Cox Proportional Hazard Ratios Overestimate Survival Benefit of Immune Checkpoint Inhibitors: Cox-TEL Adjustment and Meta-Analyses of Programmed Death-Ligand 1 Expression and Immune Checkpoint Inhibitor Survival Benefit

Abstract

Introduction: Survival benefit of immune checkpoint inhibitor (ICI) therapy in lung cancer is not fully understood.

Methods: PubMed-cataloged publications through February 14, 2022, were queried for randomized controlled trials of ICI in lung cancer, and identified publications were reviewed for inclusion. Reported Cox hazard ratios (HRs) for overall survival were transformed to Cox-TEL HR for ICI short-term survivors (ST-HR) and difference in proportions for patients with long-term survival (LT-DP). Meta-analyses were performed using a frequentist random-effect model. Outcomes of interest were pooled overall survival Cox HR, ST-HR, and LT-DP in NSCLC, stratified by programmed death-ligand 1 (PD-L1) level (primary outcome) and ICI treatment line (secondary).

Results: A total of nine publications representing eight clinical trials were selected for meta-analysis. Primary analysis yielded the following metrics for patients with PD-L1 expression less than 1%, more than or equal to 1%, and more than or equal to 50%, respectively: pooled Cox HR, 0.71 (95% confidence interval [CI]: 0.62-0.82), 0.74 (95% CI: 0.68-0.82), and 0.62 (95% CI: 0.54-0.70); pooled ST-HR, 0.91 (95% CI: 0.79-1.05), 0.88 (95% CI: 0.82-0.94), and 0.70 (95% CI: 0.60-0.83); and pooled LT-DP, 0.10 (95% CI: 0.00-0.20), 0.09 (95% CI: 0.06-0.12), and 0.11 (95% CI: 0.05-0.17). Results of secondary analysis revealed LT-DP of approximately 10% across treatment lines.

Conclusions: This study reveals an approximately 10% long-term survival probability increment in ICI long-term survivors across PD-L1-positive subpopulations in both ICI treatment lines. Furthermore, ST-HR was consistently poorer than Cox HR. For patients with PD-L1 less than 1%, neither LT-DP nor ST-HR achieved statistical significance. The analysis provides greater insight into the treatment effect of ICI in published trials.

Keywords: Cox HR; Cox-TEL; Immune checkpoint inhibitor; Long-term survival; PD-L1.