OBJECTIVES: Immune checkpoint inhibitors (ICIs) have emerged as effective treatment options for advanced melanoma. Little is known about the risk of immune-related adverse events (AEs) varies by ICI. We conducted a network meta-analysis comparing the risk of immune-related AEs between different therapies for advanced melanoma.

METHODS: We systematically searched for phase II and III randomized controlled trials (RCTs) of advanced melanoma from PubMed/MEDLINE, EMBASE, Web of Science, and Scopus (01/01/2010-06/30/2018). RCTs were included if they reported any immune-related AEs (e.g., hepatitis) comparing ICIs (i.e., ipilimumab, nivolumab, pembrolizumab) with chemotherapies (e.g., dacarbazine), different ICIs, or different doses of the same ICI. Bayesian network meta-analysis with Markov Chain Monte Carlo simulation was used to compare therapies simultaneously. We applied non-informative prior distribution, and random-effect generalized linear models. Based on the pooled odds ratios (ORs) and 95% credible intervals (95%CrI; Bayesian equivalent of confidence intervals), we estimated the probability for immune-related AEs for each treatment.

RESULTS:Ten RCTs were included (n=5,349 participants). Four RCTs compared ICIs to chemotherapy. Six RCTs compared different ICIs and/or different doses. Compared to chemotherapies, ICIs were not associated with any increased immune-related AE risk (ORs=0.41-3.20, P>0.05). Within ICIs, compared to ipilimumab 10 mg/kg, a decreased risk of immune-related AEs was observed for ipilimumab 0.3mg/kg (OR=0.13, 95%CrI=0.02-0.77) and nivolumab 3 mg/kg (OR=0.26, 95%CrI=0.09-0.78). Except comparing to ipilimumab 0.3mg/kg, pembrolizumab 2 mg/kg was associated with a decreased risk compared to other ICIs (ORs=0.19-0.72). No association was found for other ICI comparisons. The top three therapies with the lowest probabilities for immune-related AEs were ipilimumab 0.3mg/kg, pembrolizumab 2 mg/kg, and nivolumab 3 mg/kg.

CONCLUSIONS: The risk of immune-related AEs of ICIs was not different from chemotherapies. Among ICIs, ipilimumab 0.3mg/kg, pembrolizumab 2 mg/kg, and nivolumab 3 mg/kg may be preferred options for patients with advanced melanoma at high risk of immune-related AEs.