Background and Objectives
Rates of malignant melanoma are continuing to increase, and, until recently effective treatments were lacking. Since 2011, three immunotherapeutic agents, known as checkpoint inhibitors, have, however, been approved. This review aims to establish whether these three drugs - ipilimumab, nivolumab and pembrolizumab - offer greater efficacy and tolerability compared to control interventions (placebo, immunotherapy, or chemotherapy) in patients with stage III or IV unresectable cutaneous melanoma.

Methods
A search on four major medical and scientific databases yielded 7553 records, of which seven met the inclusion criteria, with a total study population of 3628. Only prospective, phase II or III randomized controlled trials (RCTs) on checkpoint inhibitors for patients with unresectable cutaneous melanoma that reported data on survival (overall, or progression-free), tumor response, or adverse events were included. Three meta-analyses were carried out.

Results
The hazard ratio for progression or death was 0.54 (0.44 – 0.67), and the odds ratio for best overall response rate was 4.48 (2.77 – 7.24), both in favor of checkpoint inhibitors. However, control treatments were Discussion
This study finds that checkpoint inhibitors are more effective than control interventions, both in terms of survival and tumor response, and yet, no less tolerable. PD-1 therapies (nivolumab and pembrolizumab) appear to offer greater efficacy than CTLA-4 therapy (ipilimumab). The combination of nivolumab and ipilimumab was, however, the most effective, but significantly less tolerable than monotherapy. The lack of published clinical data does, however, limit this study.

Further research is needed into two areas in particular; first, to determine the optimal use of checkpoint inhibitors, specifically in terms of combination therapy, and second, to identify reliable biomarkers to predictive responders and guide treatment assignment.