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Master of Public Health

Cox Proportional Hazard Ratios Overestimate Survival Benefit of Immune Checkpoint Inhibitors (ICI): Cox-TEL Adjustment and Meta-analyses of PD-L1 Expression and ICI Survival Benefit

AUTHORS

Pei-Ying Lin E , Hsu CY , Chiou JF , Berry L , Horn L , Bunn P , Chih-Hsin Yang J , Yang PC , Adjei AA , Shyr Y , . Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2022 8 29; ().

ABSTRACT

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

METHOD: PubMed-catalogued 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 (HR) for overall survival were transformed to Cox-TEL HR (ST-HR, for ICI short-term survivors) and difference in proportions (LT-DP, for patients with long-term survival). 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 non-small cell lung cancer, stratified by PD-L1 level (primary outcome) and ICI treatment line (secondary).

RESULTS: A total of nine publications representing eight clinical trials was selected for meta-analysis. Primary analysis yielded the following metrics for patients with PD-L1 expression <1%, >1%, and >50%, respectively: pooled Cox HR, 0.71 (95% 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). Secondary analysis showed LT-DP of ∼10% across treatment lines.

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

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