Comparison of efficacy and tolerability of adjuvant therapy for resected high-risk stage III-IV cutaneous melanoma: a systemic review and Bayesian network meta-analysis

Background: Although immune checkpoint inhibitors (ICIs) and targeted therapies have been widely used as adjuvant treatment for resected melanoma, the optimal therapy remains controversial. Therefore, we conducted this updated network meta-analysis (NMA) to assess the efficacy and tolerability of adjuvant therapies for cutaneous melanoma. Methods: PubMed, Embase, Cochrane library, and Web of Science were systematically searched for relevant literatures published in the last 30 years. Disease-free survival (DFS), overall survival (OS), and serious adverse events were considered as the efficacy and tolerability outcomes. Results: In all, 27 randomized controlled trials (RCTs) including 16,709 stage III-IV melanoma patients were enrolled in this NMA. For BRAF wild-type melanoma, our analysis showed that both nivolumab and pembrolizumab demonstrated significantly better DFS and tolerability than ipilimumab (10 mg/kg). Nivolumab, pembrolizumab, ipilimumab (3 mg/kg), and ipilimumab (10 mg/kg) all appeared to be effective in prolonging OS, but no therapy demonstrated significantly better OS than ipilimumab (10 mg/kg). Nivolumab + ipilimumab showed the best DFS, but did not appear to be effective in improving OS and ranked only seventh in tolerability. Vaccines and granulocyte-macrophage colony-stimulating factor therapies were well tolerated, but all failed to improve the DFS or OS in stage III melanoma patients. In terms of BRAF mutation-positive melanoma, ICIs (nivolumab + ipilimumab, nivolumab, pembrolizumab, ipilimumab; 10 mg/kg) exhibited comparable efficacy to dabrafenib + trametinib, and all these therapies showed significantly better DFS than placebo. Conclusion: Considering efficacy and tolerability, nivolumab and pembrolizumab seem to be preferable adjuvant therapies for patients with stage III-IV melanoma. For BRAF mutation-positive patients, more RCTs are still required to determine which is better between ICIs and targeted therapy.