OBJECTIVES : 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.

METHODS : 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.

RESULTS : 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.

CONCLUSIONS : 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.