Outcomes with targeted therapy for NRAS-mutated melanoma: A systematic review and meta-analysis.

Abstract

e21506 Background: Despite advancements in targeted therapy, NRAS-mutated melanoma remains a significant therapeutic challenge. This meta-analysis aims to evaluate the efficacy and safety of targeted therapies for NRAS-mutated melanoma. Methods: Following the PRISMA guidelines, a comprehensive literature search was performed on PubMed, Cochrane, and ClinicalTrials.gov from date of inception through January 1, 2025. A total of 829 studies were identified and four original studies reporting the outcomes of targeted therapy for NRAS-mutated melanoma in adult patients were included after primary and secondary screening. Data analysis was performed using R version 4.4.0, employing the “meta” and “metasens” packages. Proportions and corresponding 95% confidence intervals (CIs) were calculated. To stabilize variances, the inverse variance method was applied to Freeman-Tukey double arcsine-transformed data. Confidence intervals were adjusted using the Hartung-Knapp method, and tau² was estimated using a restricted maximum-likelihood approach. Results: A total of 527 patients were included in our meta-analysis. The age of patients ranged from 18–90 years, 51% were male, and median follow-up ranged from 1.4 to 5.0 months. 96 patients (18%) had received ≥1 line of prior therapy including chemotherapy, immunotherapy, or radiation therapy. The targeted therapies investigated included Binimetinib (n = 299; 56.7%), Naporafenib plus Rineterkib (n = 29; 5%), Naporafenib plus Trametinib (n = 24; 4.5%), Trametinib (n = 17; 3.2%), Naporafenib plus Ribociclib (n = 15; 2.8%), and Binimetinib plus Bocodepsin (n = 9; 1.7%). The pooled objective response rate (ORR) was 14% (95% CI, 4-30; I2 = 0%, P = 0.62) with pooled complete response (CR) of 1% (95% CI, 0-6;I2 = 0%, P = 0.72) and partial response (PR) of 14% (95% CI, 8-21; I2 = 12%, P = 0.33) while pooled rate of stable disease (SD) and progressive disease (PD) was 41% (95% CI, 37-46; I2 = 0%, P = 0.84), and 27% (95% CI, 22-32;I2 = 0%, P = 0.80), respectively. The pooled progression-free survival (PFS) was 9% (95% CI, 0–64; I2 = 29%, P = 0.24), 3% (95% CI, 0–78; I2 = 56%, P = 0.13), and 2% (95% CI, 0–26; I2 = 0%, P = 0.33) at 6, 9, and 12 months follow-up, respectively. Dermatitis acneiformis (48%, n = 113) was the most reported adverse effect followed by CPK increase (42%, n = 124), diarrhea (38%, n = 116), peripheral edema (36%, n = 107), and rash (31%, n = 104). Conclusions: Targeted therapies in NRAS-mutated melanoma show modest efficacy with frequent adverse effects. Innovative approaches, including novel therapeutic agents with different mechanisms of action, are urgently needed to improve clinical outcomes and address this unmet medical need.