Cutaneous immune-related adverse events and survival during immune checkpoint inhibitor therapy: a pilot meta-analysis stratified by handling of immortal-time bias.
DOI:
https://doi.org/10.51168/z1c5w423Keywords:
Immune checkpoint inhibitors, cutaneous immune-related adverse events, immortal time bias, overall survival, meta-analysisAbstract
Importance:
Cutaneous immune-related adverse events (cirAEs) are read as a sign that checkpoint blockade is working, but a cirAE is recorded only in patients who survive long enough to develop it, so analyses that fix cirAE status at baseline credit the exposed group with immortal time.
Objective:
To describe the association of cirAEs with overall survival (OS) and progression-free survival (PFS) in estimates that handle immortal time, and to compare these with estimates that do not.
Methods:
Studies came from author-held reports and web searches seeded with known studies (17–18 October 2026); no bibliographic database was searched. Cohort studies reporting a hazard ratio (HR) for any cirAE versus none were included. Each estimate was classified as handling immortal time (Tier A: time-dependent Cox or landmark), partially (Tier B), or not (Tier C/D). Tier A estimates were read individually; random-effects pooling and between-tier meta-regression were exploratory. Certainty was rated with GRADE.
Results:
Thirteen studies were included. OS, immortal time handled: three cohorts (4,123 patients) gave HRs of 0.21 (95% CI 0.05–0.62), 0.52 (0.35–0.78) and 0.87 (0.79–0.98); pooled 0.57 (0.13–2.56; I² = 81%). OS, not handled: five cohorts pooled to 0.55 (0.43–0.70; I² = 1%). PFS, handled: 0.63 (0.21–1.87); not handled: 0.50 (0.12–2.06). The ratios of HRs between tiers (OS 1.29, 0.67–2.49; PFS 1.22, 0.40–3.71) were not significant, so these data neither show nor exclude inflation of uncorrected estimates. Certainty was very low for every outcome.
Conclusions and relevance:
Every cohort that handled immortal time found an OS HR below 1, but the size of the association is uncertain, and the gap from uncorrected studies may reflect tumour mix and adjustment.
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Copyright (c) 2026 Dr. Harkiratjit Singh Bhullar, Dr. Pardeep Garg, Dr. Sumir kumar, Dr. Rajkumar Bhardwaj
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