Safety and Efficacy Analysis of Targeted and Immune Combination Therapy in Advanced Melanoma-A Systematic Review and Network Meta-Analysis

Abstract

The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and network meta-analysis. Four databases were systematically searched for randomized clinical studies that included patients with advanced/metastatic melanoma receiving chemotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitor therapy, or combinations thereof. The primary endpoints were treatment-related adverse events (TRAE), serious adverse events (SAE) of grade ≥ 3 adverse events, therapy discontinuation, progression-free survival (PFS), as well as objective response rate (ORR) and complete response rate (CRR). A total of 63 articles were eligible for our systematic review; 59 of them were included in the statistical analysis. A separate subgroup analysis was conducted to evaluate the efficacy outcomes, specifically in BRAF-positive patients. Triple combination therapy or triple therapy (inhibiting BRAF, MEK and PD1/PDL1 axis) showed significantly longer progression-free survival compared to BRAF + MEK combination therapies (HR = 0.76; 95% CI 0.64-0.9), but similar objective and complete response rates in BRAF-mutated melanoma. This safety analysis suggests that triple therapy is not inferior to combined immune checkpoint inhibitors (ICI) and BRAF/MEK therapies in terms of serious adverse events and therapy discontinuation rates. However, monotherapies and BRAF/MEK combinations showed notable advantage over triple therapy in terms of treatment-related adverse events. Combination strategies including BRAF/MEK-targeted therapies with ICI therapies are effective first-line options for advanced, BRAF-mutant melanoma; however, they are associated with more frequent side effects. Therefore, future RCTs are required to evaluate and identify high-risk subpopulations where triple therapy therapies should be considered.

Keywords: advanced melanoma; immune checkpoint inhibitor; network meta-analysis; targeted therapy; triple therapy.

Figure 1

PRISMA 2020 flow diagram for the selection process.

Figure 2

Comparative network plots for interventions, with nodes representing treatments and the edges indicating direct comparisons between them. The size of the nodes is proportional to the number of patients assigned to the therapy. (a) TRAE; (b) grade 3 ≤ AE; (c) SAE OS; (d) TDR; (e) ORR, CRR, PFS, OS; (f) ORR, CRR, PFS, OS. Abbreviations: ORR, objective response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; AE, adverse event; TRAE, treatment-related adverse event; SAE, serious adverse event; TDR, treatment/therapy discontinuation rate; B, BRAF inhibitor; M, MEK inhibitor; P, PD-(L)1 inhibitor; PD1, PD-1 inhibitor; PDL1, PD-L1 inhibitor; C, CTLA-4 inhibitor; K, chemotherapy.

Figure 3

Forest plots for key efficacy outcomes in BRAF-mutant subgroup. Abbreviations: CI, confidence interval; B, BRAF inhibitor; M, MEK inhibitor; PD1, PD-1 inhibitor; PDL1, PD-L1 inhibitor.