Comparative Effectiveness of Nivolumab Plus Ipilimumab Versus Nivolumab Monotherapy in BR AF-Mutated Unresectable Stage III–IV Melanoma: A Systematic Review
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Abstract
Introduction: Skin cancer is among the most prevalent malignancies worldwide, with melanoma being the most aggressive because of its invasive and metastatic potential. Advanced melanoma (unresectable stage
III/IV) carries a high mortality rate, and although targeted therapy benefits patients with BRAF mutations, immunotherapy remains central across mutation statuses. However, the optimal strategy for BRAF-mutated
disease, particularly the survival benefit of dual checkpoint blockade versus anti-programmed cell death protein 1 monotherapy, remains uncertain. This systematic review evaluated the survival and outcomes of adults with
BRAF-mutated advanced melanoma treated with nivolumab plus ipilimumab versus nivolumab alone, using literature published from 2017 to 2024. Methods: Following the Preferred Reporting Items for Systematic
reviews and Meta-Analyses guidelines and a Patient/population; Intervention; Comparison; Outcome-defined question, PubMed/MEDLINE, Scopus, and Web of Science were searched, and eligible trials and observational cohorts reporting BRAF-mutant subgroup outcomes were selected for inclusion. Two reviewers conducted screening and extraction, quality was assessed using the Jadad scale or Newcastle-Ottawa Scale, and findings were synthesized qualitatively due to the design heterogeneity. Five studies met the inclusion criteria (one phase II, three phase III, and one retrospective cohort), with high methodological quality and low-to-moderate risk of bias. Results: Across trials, combination therapy generally improved objective response, progression-free survival, treatment-free interval, and overall survival (OS) compared to nivolumab monotherapy, with long- term follow-up suggesting a durable benefit. Estimates also indicated a longer median OS with combination therapy, although several studies were not powered for formal subgroup comparisons; one retrospective analysis found no statistically significant differences after
adjustment, with potential residual confounding and selection bias. Conclusion: Overall, dual blockade appears to be beneficial despite its
higher toxicity in this setting
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