A systematic review of randomized clinical trials (RCTs) in patients with advanced melanoma showed that the risk for immune-related adverse events (irAEs) varies based on immune checkpoint inhibitor (ICI) type and dose (JAMA Netw Open. 2020;3[3]:e201611).

“Since 2011, [ICIs] have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs,” explained Ching-Yuan Chang, MS, Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, and colleagues, who sought to compare the risk for irAEs in patients with advanced melanoma receiving different treatment regimens.

Dr Chang et al conducted a network meta-analysis of all RCT articles published on PubMed/MEDLINE, Embase, Web of Science, and Scopus databases between January 1, 2010, and June 30, 2019.

Studies were included in the analysis if they were phases 2 and 3 RCTs comparing the use of ICIs (ie, ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens for the treatment of advanced melanoma.

The main end points of the study were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5).

The investigators used pooled odds ratios (ORs) and 95% credible intervals (95% CrI) to estimate the probability of each treatment regimen being tied to the lowest irAE risks. They also utilized bayesian network meta-analysis with Markov chain Monte Carlo simulation and random-effects generalized linear models to compare the different therapy regimens.

Ultimately, 9 RCTs (n = 5051) with 8 different therapy regimens for advanced melanoma were included in the analysis. The 3 ICI regimens tied to the lowest risk for any or severe irAEs were pembrolizumab 2 mg/kg administered every 3 weeks, nivolumab 3 mg/kg administered every 2 weeks, and pembrolizumab 10 mg/kg administered every 3 weeks.

“Compared with ipilimumab, 10 mg/kg, every 3 weeks, only nivolumab, 3 mg/kg, every 2 weeks, was associated with a decreased risk for any irAEs (OR, 0.34; 95% CrI, 0.13-0.94),” Dr Chang and co-investigators reported.

Furthermore, ipilimumab 3 mg/kg every 3 weeks (OR, 0.35; 95% CrI, 0.14-0.74); pembrolizumab 10 mg/kg every 2 weeks (OR, 0.22; 95% CrI, 0.05-0.95) and 10 mg/kg every 3 weeks (OR, 0.20; 95% CrI, 0.06-0.68), and nivolumab 3 mg/kg every 2 weeks (OR, 0.20; 95% CrI, 0.07-0.48) were associated with a decreased risk for severe irAEs versus ipilimumab 10 mg/kg every 3 weeks.

Nivolumab 1 mg/kg given every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks was tied to an increased risk for severe irAEs compared with other ICI regimens (ORs ranging from 4.09; 95% CrI, 1.73-10.99 to 7.40; 95% CrI, 1.12-49.29) aside from ipilimumab 10 mg/kg every 3 weeks.

“These findings suggest that for patients with advanced melanoma at high risk of irAEs, pembrolizumab, 2 mg/kg, every 3 weeks, nivolumab, 3 mg/kg, every 2 weeks, and pembrolizumab, 10 mg/kg, every 3 weeks may be the preferred treatment regimens (with respect to irAE risks) among the ICI regimens reported,” Dr Chang and colleagues concluded.

“[I]pilimumab, 10 mg/kg, every 3 weeks alone and nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks should be used with caution,” they added.—Hina Porcelli