PCN275 Network Meta-Analysis Design Considerations in a Complex and Rapidly Evolving Landscape: A Case Study in First-LINE (1L) Advanced NON-SMALL Cell LUNG Cancer (ANSCLC)

Abstract

In 1L aNSCLC, the therapeutic landscape is complex and rapidly evolving. While the introduction of different immunotherapy-based treatments reflects advances in treatment efficacy and a shift toward more personalized medicine, it poses challenges in generating unbiased relative effect estimates via network meta-analysis (NMA). Our objective was to illustrate NMA design considerations in the 1L aNSCLC setting. A comprehensive set of NMA checklists was used for presenting NMA design choices in 1L aNSCLC. Using a systematically identified evidence base of 125 randomized controlled trials (RCTs), the following were identified as key design features: 1) proportional hazards assumption violations and differing lengths of follow-up; 2) effect modification, 3) lumping vs. splitting treatment nodes, and 4) study design heterogeneity including differences in blinding, chemotherapy arms, cross-over, and use of subsequent therapies. Methodological approaches to address the identified features were presented. Proportional hazards violations and differing lengths of follow-up were evident in RCTs comparing immunotherapies against chemotherapies. Several approaches were considered, including: constant hazard ratios for trials of similar follow-up; fractional polynomial/parametric NMAs; piecewise hazard ratios; restricted mean survival time; and survival at pre-defined times. Programmed death-ligand 1 expression level and histology were key effect modifying factors for some but not all comparisons in the network. Meta-regression was considered but was infeasible; instead, stratified networks were constructed. The choice to lump/split treatment nodes was endpoint-specific, with some chemotherapy combinations showing similar efficacy yet different safety profiles. Nine RCTs involved investigator’s choice control arms, adding complexity to defining treatment nodes. The cross-over design and use of subsequent therapy evolved over time and was evaluated alongside design heterogeneity using a study-by-study assessment of the potential impact on treatment effect size. We identified and presented approaches for handling multiple NMA design issues in 1L aNSCLC. These issues can be extrapolated and applied to other therapeutic settings.