Overall Survival of Patients with Melanoma of Unknown Primary Versus Melanoma of Known Primary Under Immunotherapy and Targeted Therapy: A Systematic Review and Meta-Analysis

Background: Melanoma of unknown primary (MUP) is a rare and distinct clinical subtype of metastatic melanoma, in which no identifiable primary tumor is found. The prognosis of MUP compared to melanoma with known primary (MKP) remains unclear, especially in the era of novel therapies like immune checkpoint inhibitors (ICIs) and targeted therapies. This meta-analysis aims to compare the overall survival (OS) of MUP and MKP patients under these therapies. Methods: This systematic review was conducted in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). A systematic search of major databases was conducted, yielding six eligible studies (nine study arms) that assessed the survival outcomes of MUP and MKP patients treated with immunotherapies and targeted therapies. We pooled the hazard ratios (HRs) for OS using both fixed and random effects models. Heterogeneity was assessed with the I2 statistic followed by a Baujat plot, and publication bias was evaluated using funnel plots and Egger’s test. Results: Our analysis revealed a borderline significant HR of 0.90 (95% CI: [0.81, 1.00], p = 0.04) under the fixed effect model, suggesting a potential survival benefit for MUP patients. However, the random effects model, accounting for study heterogeneity, showed no significant difference in OS between MUP and MKP (HR = 0.87, 95% CI: [0.73, 1.05], p = 0.15). Significant heterogeneity (I2 = 66.9%, p = 0.0022) was observed across studies. No substantial publication bias was detected. Conclusion: While the trend observed in the fixed effect model suggests a potential benefit for MUP patients, the random effects analysis indicates no significant difference between MUP and MKP in terms of OS. These findings underscore the importance of accounting for study heterogeneity and highlight the need for further prospective studies to better understand the impact of novel therapies on MUP.