Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients With Advanced Melanoma: A Systematic Review and Network Meta-analysis.

Abstract

Importance Since 2011, immune checkpoint inhibitors (ICIs) have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs.

Objective To compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis. Data sources PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched for all randomized clinical trial (RCT) articles published from January 1, 2010, through June 30, 2019. Study selection Studies included phases 2 and 3 RCTs in the treatment of advanced melanoma that compared ICIs (ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens. Data extraction and synthesis Different treatment regimens were compared using bayesian network meta-analysis with Markov chain Monte Carlo simulation with noninformative prior distribution and random-effects generalized linear models. Main outcomes and measures Primary outcomes were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5). Based on the pooled odds ratios (ORs) and 95% credible intervals (95% CrI), the probability of being associated with the lowest irAE risks was estimated for each treatment regimen.

Results Nine RCTs with 8 different treatment regimens for advanced melanoma and involving a total of 5051 patients were included. Overall, the 3 ICI treatment regimens associated with the lowest risk of any or severe irAEs were pembrolizumab, 2 mg/kg, every 3 weeks; nivolumab, 3 mg/kg, every 2 weeks; and pembrolizumab, 10 mg/kg, 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). A decreased risk for severe irAEs was observed for 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) compared with ipilimumab, 10 mg/kg, every 3 weeks. An increased risk for severe irAEs was associated with nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks 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]) except ipilimumab, 10 mg/kg, every 3 weeks.

Conclusions and relevance 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, whereas ipilimumab, 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. A network analysis may be valuable for clinical decision-making when evidence from head-to-head comparisons is lacking.