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

Abstract

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.

Keywords: adjuvant therapy; efficacy; melanoma; network meta-analysis; tolerability.

Figure 1.

Flow chart of study searching and selection.

Figure 2.

Network diagrams of eligible comparisons for DFS (a), OS (b), and tolerability (c). The thickness of the lines in the network diagram is in proportion to the number of direct comparisons of trials; the node size depends on the total sample size of the treatment. DFS, disease-free survival; GMCSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; OS, overall survival.

Figure 3.

Forest plots of network comparisons of therapeutic regimens with placebo/observation for DFS (a), OS (b), and tolerability (c). DFS, disease-free survival; GMCSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; OS, overall survival.

Figure 4.

Two-dimensional ranking plot of DFS and OS (a), DFS and tolerability (b), OS and tolerability (c). Dots with different colors represent different treatment options, with dots positioned lower indicating the better safety of the represented treatment option, and dots to the left indicating the better efficacy of the option. DFS, disease-free survival; GMCSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; OS, overall survival.

Figure 5.

Network diagrams of eligible comparisons for DFS (a), and forest plots of network comparisons for DFS (b) in BRAF mutation-positive patients. The thickness of the lines in the network diagram is in proportion to the number of direct comparisons of trials; the node size depends on the total sample size of the treatment. DFS, disease-free survival.