Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules.,The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1).,Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression.,Patients responding to the ICI treatment showed long-lasting remission or disease control status.,However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms.,Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME).,This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance.,These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy.,New therapeutic approaches targeting other immune checkpoint molecules are also discussed.
This systematic review and meta-analysis evaluates the immune checkpoint inhibitor regimens used along with the incidence of adverse events reported in randomized clinical trials for treatment of advanced melanoma.,Does the risk of immune-related adverse events differ across immune checkpoint inhibitors used by patients with advanced melanoma?,In this systematic review and network meta-analysis of randomized clinical trials of advanced melanoma treatment, the risk of immune-related adverse events varied by the immune checkpoint inhibitors used and by the different doses of these same immune checkpoint inhibitors.,Pembrolizumab, 2 mg/kg, every 3 weeks and 10 mg/kg every 3 weeks as well as nivolumab, 3 mg/kg, every 2 weeks were the 3 immune checkpoint inhibitor regimens associated with the lowest risk of any or severe immune-related adverse events.,Results of this study suggest that network analysis comparing different treatment regimens for advanced melanoma may be valuable for clinical decision-making in the absence of evidence from randomized clinical trials with head-to-head comparisons.,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.,To compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis.,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.,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.,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.,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.,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.,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.