Immortal Time Bias in the Association Between Toxicity and Response for Immune Checkpoint Inhibitors: A Meta-Analysis

Only a minority of studies addressing the association between immune-related adverse events (IrAE) and outcome considered the immortal time bias, with conflicting results. PubMed, Embase, Web of Science and Scopus were searched through 2 January 2020. Studies reporting the impact of IrAE on outcome in patients treated with antiprogrammed death receptor 1 or PD-L1 were included. Twenty nine articles were included. IrAEs were associated with improved outcomes with high heterogeneity. With a landmark approach, the association between IrAE and outcome remains significant but the effect size was smaller (hazard ratio 0.61 vs 0.41 for overall survival; p = 0.015; hazard ratio 0.66 vs 0.47 for progression-free survival, p = 0.029; odds ratio 2.59 vs 6.77 for overall response rate; p < 0.001), no significant heterogeneity. Our analysis suggests a confounding effect of immortal time bias and a real effect of IrAE on outcome.