Cost-effectiveness analysis of a single-inhaler triple therapy for patients with advanced chronic obstructive pulmonary disease (COPD) using the FULFIL trial: A UK perspective

Objectives: The clinical benefit of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily budesonide/formoterol (BUD/FOR) for patients with symptomatic chronic obstructive pulmonary disease (COPD) was demonstrated in a clinical trial setting (FULFIL [NCT02345161]). The lifetime cost-effectiveness analysis of FF/UMEC/VI versus BUD/FOR, based on FULFIL data, is reported here. Methods: A previously developed and validated GALAXY-COPD linked-risk equation model was used to assess the cost-effectiveness of FF/UMEC/VI from the UK National Health Service (NHS) perspective. Baseline characteristics and efficacy results from FULFIL and UK NHS reference cost data (2017) were included as inputs. Exacerbation rates (undiscounted), costs, life years (LYs; undiscounted) and quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were calculated over a lifetime horizon. Costs and QALYs were discounted at 3.5% per year, beyond one year, in accordance with National Institute for Health and Care Excellence (NICE) guidelines. Deterministic and probabilistic sensitivity analyses were performed to evaluate the robustness of the results. Results: Predicted cumulative exacerbations per patient over a lifetime were 8.393 with FF/UMEC/VI and 10.456 with BUD/FOR. Patients receiving FF/UMEC/VI gained an additional 0.764 LYs and 0.492 QALYs, at an additional mean cost of £1,652, resulting in an ICER of £3,357 per QALY gained (95% confidence interval: £1,816, £5,194) compared with BUD/FOR. The ICER remained below £6,000 in all but one of the scenario and sensitivity analyses. Conclusions: Compared with BUD/FOR, treatment with FF/UMEC/VI was predicted to improve health outcomes at an additional cost that suggests it would be cost-effective for patients with COPD in the UK

A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer

Introduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel

Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review

Background Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes.Methods Embase®, Medline®, and EBM Reviews were searched via the OVID® platform on February 15, 2022. Conference proceedings, clinical trial registries, and global regulatory and reimbursement body websites were also searched. Eligible publications included clinical trials enrolling patients receiving cancer treatment with either PD-1, PD-L1, or CTLA-4 reporting outcomes including incidence or prevalence of ADAs and the impact of immunogenicity on treatment safety and efficacy. Reference lists of eligible publications were also searched. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and evidence quality assessment was conducted using the appropriate Joanna Briggs Institute Critical Appraisal tool.Results After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics.Conclusions Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes

Supplementary appendix: A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer

These are peer-reviewed supplementary materials for the article 'A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer' published in the Journal of Comparative Effectiveness Research.Additional Methodology: 3Figures: 5Tables: 7Inputs: 15Results: 19References: 31Introduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.</p

Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor-methotrexate combination therapy versus triple therapy in rheumatoid arthritis

Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi-methotrexate versus triple therapy in patients with RA. A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi-methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi-methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models. We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi-methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi-methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate. In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi-methotrexate, no clear differences were observed. The odds of infection were greater with TNFi-methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therap

Supplementary materials: A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer

These are peer-reviewed supplementary materials for the article 'A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer' published in the Journal of Comparative Effectiveness Research.Additional MethodologySurvival analysisProportional hazards assumptionPiecewise constant hazard ratios modelsFiguresFig. S1: Network of evidence for first-line to progression - progression-freeFig. S2: Network of evidence for first-line to progression - overall survivalFig. S3: Network of evidence for first-line to progression - progression-free survival and overall survival for the PD-L1 ≥50% subgroup survivalTablesTable S1a: Medline search terms used for SLRTable S1b: Embase search terms used for SLRTable S1c: Cochrane CENTRAL search terms used for SLRTable S2: PICOS StatementTable S3: Reasons for exclusion of studies from the first-line to progression NMA base case analysesTable S4: Reasons for exclusion of studies from the second-line NMA base case analysesData InputsTable S5: Input data for first-line to progression PFS – HRTable S6: Input data for first-line to progression OS – HRTable S7: Input data for second-line PFS – HRTable S8: Input data for second-line PFS – medianTable S9: Input data for second-line OS – HRTable S10: Input data for second-line OS – medianResultsTable S11: Model assessment statistics for the piecewise constant hazard ratio survival models on both OS and PFSTable S12: Pairwise hazard ratios for first-line to progression OS (using random effects model)Table S13: Pairwise hazard ratios for first-line to progression PFS (using random effects model)Table S14: Piecewise analysis: pairwise hazard ratios for first-line to progression - OS (using random effects model)Table S15: Piecewise analysis: pairwise hazard ratios for first-line to progression PFS (using random effects model)Table S16: Pairwise hazard ratios for first-line to progression OS (using fixed effects model) in the PD-L1 ≥50 subgroupTable S17: Pairwise hazard ratios for first-line to progression OS (using random effects model) in the PD-L1 ≥50 subgroupTable S18: Pairwise hazard ratios for first-line to progression PFS (using fixed effects model) in the PD-L1 ≥50 subgroupTable S19: Pairwise hazard ratios for first-line to progression PFS (using random effects model) in the PD-L1 ≥50 subgroupTable S20: Pairwise hazard ratios (and credible intervals) for second-line overall survival (using random effects model)Table S21: Pairwise hazard ratios (and credible intervals) for second-line progression-free survival (using random effects model)ReferencesIntroduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.</p