Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database

Background: The association between immune checkpoint inhibitors (ICIs) and Stevens-Johnsons syndrome (SJS) /toxic epidermal necrolysis (TEN) is unclear. We assessed the risk of SJS and TEN related to ICIs, via a systematic analysis of SJS/TEN cases reported in clinical trials and the FDA Adverse Event Reporting System (FAERS). Methods: We explored ICIs related SJS/TEN events in randomized control trials available in ClinicalTrials.gov and electronic databases (Pubmed, Embase, the Cochrane Central Register of Controlled Trials) up to 12 January 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% CIs. In a separate retrospective pharmacovigilance study of FAERs, cases of ICIs related SJS/TEN were extracted between the first quarter (Q1) of 2004 and Q4 of 2020. Disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). PROSPERO registration number: CRD42021232399. Findings: A total of 20 RCTs (11597 patients) were included. ICIs were associated with an increased risk of SJS/TEN (OR= 4.33, 95%CI:1.90–9.87). FAERS pharmacovigilance data identified 411 cases of SJS (n = 253) or TEN (n = 184) related to ICIs therapy. ICIs were significantly associated with SJS/TEN (n = 411; ROR=2.88, 95%CI:2.61–3.17; IC=1.49, 95%CI:1.35–1.65). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days) (n = 190), 97.5% of patients discontinued use of ICIs when suffering from SJS/TEN (n = 201). Of 305 cases that reported outcomes, 113 (37%) resulted in death (SJS:19.9%, TEN:61.6%). Interpretation: These data suggest that ICIs were significantly associated with increased risk of SJS/TEN.