogression" (13.08 vs 7.90 and 6.08 months) and "postprogression" (47.30 vs 29.49 and 14.78 months) health states versus pembrolizumab and chemotherapy, respectively. Compared with pembrolizumab and chemotherapy, cemiplimab generated 1.00 (95% CI -0.266 to 2.440) and 1.78 (95% CI 0.607-3.20) incremental QALYs, respectively, with incremental cost-effectiveness ratios of $68 254 and $89 219 per QALY for cemiplimab versus pembrolizumab and cemiplimab versus chemotherapy, respectively. The probability of cemiplimab being cost-effective at a willingness-to-pay threshold of $100 000 to $150 000 per QALY was 62% to 76% versus pembrolizumab and 56% to 84% versus chemotherapy. CONCLUSIONS: Findings suggest that cemiplimab, versus pembrolizumab or versus chemotherapy, is a cost-effective first-line treatment option for advanced non-small cell lung cancer with programmed death-ligand 1 expression ≥50%.

Gastrointestinal adverse events with insulin glargine/lixisenatide fixed-ratio combination versus glucagon-like peptide-1 receptor agonists in people with type 2 diabetes mellitus: A network meta-analysis.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. MATERIALS AND METHODS: The PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web-based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). RESULTS: Treatment-specific NMA included 17 trials (n = 9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 µg twice daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 µg (0.35; 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. CONCLUSIONS: During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence.

Insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) compared with premix or addition of meal-time insulin to basal insulin in people with type 2 diabetes: A systematic review and Bayesian network meta-analysis.

AIM: To assess the efficacy and safety of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, relative to premix insulin and other insulin options through network meta-analysis. METHODS: A systematic literature search identified randomized controlled trials (RCTs) comparing iGlarLixi, premix insulin or basal insulin (BI) in combination with meal-time insulin, in people inadequately controlled with BI. Eligible RCTs were compared using Bayesian network meta-analysis. RESULTS: Eight RCTs, some open-label, involving 3538 participants, with a study duration of 24-30 weeks were included. The estimated difference in HbA1c reduction with iGlarLixi compared with premix insulin was -0.50%-units (95% credible interval: -0.93 to -0.06) with 98% probability of iGlarLixi being superior to premix. Estimates for iGlarLixi versus meal-time + BI (thrice-daily meal-time insulin + basal) and basal-plus (once-daily meal-time insulin + BI) were -0.35 (-0.89 to +0.13)%-units and -0.68 (-1.18 to -0.17)%-units with probabilities of real difference of 94% and 99%, respectively. Safety outcome analysis suggested that iGlarLixi had lower rates of both confirmed and documented symptomatic hypoglycaemia compared with premix insulin (probabilities of 85% and 93%, respectively) and lower weight gain (probability 98%). CONCLUSIONS: iGlarLixi showed similar or improved efficacy and safety versus other intensification choices from BI included in this study, providing a clinically relevant treatment option in people with type 2 diabetes not well controlled on BI.

Efficacy and safety of iGlarLixi versus IDegLira in adults with type 2 diabetes inadequately controlled by glucagon-like peptide-1 receptor agonists: a systematic literature review and indirect treatment comparison.

AIMS: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. MATERIALS AND METHODS: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. RESULTS: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was -0.36 (95% credible intervals -0.58, -0.14) % [-3.9 (-6.3, -1.5) mmol/mol] for HbA1c and -1.0 (-1.6, -0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial self-monitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). CONCLUSIONS: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches.

Matching-adjusted indirect comparison of isatuximab plus carfilzomib and dexamethasone with daratumumab plus lenalidomide and dexamethasone in relapsed multiple myeloma.

BACKGOUND: Lenalidomide-based regimens are commonly used for early relapse in patients with relapsed and/or refractory multiple myeloma (RRMM) receiving at least one prior line of therapy. In the absence of head-to-head comparison, matching-adjusted indirect comparison (MAIC) was conducted to demonstrate efficacy and safety of isatuximab+carfilzomib+dexamethasone (Isa-Kd) versus daratumumab + lenalidomide + dexamethasone (Dara-Rd) in RRMM. METHODS: Patient-level data from IKEMA trial (Isa-Kd, n = 179) were matched to aggregate data from POLLUX (Dara-Rd, n = 286). Hazard ratios (HR) and 95% confidence intervals (CI) for progression-free survival (PFS) and overall survival (OS) were generated by weighted Cox proportional hazard models. Odds ratios (OR), 95% CI, and p-value were calculated for ≥very good partial response (≥VGPR) and treatment-emergent adverse events (TEAEs). RESULTS: After matching, no significant differences were observed between Isa-Kd and Dara-Rd in baseline characteristics except for patients with >3 prior lines (0.0% vs. 4.9%). Isa-Kd showed significantly better PFS (HR [95% CI]: 0.46 [0.24-0.86]; p = 0.0155), statistically non-significant improvement favoring Isa-Kd in OS (0.47 [0.20-1.09]; 0.0798), and ≥VGPR (OR [95% CI]: 1.53 [0.89-2.64]; p = 0.1252) than Dara-Rd. Odds of occurrence were significantly lower for some all-grade and grade 3/4 TEAEs with Isa-Kd than Dara-Rd. CONCLUSION: These results support Isa-Kd as an efficacious treatment for early relapse in non-lenalidomide refractory patients.

Clinical Efficacy of Sarilumab Versus Upadacitinib Over 12 weeks: An Indirect Treatment Comparison.

INTRODUCTION: The efficacy of sarilumab and upadacitinib, in combination with disease-modifying antirheumatic drugs (DMARDs), was demonstrated in phase 3 clinical trials of patients with rheumatoid arthritis (RA) refractive to previous biologic DMARDs. In the absence of head-to-head clinical trials, the matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) estimate the relative efficacy of sarilumab and upadacitinib in patients with RA who had an inadequate response to previous biologic DMARDs. METHODS: Patient-level data for sarilumab were obtained from the TARGET trial (NCT01709578) and published aggregate data for upadacitinib were obtained from the SELECT-BEYOND trial (NCT02706847). For the MAIC, individual patient data from the TARGET trial were assigned weights such that weighted mean baseline characteristics of the treatment effect modifiers matched those from SELECT-BEYOND. For the STC, the TARGET patient-level data and mean baseline values from SELECT-BEYOND were used to simulate sarilumab treatment effects for a SELECT-BEYOND population. Endpoints evaluated included the American College of Rheumatology (ACR) response criteria ACR20/50/70, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP) < 3.2, DAS28-CRP < 2.6, Simple Disease Activity Index (SDAI) < 3.3, and Clinical Disease Activity Index (CDAI) < 2.8 at 12 weeks. RESULTS: The analysis included 365 patients from TARGET and aggregated data of 333 patients from SELECT-BEYOND. Matching for potential treatment effect baseline modifiers (i.e., age, oral glucocorticoid use, tender joint count of 68 counts, swollen joint count of 66 counts, serum CRP level, and patient global assessment of disease activity) resulted in a reduction of the effective sample size of TARGET population to 166. Following MAIC and STC analysis, the odds of achieving all aforementioned clinical outcomes versus placebo at week 12 were similar for sarilumab and upadacitinib. CONCLUSION: In the MAIC and STC analyses from TARGET and SELECT-BEYOND trials, the efficacy of sarilumab and upadacitinib were comparable.

Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.

BACKGROUND: The results of Randomized Controlled Trials (RCTs) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. These do not constitute the sufficient statistics required for meta-analysis or cost-effectiveness analysis, and their use in secondary analyses requires strong assumptions that may not have been adequately tested. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. METHODS: We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations, using where available information on number of events and numbers at risk. The reproducibility and accuracy of survival probabilities, median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics (survival probabilities, medians and hazard ratios) with statistics based on repeated reconstructions by multiple observers. RESULTS: The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics. Accuracy was excellent for survival probabilities and medians, for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported. CONCLUSION: The algorithm is a reliable tool for meta-analysis and cost-effectiveness analyses of RCTs reporting time-to-event data. It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves.

Network meta-analysis of immune-oncology monotherapy as first-line treatment for advanced non-small-cell lung cancer in patients with PD-L1 expression ⩾50.

Background: For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published in November 2010-2020. Methods: Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50-0.86), 1-12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04-2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54-1.10), 1-12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3-5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83-2.60)], immune-mediated AEs [1.75 (0.33-7.49)], and all-cause discontinuation due to AEs [1.21 (0.58-2.61)]. Conclusions: Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer.

Objectives: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. Methods: Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). Results: In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction-the most suitable method based on published guidelines and trial characteristics-produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. Conclusions: After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.

Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma.

BACKGROUND: Currently, five biologic treatment options are available for use in patients with uncontrolled persistent asthma: three interleukin (IL)-5 antagonists, which either bind to the anti-IL-5 ligand (mepolizumab, reslizumab) or to the IL-5 receptor (benralizumab); one anti-immunoglobulin E (anti-IgE) therapy (omalizumab); and one anti-IL-4/IL-13 therapy (dupilumab). To date, no comparative data from head-to-head clinical trials are available for these biologics. OBJECTIVE: An indirect treatment comparison (ITC) of dupilumab versus each of the anti-IL-5 and anti-IgE therapies using the endpoints of annualized severe asthma exacerbation rates and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1). METHODS: Embase®, MEDLINE®, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published between January 1, 1980 and March 25, 2019. Eligible articles included randomized controlled trials (RCTs) in patients aged ≥ 12 years with persistent/uncontrolled asthma using at least medium-to-high dose inhaled corticosteroid plus long-acting ß2-agonist with add-on biologic therapy. Bucher ITCs were performed to compare subgroups of dupilumab patients with the anti-IL-5s and anti-IgE trial populations. RESULTS: Fourteen RCTs were included in the analyses. The matched dupilumab subgroups were associated with greater reductions in annualized severe exacerbation rates compared with benralizumab, mepolizumab, reslizumab, and omalizumab (54%, 28%, 38%, and 26% greater reduction, respectively). A greater improvement in FEV1 was also observed for dupilumab at week 12 and/or week 24/52 than for the other biologics (0.06-0.14 L). CONCLUSION: In this ITC, dupilumab was associated with lower severe asthma exacerbation rates and greater improvements in lung function than anti-IL-5s and omalizumab.

Survival time outcomes in randomized, controlled trials and meta-analyses: the parallel universes of efficacy and cost-effectiveness.

OBJECTIVES: Many regulatory agencies require that manufacturers establish both efficacy and cost-effectiveness. The statistical analysis of the randomized, controlled trial (RCT) outcomes should be the same for both purposes. The question addressed by this article is the following: for survival outcomes, what is the relationship between the statistical analyses used to support inference and the statistical model used to support decision making based on cost-effectiveness analysis (CEA)? METHODS: We performed a review of CEAs alongside trials and CEAs based on a synthesis of RCT results, which were submitted to the National Institute for Health and Clinical Excellence (NICE) Technology Appraisal program and included survival outcomes. We recorded the summary statistics and the statistical models used in both efficacy and cost-effectiveness analyses as well as procedures for model diagnosis and selection. RESULTS: In no case was the statistical model for efficacy and CEA the same. For efficacy, relative risks or Cox regression was used. For CEA, the common practice was to fit a parametric model to the control arm, then to apply the hazard ratio from the efficacy analysis to predict the treatment arm. The proportional hazards assumption was seldom checked; the choice of model was seldom based on formal criteria, and uncertainty in model choice was seldom addressed and never propagated through the model. CONCLUSIONS: Both inference and decisions based on CEAs should be based on the same statistical model. This article shows that for survival outcomes, this is not the case. In the interests of transparency, trial protocols should specify a common procedure for model choice for both purposes. Further, the sufficient statistics and the life tables for each arm should be reported to improve transparency and to facilitate secondary analyses of results of RCTs.

Indirect Treatment Comparison of Biologics in Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: Among patients with chronic rhinosinusitis with nasal polyps (CRSwNP), randomized clinical trials (RCTs) of biologics, such as anti-interleukin-4/interleukin-13 (dupilumab) and anti-immunoglobulin E (omalizumab), have demonstrated efficacy compared with intranasal corticosteroids (INCS). However, no head-to-head RCTs exist between biologics. OBJECTIVE: To perform an indirect treatment comparison (ITC) of the efficacy of biologics plus INCS versus placebo (INCS) as a common comparator. METHODS: Embase, MEDLINE, and Cochrane were searched for RCTs of biologics in CRSwNP. Bucher ITCs were performed for outcomes at week 24: nasal polyp score (NPS) (range, 0-8), nasal congestion (NC) (range, 0-3), loss of smell (range, 0-3), University of Pennsylvania Smell Identification Test (range, 0-40), total symptom score (range, 0-12), 22-item sinonasal outcome test (range, 0-110), and responder analyses based on NPS or NC improvement of 1 point or greater. RESULTS: Assessment of trial design, baseline characteristics, and outcome measures suggested that ITC was feasible with four phase 3 RCTs: dupilumab SINUS-24 and SINUS-52 (NCT02912468/NCT02898454) and omalizumab POLYP 1 and POLYP 2 (NCT03280550/NCT03280537). In the intent-to-treat population, dupilumab had significantly greater improvements from baseline to week 24 versus omalizumab across key outcomes: NPS (least squares mean difference [95% confidence interval], -1.04 [-1.63 to -0.44]), NC (-0.35 [-0.60 to -0.11]), loss of smell (-0.66 [-0.90 to -0.42]), University of Pennsylvania Smell Identification Test (6.70 [4.67-8.73]), and total symptom score (-1.18 [-1.95 to -0.41]). Improvement in the 22-item sinonasal outcome test was greater in dupilumab versus omalizumab but was not statistically significant. Dupilumab patients were significantly more likely to achieve ≥1-point improvement in NPS (odds ratio [95% CI] = 3.58 [1.82-7.04]) and NC (2.13 [1.12-4.04]) versus omalizumab. CONCLUSIONS: Although ITCs have limitations, these results demonstrated that dupilumab had consistently greater improvements in key CRSwNP outcomes versus omalizumab at week 24.

Cost-effectiveness analysis of cemiplimab vs pembrolizumab for treatment of advanced cutaneous squamous cell carcinoma.

BACKGROUND: Most cutaneous squamous cell carcinomas (CSCCs) can be treated with surgical excision or radiation; however, approximately 1% of patients develop advanced disease. In 2018, the FDA approved cemiplimab-rwlc as the first programmed cell death-1 (PD-1) monoclonal antibody for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In June 2020, pembrolizumab, another PD-1 monoclonal antibody, was approved for the treatment of patients with recurrent or metastatic CSCC who are not candidates for curative surgery or radiation. We previously reported on the cost-effectiveness of cemiplimab vs historical standard of care for the treatment of advanced CSCC from a US perspective. OBJECTIVE: To estimate the cost-effectiveness of cemiplimab vs pembrolizumab for patients with advanced CSCC in the United States. METHODS: A "partitioned survival" framework was used to assess the cost-effectiveness of cemiplimab vs pembrolizumab. Clinical inputs were based on the most recent data cut of the phase 2 trials for cemiplimab (EMPOWER-CSCC-1; NCT02760498) and pembrolizumab (KEYNOTE-629). Progression-free survival and overall survival were extrapolated using parametric models until all patients had progressed or died. Health state utilities were derived from data collected in the EMPOWER-CSCC-1 trial. Costs included drug acquisition, drug administration, disease management, terminal care, and adverse events and were based on published 2020 US list prices. To assess model uncertainty, 1-way sensitivity and probabilistic sensitivity analyses (PSA) were conducted, alongside scenario analyses evaluating key modeling assumptions. RESULTS: In the base case, cemiplimab resulted in an incremental gain of 3.44 life-years (discounted) and incremental cost-effectiveness ratio (ICER) of $130,329 per quality-adjusted life-year (QALY) vs pembrolizumab. At a willingness-to-pay threshold of $150,000/QALY, PSA indicated a 71% probability that cemiplimab is cost-effective when compared with pembrolizumab. Scenario analysis resulted in ICERs ranging from $115,909 to $187,374. CONCLUSIONS: Findings suggest that cemiplimab is a cost-effective treatment for patients with advanced CSCC, compared with pembrolizumab. These results should be interpreted cautiously in the absence of head-to-head trials; however, in the absence of such data, these results can be used to inform health care decisions over resource allocation. DISCLOSURES: This study was supported by Regeneron Pharmaceuticals, Inc., and Sanofi. Paul, Cope, Keeping, Mojebi, and Ayers are employees of PRECISIONheor, which received funding to produce this work. Chen, Kuznik, and Xu are employees and stockholders of Regeneron Pharmaceuticals, Inc. Sasane is an employee and stockholder of Sanofi, Inc. Konidaris, Atsou, and Guyot are employees of Sanofi, Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Botulinum Toxins Type A (Bont-A) in the Management of Lower Limb Spasticity in Children: A Systematic Literature Review and Bayesian Network Meta-analysis.

BACKGROUND: Botulinum neurotoxins type A (BoNT-As) are used in pediatric lower limb spasticity, which affects more than 2.5 million children worldwide. Botulinum neurotoxins type-A improve active function and delay musculoskeletal complications. The objective of this analysis was to evaluate the efficacy and safety of abobotulinumtoxinA versus other botulinum neurotoxins type A in pediatric spasticity, in the absence of head-to-head evidence. METHODS: A systematic literature review was conducted to identify relevant randomized controlled trials. The evidence base was synthesized with Bayesian network meta-analyses. Outcomes analyzed included Modified Ashworth Scale, Tardieu Scale (TS) spasticity grade, and Goal Attainment Scale (standard mean difference only) at 12 weeks postinjection, and adverse events occurring during study periods. RESULTS: Thirty-eight studies were identified, 10 of which met inclusion criteria for quantitative synthesis. On Modified Ashworth Scale, abobotulinumtoxinA 15 U/kg/leg was significantly more efficacious than onabotulinumtoxinA 4 U/kg/leg (-0.99 [-1.34, -0.64]) and onabotulinumtoxinA 4 U/kg/leg+casting (-0.81 [-1.16, -0.46]) and numerically better than onabotulinumtoxinA 8 U/kg (-0.40 [-0.67, -0.14]). AbobotulinumtoxinA 10 U/kg/leg was significantly more efficacious than onabotulinumtoxinA 4 U/kg/leg (±casting). On Goal Attainment Scale, abobotulinumtoxinA 15 U/kg/leg and 10 U/kg/leg were significantly more efficacious than onabotulinumtoxinA 12 U/kg/leg. On Tardieu Scale spasticity grade, abobotulinumtoxinA was comparable to other treatments. AbobotulinumtoxinA demonstrated adverse event rates comparable to all doses of onabotulinumtoxinA. CONCLUSIONS: In pediatric lower limb spasticity, abobotulinumtoxinA offered significant or numerical efficacy advantages on tone (Modified Ashworth Scale) and functional outcomes (Goal Attainment Scale), and comparable efficacy on Tardieu Scale spasticity grade. AbobotulinumtoxinA was comparable to onabotulinumtoxinA on tolerability. Results should be interpreted in the context of heterogeneity and sparsity of the evidence base.

Number needed to treat in indirect treatment comparison.

AIM: For dichotomous outcomes, odds ratio (OR) is one of the usual summary measures of indirect treatment comparison. A corresponding number needed to treat (NNT) estimate may facilitate understanding of the treatment effect. METHODS: We show how to estimate NNT based on OR results of a matching adjusted indirect comparison. We also have derived the explicit formula of its 95% CIs by applying the delta method, and as an alternative, a simulation-based method. RESULTS: The method was applied in a case study example in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients, comparing lenvatinib to sorafenib. For every two RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have progressed and for every eight RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have died. CONCLUSION: Using NNT to summarize the results of a matching adjusted indirect comparison can help the clinicians to better understand the results in addition to OR.

Efficacy and safety of diclofenac in osteoarthritis: Results of a network meta-analysis of unpublished legacy studies.

BACKGROUND AND AIM: Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of non-steroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials. METHODS: We identified randomised controlled trials (RCTs) of diclofenac with planned study duration of at least 4 weeks for the treatment of osteoarthritis (OA) from 'legacy' studies conducted by Novartis but not published in a peer reviewed journal or included in any previous pooled analyses. All studies reporting efficacy and/or safety of treatment with diclofenac or other active therapies or placebo were included. We used a Bayesian NMA model, and estimated relative treatment effects between pairwise treatments. Main outcomes included pain relief measured using visual analogue scale at 2, 4 and 12 weeks and patient global assessment (PGA) at 4 and 12 weeks for efficacy, all-cause withdrawals, and adverse events. RESULTS: A total of 19 RCTs (5030 patients) were included; 18 of which were double-blind and one single-blind. All studies were conducted before cyclooxygenase 2 inhibitors (COXIBs) became commercially available. Data permitted robust efficacy comparison between diclofenac and ibuprofen, but the amount of data for other comparators was limited. Diclofenac 150mg/day was more efficacious than ibuprofen 1200mg/day and had likely favourable outcomes for pain relief compared to ibuprofen 2400mg/day. Diclofenac 100mg/day had likely favourable outcomes compared to ibuprofen 1200mg/day in alleviating pain. Based on PGA, diclofenac 150mg/day was more efficacious and likely to be favourable than ibuprofen 1200mg/day and 2400mg/day, respectively. Risk of withdrawal due to all causes with diclofenac and ibuprofen were comparable. Diclofenac 150mg/day was likely to have favourable efficacy and comparable tolerability with diclofenac 100mg/day. Results comparing diclofenac and ibuprofen were similar to those from NMAs of published trials. CONCLUSIONS: Results from these unpublished 'legacy' studies were similar to those from NMAs of published trials. The favourable efficacy results of diclofenac compared to ibuprofen expand the amount of available evidence comparing these two NSAIDs. The overall benefit-risk profile of diclofenac was comparable to that of ibuprofen in OA. IMPLICATIONS: The present NMA results reassures that the older unpublished blinded trials have similar results compared to more recently published trials and also contributes to increase the transparency of clinical trials performed with diclofenac further back in the past.

Extrapolation of Survival Curves from Cancer Trials Using External Information.

BACKGROUND: Estimates of life expectancy are a key input to cost-effectiveness analysis (CEA) models for cancer treatments. Due to the limited follow-up in Randomized Controlled Trials (RCTs), parametric models are frequently used to extrapolate survival outcomes beyond the RCT period. However, different parametric models that fit the RCT data equally well may generate highly divergent predictions of treatment-related gain in life expectancy. Here, we investigate the use of information external to the RCT data to inform model choice and estimation of life expectancy. METHODS: We used Bayesian multi-parameter evidence synthesis to combine the RCT data with external information on general population survival, conditional survival from cancer registry databases, and expert opinion. We illustrate with a 5-year follow-up RCT of cetuximab plus radiotherapy v. radiotherapy alone for head and neck cancer. RESULTS: Standard survival time distributions were insufficiently flexible to simultaneously fit both the RCT data and external data on general population survival. Using spline models, we were able to estimate a model that was consistent with the trial data and all external data. A model integrating all sources achieved an adequate fit and predicted a 4.7-month (95% CrL: 0.4; 9.1) gain in life expectancy due to cetuximab. CONCLUSIONS: Long-term extrapolation using parametric models based on RCT data alone is highly unreliable and these models are unlikely to be consistent with external data. External data can be integrated with RCT data using spline models to enable long-term extrapolation. Conditional survival data could be used for many cancers and general population survival may have a role in other conditions. The use of external data should be guided by knowledge of natural history and treatment mechanisms.