Efficacy and safety of immune checkpoint inhibitor rechallenge following immune-related adverse events: a review

Abstract Immune checkpoint inhibitors (ICIs), which target immune regulatory molecules such as cytotoxic T-lymphocyte–associated protein 4 and programmed death-ligand 1, are widely used as standard treatments for various cancer types. However, by overcoming T-cell suppression, they can also trigger immune-related adverse events (irAEs) that may necessitate treatment discontinuation. Rechallenging with an ICI after irAE resolution remains a clinical dilemma. This review evaluates current evidence on the efficacy and safety of ICI rechallenge. Systematic reviews and meta-analyses have demonstrated notable efficacy, with pooled objective response rates (ORR) ranging from 21.8% to 43.1% and disease control rates from 62.0% to 71.9%. Efficacy appears higher among patients who initially discontinued treatment due to an irAE than among those who stopped because of disease progression. For instance, a recent phase II study of nivolumab rechallenge in non–small cell lung cancer patients who relapsed after an initial response reported a modest ORR of 8.5%. Nonetheless, this potential benefit must be balanced against the risk of toxicity recurrence. The recurrence rate of the same irAE is ~32%, with risk varying by organ systems. Safety comparisons between initial treatment and rechallenge yield mixed results, with some studies reporting higher and others similar rates of severe events. Although major guidelines recommend permanent discontinuation for severe (Grade ≥ 3) irAEs, emerging evidence—including class-switching strategies and organ-specific prophylaxis—suggests that rechallenge may be feasible in selected patients. A personalized risk–benefit assessment remains essential, considering the type and severity of the initial irAE and the reason for discontinuation.